CA3075146A1 - Methods and uses of compounds for treatment of choriocapillaris disorders - Google Patents

Abstract

The disclosure provides, in general, therapies for diseases that disrupt the choriocapillaris vasculature.

Description

PATENT
Attorney Docket No.: 14002.6004-00000 METHODS AND USES OF COMPOUNDS FOR TREATMENT OF
CHORIOCAPILLARY DISORDERS
FIELD
[0001] The present invention is directed to improved therapies for diseases that disrupt the choriocapillaris vasculature.
BACKGROUND

[0002] Impacting 30-50 million people worldwide, age-related macular degeneration (AMD) is the leading cause of vision loss in the industrialized world (1). By 2040, this number is expected to grow to over 288 million, representing an ever-increasing burden on the global health system (2). Despite decades of research, the pathophysiology of AMD remains incompletely understood. Several contributing factors have been identified, including inflammation, complement activation, oxidative stress and hypoxia (3). Clinically, early AMD is characterized by subretinal drusen deposition and pigment alterations in the retinal pigmented epithelium (RPE)(4). Defects in choroidal blood flow are observed, and reduced perfusion of the choriocapillaris, a unique vascular bed which supplies the outer retina (FIG. 1), is correlated with disease progression (5-7), suggesting a potential link between retinal ischemia and AMD

[0003] Late-stage AMD is divided into two types: Neovascular (wet) and atrophic (dry), which can coexist in the same eye. Dry AMD is characterized by = PATENT
Attorney Docket No.: 14002.6004-00000 choriocapillaris atrophy combined with RPE degeneration and photoreceptor dysfunction. This syndrome is known as geographic atrophy and no treatment is currently available, although it is responsible for the majority of AMD-associated vision loss (8). Wet AMD is characterized by choroidal neovascularization (CNV) caused by excessive production of vascular endothelial growth factor (VEGF), leading to intra- and subretinal fluid leakage (9). Studies of neovascular membranes in wet AMD have revealed activation of hypoxia inducible factor (HIF) signaling (10, 11). As the majority of CNV occurs in regions with poor choroidal perfusion (12-14), this suggests that RPE
hypoxia due to reduced choriocapillaris blood flow leads to excessive VEGF
production and ultimately CNV and CNV associated fluid leakage. VEGF is central to disease progression and wet AMD is treated with intravitreal VEGF inhibitors which have transformed disease prognosis. However, these drugs are not curative, nor are they effective for all patients. Following repeated injections, 10-50% of patients develop reduced visual acuity and choriocapillaris or RPE atrophy (15), possibly due to the necessity of VEGF signaling for choriocapillaris and photoreceptor maintenance (16-19). Supporting this hypothesis, the GAIT and IVAN trials have suggested that increased VEGF inhibitor treatment intensity is associated with higher incidence of geographic atrophy after two years, underscoring the importance of VEGF for choriocapillaris homeostasis and the need for alternative therapeutic options (20, 21).

[0004] The potential links between VEGF inhibition and geographic atrophy highlight the need to recognize clinical features distinguishing nonresponsive patients PATENT
Attorney Docket No.: 14002.6004-00000 before subjecting them to increasing doses of anti-VEGF therapy. Polypoidal choroidal vasculopathy (PCV), a subtype of neovascular AMD particularly prevalent in African-American and Asian patient populations, may be one such group (22, 23). PCV is characterized by a disorganized network of dilated choroidal vessels and sub-RPE
polypoid lesions which lead to subretinal hemorrhage and lipid exudate (24-26). Small trials have found poor results with ranibizumab (27, 28) and although improved outcomes using aflibercept have been reported (29), recent large-scale trials have shown that anti-VEGF monotherapy leads to incomplete polyp closure (30-32).
Intriguingly, while the cause of PCV is unknown, a recent study identified several SNPs in the ANGPT2 locus in an Asian PCV cohort (33), supporting the possibility that Angiopoietin-TIE2 signaling is implicated in this disease.

[0005] The choriocapillaris is a polarized, fenestrated vascular bed with a unique lobular architecture. Unlike retinal vessels, which form through vasculo- and angiogenesis, the choriocapillaris develops through the hemo-vasculogenesis, in which common precursors give rise to both blood and endothelial cells arranged in blood-island-like structures (34, 35). Little is known about the pathways regulating this developmental process. However, VEGF signaling is essential for choriocapillaris development (16), and in adult mice, RPE-produced VEGF is required for choriocapillaris and photoreceptor maintenance (19, 36). This ongoing requirement for VEGF highlights the relationship between RPE, choriocapillaris and retinal health, and emphasizes the potential impact of pharmacologic VEGF inhibition. The importance of PATENT
Attorney Docket No.: 14002.6004-00000 VEGF for choriocapillaris homeostasis underscores the need for novel AMD
therapeutic targets and strategies that suppress neovascularization while sparing choriocapillaris function. While anti-VEGF drugs have proven effective in the wet form of AMD, they are not curative and fail to provide relief to some patients, particularly those with atypical AMD or during the end stages of disease progression. Furthermore, as pathological VEGF production is a consequence rather than the primary pathogenic factor in AMD, there is an urgent, unmet need for new therapeutic approaches that improve choroidal perfusion, slow disease progression, and protect the choriocapillaris vasculature during anti-VEGF therapy.
SUMMARY

[0006] The present invention is directed, in general, to therapies for diseases that disrupt choriocapillaris, including AMD, and to mice carrying at least one angiopoietin 1 allele and at least one Wnt-Cre allele. Several of the various features of the invention will be described hereinafter. It is to be understood that the invention is not limited in its application to the details set forth in the following embodiments, claims, description and figures. The invention is capable of other embodiments and of being practiced or carried out in numerous other ways.

[0007] Embodiment 1: A method of treating age-related macular degeneration (AMD) or PCV in a subject in need thereof, comprising administering to the subject a PATENT
Attorney Docket No.: 14002.6004-00000 therapeutically effective amount of a Tie2 activator, optionally in combination with anti-VEGF therapy.

[0008] Embodiment 2: A method of treating AMD or PCV in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a VE-PTP inhibitor, optionally in combination with anti-VEGF therapy.

[0009] Embodiment 3: A method of improving vision in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a Tie2 activator and/or a VE-PTP inhibitor, optionally in combination with anti-VEGF
therapy, wherein the subject has AMD, preferably variants of choroid polypoid vasculopathy, geographic atrophy associated with anti-VEGF therapy, and any other loss of choroid perfusion (e.g. diabetic eye disease).

[0010] Embodiment 4: A method of increasing and/or improving choriocapillaris vascularization in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a Tie2 activator, optionally in combination with anti-VEGF therapy, wherein choriocapillaris vascularization is increased and/or improved in the subject.

[0011] Embodiment 5: A method of increasing and/or improving choriocapillaris vascularization in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a VE-PTP inhibitor optionally in combination with anti-VEGF therapy, wherein choriocapillaris vascularization is increased and/or improved in the subject.

PATENT
Attorney Docket No.: 14002.6004-00000

[0012] Embodiment 6: A method of reducing choriocapillaris dropout during anti-VEGF therapy in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a Tie2 activator optionally in combination with anti-VEGF therapy, wherein choriocapillaris dropout is reduced

[0013] Embodiment 7: A method of reducing choriocapillaris dropout during anti-VEGF therapy in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a VE-PTP inhibitor optionally in combination with anti-VEGF therapy, wherein choriocapillaris dropout is reduced.

[0014] Embodiment 8: A method of improving choroidal perfusion in a subject in need thereof having age-related macular degeneration (AMD), the method comprising administering to the subject a therapeutically effective amount of a Tie2 activator, wherein choroidal perfusion is increased; and optionally wherein the subject is being treated with anti-VEGF therapy.

[0015] Embodiment 9: A method of improving choroidal perfusion in a subject in need thereof having age-related macular degeneration (AMD), the method comprising administering to the subject a therapeutically effective amount of a VE-PTP
inhibitor, wherein choroidal perfusion is increased; and optionally wherein the subject is being treated with anti-VEGF therapy.

[0016] Embodiment 10: A method of protecting the choriocapillaris vasculature in a subject in need thereof having AMD, the method comprising administering to the subject a therapeutically effective amount of a Tie2 activator, wherein the PATENT
Attorney Docket No.: 14002.6004-00000 choriocapillaris vasculature is protected; and optionally wherein the subject is being treated with anti-VEGF therapy.

[0017] Embodiment 11: A method of protecting the choriocapillaris vasculature in a subject in need thereof having AMD, the method comprising administering to the subject a therapeutically effective amount of a VE-PTP inhibitor, wherein the choriocapillaris vasculature is protected; and optionally wherein the subject is being treated with anti-VEGF therapy

[0018] Embodiment 12: The method of any one of embodiments 1 through 11, wherein the choriocapillaris is manipulated in the context of AMD.

[0019] Embodiment 13: The method of any one of embodiments 1 through 11, wherein the choriocapillaris is manipulated in the context of polypoidal choroidal vasculopathy (PCV).

[0020] Embodiment 14: The method of embodiment 13, wherein the PCV is pachychoroid vasculopathy.

[0021] Embodiment 15: The method of any one of embodiments 1 through 14, wherein the Tie2 activator is selected from recombinant angiopoietin, BowAng1, COMP-Ang1, TSL1, Vasculotide, an Anti-Angiopoietin-2 Binding and Oligomerizing Antibody, an Anti-Tie2 Receptor Agonistic Antibody, an Anti-VE-PTP Antibody, a Small Molecule VE-PTP Inhibitor, and the like.

PATENT
Attorney Docket No.: 14002.6004-00000

[0022] Embodiment 16: The method of embodiment 15, wherein the VE-PTP
inhibitor is selected from the small molecule VE-PTP inhibitors as Tie2 activators described in the specification.

[0023] Embodiment 17: The method of any one of embodiments 1 through 16, wherein the Tie2 activator and/or the VE-PTP inhibitor are administered to the eye.

[0024] Embodiment 18: The method of any one of embodiments 1 through 17, wherein the anti-VEGF therapy is selected from Aflibercept, Bevacizumab, Pegaptanib sodium, Ranibizumab, Brolucizumab, Conbercept, Ramucirumab, Faricimab ,Nesvacumab-Aflibercept, Designed ankyrin repeat proteins, Gene-therapy-targeting VEGF, and biosimilar versions thereof.

[0025] Embodiment 19: The method of embodiment 11, wherein the anti-VEGF

therapy is administered to the eye.

[0026] Embodiment 20: A mouse carrying at least one angiopoietin 1 null allele and at least one wnt1-Cre allele.

[0027] Embodiment 21: The use of a therapeutically effective amount of a Tie2 activator, optionally in combination with anti-VEGF therapy, for treating AMD
or PCV in a subject in need thereof.

[0028] Embodiment 22: The use of a therapeutically effective amount of a Tie2 activator for treating AMD or PCV in a subject in need thereof.

PATENT
Attorney Docket No.: 14002.6004-00000

[0029] Embodiment 23: The use of a therapeutically effective amount of a VE-PTP inhibitor, optionally in combination with anti-VEGF therapy, for treating AMD or PCV in a subject in need thereof.

[0030] Embodiment 24: The use of a therapeutically effective amount of a VE-PTP inhibitor for treating AMD or PCV in a subject in need thereof.

[0031] Embodiment 25: The use of a therapeutically effective amount of a Tie2 activator and/or a VE-PTP inhibitor, optionally in combination with anti-VEGF
therapy, for improving vision in a subject having any one or more of a group of choriocapillaris disorders comprising AMD, PCV, variants of choroid polypoid vasculopathy, geographic atrophy associated with anti-VEGF therapy, and any other loss of choroid perfusion (e.g. diabetic eye disease).

[0032] Embodiment 26: The use of a therapeutically effective amount of a Tie2 activator and/or a VE-PTP inhibitor for improving vision in a subject having any one or more of a group of choriocapillaris disorders comprising AMD, PCV, variants of choroid polypoid vasculopathy, geographic atrophy associated with anti-VEGF therapy, and any other loss of choroid perfusion (e.g. diabetic eye disease).

[0033] Embodiment 27: The use of a therapeutically effective amount of a Tie2 activator, optionally in combination with anti-VEGF therapy, for increasing and/or improving choriocapillaris vascularization in a subject in need thereof.

PATENT
Attorney Docket No.: 14002.6004-00000

[0034] Embodiment 28: The use of a therapeutically effective amount of a Tie2 activator for increasing and/or improving choriocapillaris vascularization in a subject in need thereof.

[0035] Embodiment 29: The use of a therapeutically effective amount of a VE-PTP inhibitor, optionally in combination with anti-VEGF therapy, for increasing and/or improving choriocapillaris vascularization in a subject in need thereof.

[0036] Embodiment 30: The use of a therapeutically effective amount of a VE-PTP inhibitor for increasing and/or improving choriocapillaris vascularization in a subject in need thereof.

[0037] Embodiment 31: The use of a therapeutically effective amount of a Tie2 activator for reducing choriocapillaris dropout during anti-VEGF therapy in a subject in need thereof.

[0038] Embodiment 32: The use of a therapeutically effective amount of a VE-PTP inhibitor for reducing choriocapillaris dropout during anti-VEGF therapy in a subject in need thereof.

[0039] Embodiment 33: The use of a therapeutically effective amount of a Tie2 activator, optionally in combination with anti-VEGF therapy, for improving choroidal perfusion in a subject in need thereof having AMD.

[0040] Embodiment 34: The use of a therapeutically effective amount of a Tie2 activator for improving choroidal perfusion in a subject in need thereof having AMD.
= 11 PATENT
Attorney Docket No.: 14002.6004-00000

[0041] Embodiment 35: The use of a therapeutically effective amount of a VE-PTP inhibitor, optionally in combination with anti-VEGF therapy, for improving choroidal perfusion in a subject in need thereof having AMD.

[0042] Embodiment 36: The use of a therapeutically effective amount of a VE-PTP inhibitor for improving choroidal perfusion in a subject in need thereof having AMD.

[0043] Embodiment 37: The use of a therapeutically effective amount of a Tie2 activator, optionally in combination with anti-VEGF therapy, for protecting the choriocapillaris vasculature in a subject in need thereof having AMD.

[0044] Embodiment 38: The use of a therapeutically effective amount of a Tie2 activator for protecting the choriocapillaris vasculature in a subject in need thereof having AMD.

[0045] Embodiment 39: The use of a therapeutically effective amount of a VE-PTP inhibitor, optionally in combination with anti-VEGF therapy, for protecting the choriocapillaris vasculature in a subject in need thereof having AMD.

[0046] Embodiment 40: The use of a therapeutically effective amount of a VE-PTP inhibitor protecting the choriocapillaris vasculature in a subject in need thereof having AMD.

[0047] Embodiment 41: The use in any one of embodiments 21 through 40, wherein the choriocapillaris is manipulated in the context of one or more choriocapillaris disorders comprising AMD, PCV, pachychoroid vasculopathy, variants of choroid PATENT
Attorney Docket No.: 14002.6004-00000 polypoid vasculopathy, geographic atrophy associated with anti-VEGF therapy, and any other loss of choroid perfusion (e.g. diabetic eye disease)..

[0048] Embodiment 42: The use in any one of embodiments 21 through 41, wherein the Tie2 activator is selected from recombinant angiopoietin, BowAng1, COMP-Ang1, TSL1, Vasculotide, an Anti-Angiopoietin-2 Binding and Oligomerizing Antibody, an Anti-Tie2 Receptor Agonistic Antibody, an Anti-VE-PTP Antibody, a Small Molecule VE-PTP Inhibitor, and the like.

[0049] Embodiment 43: The use in any one of embodiments 21 through 41, wherein the VE-PTP inhibitor is selected from the small molecule VE-PTP
inhibitors as Tie2 activators described in the specification.

[0050] Embodiment 44: The use in any one of embodiments 21 through 41, wherein the anti-VEGF therapy is selected from Aflibercept, Bevacizumab, Pegaptanib sodium, Ranibizumab, Brolucizumab, Conbercept, Ramucirumab, Faricimab ,Nesvacumab-Aflibercept, Designed ankyrin repeat proteins, Gene-therapy-targeting VEGF, and biosimilar versions thereof.
BRIEF DESCRIPTION OF DRAWINGS

[0051] The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawings will be PATENT
Attorney Docket No.: 14002.6004-00000 provided by the U.S. Patent and Trademark Office upon request and payment of the necessary fee.

[0052] FIG. 1: The choriocapillaris is a unique vascular bed which supplies the outer retina. Schematic illustration of the human eye highlighting the location of the choriocapillaris (CC, red) adjacent to the outer retina. Schlemm's canal, a lymphatic-like vessel in the anterior chamber is shown in green. Drawing is not to scale

[0053] FIG. 2A and 2B: ANGPT1 is essential for choriocapillaris development.
(FIG. 2A) Compared to control littermates, whole-body Angpt1 knockout mice induced at E13.5 exhibit sparse EMCN positive capillaries in the peripheral choriocapillaris (CC) when imaged at PO. (FIG. 2B) A more severe form of the same phenotype is observed in mice lacking Angpt1 in cells of the neural crest lineage, which exhibit severely attenuated choriocapillaries when imaged at P1. 20x fields represent an area of 65,536 pm2, ** p<0.01, *** p <0.001.

[0054] FIG. 3A and 3B: Angiopoietin ligands are highly expressed in the mouse choroid. (FIG. 3A) Cryosections from Angpt1GFP mouse eyes reveal robust Angpt1 expression in the choroid as well as in the choroidal melanocytes and retinal pigmented epithelium (RPE). Confocal reflectance microscopy (CRM) was used to visualize these pigmented tissues. (FIG. 3B) X-Gal staining was used to label Angpt2 expression in the choroid of adult Angpt2LacZ mice. Angpt2 was observed in the choriocapillaris, as well as the choroidal vessels.

PATENT
Attorney Docket No.: 14002.6004-00000

[0055] FIG. 4: Disorganized EMCN-negative vessels invade the choriocapillaris of Angpt1ANC mice by P11. In contrast to the organized pattern of choroidal vessels observed in control littermates, a disorganized network of EMCN-negative vessels was observed throughout the choriocapillaris of neural crest specific Angpt1 knockout mice by P11.

[0056] FIG. 5A-5D: VE-PTP is an important regulator of CC development.
(FIG.
5A) Imaged in 5 pm sections or (FIG. 5B) whole-mounts, Ve-ptpNLS-LacZ mice stained with anti-Gal antibody reveal strong endothelial Ve-ptp promotor activity in the choriocapillaris (CC). (FIG. 5C, quantified in FIG. 5D) Visualized using anti-endomucin (EMCN) antibody, whole-body Ve-ptp knockout mice induced at E13.5 have increased CC area by PO, indicating an important role for VE-PTP in CC development and morphogenesis. 20x fields represent an area of 65,536 pm2, * p<0.05, *** p <0.001 DETAILED DESCRIPTION
DEFINITIONS

[0057] Unless otherwise defined herein, scientific and technical terms used in connection with the present disclosure shall have the meanings that are commonly understood by those of ordinary skill in the art.

[0058] Unless mentioned otherwise, the techniques employed or contemplated herein are standard methodologies well known to one of ordinary skill in the art. The practice of the present disclosure will employ, unless otherwise indicated, conventional PATENT
Attorney Docket No.: 14002.6004-00000 techniques of microbiology, tissue culture, molecular biology, chemistry, biochemistry and recombinant DNA technology, which are within the skill of the art. The materials, methods and examples are illustrative only and not limiting.

[0059] All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g. "such as") provided with respect to certain embodiments herein is intended merely to better illuminate the present disclosure and does not pose a limitation on the scope of the present disclosure otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the present disclosure.

[0060] Unless specifically stated or obvious from context, as used herein, the terms "a", "an", and "the" are understood to be singular or plural.

[0061] Furthermore, "and/or" where used herein is to be taken as specific disclosure of each of the two specified features or components with or without the other.
Thus, the term "and/or" as used in a phrase such as "A and/or B" herein is intended to include "A and B," "A or B," "A," (alone) and "B" (alone). Likewise, the term "and/or" as used in a phrase such as "A, B, and/or C" is intended to encompass each of the following embodiments: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0062] Unless specifically stated or obvious from context, as used herein, the term "about" is understood as within a range of normal tolerance in the art, for example PATENT
Attorney Docket No.: 14002.6004-00000 within 2 standard deviations of the mean. About can be understood as within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, or 0.01% of the stated value.
Unless otherwise clear from context, all numerical values provided herein are modified by the term about.

[0063] As used herein, the term "administering" refers to the placement of a compound and/or a pharmaceutical composition comprising the compound into a mammalian tissue or a subject by a method or route that results in at least partial localization of the compound and/or composition at a desired site or tissue location.

[0064] Any compositions, apparatus, systems or methods provided herein can be combined with one or more of any of the other compositions, apparatus, systems or methods provided herein.

[0065] The terms "disease" or "disorder" are used interchangeably herein and refer to any alteration in state of the body or of some of the organs, interrupting or disturbing the performance of the functions and/or causing symptoms such as discomfort, dysfunction, distress, or even death to the person afflicted or those in contact with a person. A disease or disorder can also relate to a distemper, ailing, ailment, malady, sickness, illness, complaint, indisposition, or affection.

[0066] In this disclosure, the terms "comprise," "have" and "include"
are open-ended linking verbs. Any forms or tenses of one or more of these verbs, such as "comprises," "comprising," "has," "having," "includes" and "including," are also open-ended. For example, any method that "comprises," "has" or "includes" one or more PATENT
Attorney Docket No.: 14002.6004-00000 steps is not limited to possessing only those one or more steps and can also cover other unlisted steps. Similarly, any composition that "comprises," "has" or "includes" one or more features is not limited to possessing only those one or more features and can cover other unlisted features.

[0067] The terms "consisting essentially of or "consists essentially" of likewise has the meaning ascribed in U.S. Patent law and the term is open-ended, allowing for the presence of more than that which is recited so long as basic or novel characteristics of that which is recited is not changed by the presence of more than that which is recited, but excludes prior art embodiments.

[0068] The term "consisting of refers to compositions, methods, and respective components thereof as described herein, which are exclusive of any element not recited in that description of the embodiment.

[0069] The term "choriocapillaris attenuation" refers to the reduction of capillary density in the choroid. It is visible on, for example, flat mount, histologic sections through the choroid and by immunohistochemical analysis. It results in loss of blood flow and delivery of nutrients to key cells of the choroid including the RPEs.

[0070] The "effectiveness" of a compound or composition of the disclosure can be assessed by any method known to one of ordinary skill in the art, including those described in the examples of this disclosure. Effectiveness can be established in vitro (biochemical and/or biological in cultured cells) and/or in vivo (including in animal models). Effectiveness in vitro may be used to extrapolate or predict some degree of PATENT
Attorney Docket No.: 14002.6004-00000 effectiveness in vivo, in an animal or in a human subject. A reference or standard or comparison may be used. Effective amounts and dosages can be estimated initially from in vitro assays. For example, an initial dosage for use in animals can be formulated to achieve a circulating blood or serum concentration of active compound that is at or above an IC50 of the particular compound as measured in an in vitro assay.
Calculating dosages to achieve such circulating blood or serum concentrations taking into account the bioavailability of the particular compound is well within the capabilities of skilled artisans. For guidance, the reader is referred to Fingl & Woodbury, "General Principles,"
In: Goodman and Gilman's The Pharmaceutical Basis of Therapeutics, Chapter 1, pp. 1-46, latest edition, Pergamagon Press, and the references cited therein, which methods are incorporated herein by reference in their entirety. Initial dosages can also be estimated from in vivo data, such as animal models. Animal models useful for testing the efficacy of compounds to treat or prevent the various diseases described in this disclosure are either described herein (see EXAMPLES) or known in the art.

[0071] As used herein, the terms "treatment," "treating," "effective,"
"therapeutically effective" and the like, refer to obtaining a desired pharmacologic and/or physiologic effect. The effect can be prophylactic in terms of completely or partially preventing a disease or symptom thereof and/or can be therapeutic in terms of a partial or complete cure for a disease and/or adverse effect attributable to the disease.

[0072] By "subject" is meant a mammal, including, but not limited to, a human or non-human mammal, such as a bovine, equine, canine, ovine, or feline.

PATENT
Attorney Docket No.: 14002.6004-00000

[0073] Ranges provided herein are understood to be shorthand for all of the values within the range. For example, a range of 1 to 50 is understood to include any number, combination of numbers, or sub-range from the group consisting 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50.
EXEMPLARY METHODS OF TREATMENT OF THE DISCLOSURE

[0074] In one embodiment, the disclosure provides a method of treating age-related macular degeneration (AMD) (e.g., polypoidal choroidal vasculopathy (PCV)) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a Tie2 activator, optionally in combination with anti-VEGF
therapy.
In an embodiment, the disclosure provides for a use of a therapeutically effective amount of a Tie2 activator, optionally in combination with anti-VEGF therapy, for treating AMD or PCV in a subject in need thereof. In an embodiment, the disclosure provides for a use of a therapeutically effective amount of a Tie2 activator for treating AMD or PCV in a subject in need thereof.

[0075] In one embodiment, the disclosure provides a method of treating AMD or PCV in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a VE-PTP inhibitor, optionally in combination with anti-VEGF therapy. In an embodiment, the disclosure provides for a use of a PATENT
Attorney Docket No.: 14002.6004-00000 therapeutically effective amount of a VE-PTP inhibitor, optionally in combination with anti-VEGF therapy, for treating AMD or PCV in a subject in need thereof. In an embodiment, the disclosure provides for a use of a therapeutically effective amount of a VE-PTP inhibitor for treating AMD or PCV in a subject in need thereof.

[0076] In one embodiment, the disclosure provides a method of improving vision in a subject comprising administering to the subject a therapeutically effective amount of a Tie2 activator and/or a VE-PTP inhibitor, optionally in combination with anti-VEGF
therapy, wherein the subject has AMD, choroid polypoid vasculopathy, or choroid defects due to complement deficiency or hyperglycemic conditions. In an embodiment, the disclosure provides for a use of a therapeutically effective amount of a Tie2 activator and/or a VE-PTP inhibitor, optionally in combination with anti-VEGF therapy, for treating AMD or PCV in a subject in need thereof. In an embodiment, the disclosure provides for a use of a therapeutically effective amount of a Tie2 activator and/or a VE-PTP inhibitor for treating AMD or PCV in a subject in need thereof.

[0077] In one embodiment, the disclosure provides a method of increasing or improving choriocapillaris vascularization in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a Tie2 activator, optionally in combination with anti-VEGF therapy, wherein choriocapillaris vascularization is increased and/or improved in the subject. In an embodiment, the PATENT
Attorney Docket No.: 14002.6004-00000 disclosure provides for a use of a therapeutically effective amount of a Tie2 activator, optionally in combination with anti-VEGF therapy, for increasing and/or improving choriocapillaris vascularization in a subject in need thereof. In an embodiment, the disclosure provides for a use of a therapeutically effective amount of a Tie2 activator for increasing and/or improving choriocapillaris vascularization in a subject in need thereof.

[0078] In one embodiment, the disclosure provides a method of increasing and/or improving choriocapillaris vascularization in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a VE-PTP inhibitor optionally in combination with anti-VEGF therapy, wherein choriocapillaris vascularization is increased and/or improved in the subject.
In an embodiment, the disclosure provides for a use of a therapeutically effective amount of a VE-PTP inhibitor, optionally in combination with anti-VEGF therapy, for increasing and/or improving choriocapillaris vascularization in a subject in need thereof. In an embodiment, the disclosure provides for a use of a therapeutically effective amount of a VE-PTP inhibitor for increasing and/or improving choriocapillaris vascularization in a subject in need thereof.

[0079] In one embodiment, the disclosure provides a method of reducing choriocapillaris dropout during anti-VEGF therapy in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a Tie2 activator optionally in combination with anti-VEGF therapy, wherein choriocapillaris PATENT
Attorney Docket No.: 14002.6004-00000 dropout is reduced. In an embodiment, the disclosure provides for a use of a therapeutically effective amount of a Tie2 activator, optionally in combination with anti-VEGF therapy, for reducing choriocapillaris dropout during anti-VEGF therapy in a subject in need thereof.

[0080] In one embodiment, the disclosure provides a method of reducing choriocapillaris dropout during anti-VEGF therapy in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a VE-PTP inhibitor optionally in combination with anti-VEGF therapy, wherein choriocapillaris dropout is reduced. In an embodiment, the disclosure provides for a use of a therapeutically effective amount of a VE-PTP inhibitor, optionally in combination with anti-VEGF therapy, for reducing choriocapillaris dropout during anti-VEGF
therapy in a subject in need thereof.

[0081] In one embodiment, the disclosure provides a method of improving choroidal perfusion in a subject in need thereof having age-related macular degeneration (AMD), the method comprising administering to the subject a therapeutically effective amount of a Tie2 activator, wherein choroidal perfusion is increased; and optionally wherein the subject is being treated with anti-VEGF
therapy. .
In an embodiment, the disclosure provides for a use of a therapeutically effective amount of a Tie2 activator, optionally in combination with anti-VEGF therapy, for improving and/or increasing choroidal perfusion in a subject in need thereof.
In an PATENT
Attorney Docket No.: 14002.6004-00000 embodiment, the disclosure provides for a use of a therapeutically effective amount of a Tie2 activator for improving and/or increasing choroidal perfusion in a subject in need thereof.

[0082] In one embodiment, the disclosure provides a method of improving choroidal perfusion in a subject in need thereof having age-related macular degeneration (AMD), the method comprising administering to the subject a therapeutically effective amount of a VE-PTP inhibitor, wherein choroidal perfusion is increased; and optionally wherein the subject is being treated with anti-VEGF
therapy.
In an embodiment, the disclosure provides for a use of a therapeutically effective amount of a VE-PTP inhibitor, optionally in combination with anti-VEGF
therapy, for improving and/or increasing choroidal perfusion in a subject in need thereof.
In an embodiment, the disclosure provides for a use of a therapeutically effective amount of a VE-PTP inhibitor for improving and/or increasing choroidal perfusion in a subject in need thereof.

[0083] In one embodiment, the disclosure provides a method of protecting the choriocapillaris vasculature in a subject in need thereof having AMD, the method comprising administering to the subject a therapeutically effective amount of a Tie2 activator, wherein the choriocapillaris vasculature is protected; and optionally wherein the subject is being treated with anti-VEGF therapy. In an embodiment, the disclosure PATENT
Attorney Docket No.: 14002.6004-00000 provides for a use of a therapeutically effective amount of a Tie2 activator, optionally in combination with anti-VEGF therapy, for protecting choriocapillaris vasculature in a subject in need thereof. In an embodiment, the disclosure provides for a use of a therapeutically effective amount of a Tie2 activator for protecting choriocapillaris vasculature in a subject in need thereof.

[0084] In one embodiment, the disclosure provides a method of protecting the choriocapillaris vasculature in a subject in need thereof having AMD, the method comprising administering to the subject a therapeutically effective amount of a VE-PTP
inhibitor, wherein the choriocapillaris vasculature is protected; and optionally wherein the subject is being treated with anti-VEGF therapy. In an embodiment, the disclosure provides for a use of a therapeutically effective amount of a VE-PTP
inhibitor, optionally in combination with anti-VEGF therapy, for protecting choriocapillaris vasculature in a subject in need thereof. In an embodiment, the disclosure provides for a use of a therapeutically effective amount of a VE-PTP inhibitor for protecting choriocapillaris vasculature in a subject in need thereof.
DISORDERS IN WHICH THE CHOROIDAL VASCULATURE IS IMPAIRED

PATENT
Attorney Docket No.: 14002.6004-00000

[0085] The choriocapillaris represents an approximately 10-pm-thin layer of relatively large-diameter capillaries interconnected in a densely packed arrangement with very small intercapillary pillars located at the inner aspect of the choroid. The choriocapillaris is an important vascular layer that is subject to physiologic changes with increasing age and that is also associated with a wide range of chorioretinal diseases, including age-related macular degeneration (AMD) and central serous chorioretinopathy (CSC), which are major causes of vision loss. Diseases or disorders in which the choroidal vasculature is impaired (e.g., decreased, functionally impaired, increased, damaged, otherwise not normal) are referred to herein as choriocapillaris disorders. In one embodiment, the disorder is age-related macular degeneration. In one embodiment, the disorder is wet AMD. In one embodiment, the disorder is dry AMD. In one embodiment, the disorder is polypoidal choroidal vasculopathy (PCV). PCV is pachychoroid vasculopathy. In one embodiment, the disorder is reduced choroid perfusion in diabetic eye disease.

[0086] Age-related macular degeneration (AMD) is a leading cause of central vision loss worldwide. The progression of dry AMD from early to intermediate stages is primarily characterized by increasing drusen formation and adverse impact on outer retinal cells. Late stage AMD consists of either geographic atrophy (GA), which is the non-exudative (dry) AMD subtype, or choroidal neovascularization, which is the exudative (wet) AMD subtype. GA is characterized by outer retinal and choroidal atrophy, specifically the photoreceptor layer, RPE, and choriocapillaris.

PATENT
Attorney Docket No.: 14002.6004-00000 METHODS OF ASSESSING CHORIOCAPILLARIS VASCULARIZATION

[0087] The choriocapillaris can be visualized in vivo by a variety of methods known to one of ordinary skill in the art. In one embodiment, the method involves either en face swept-source optical coherence tomography (SS-OCT) or SS-OCT
angiography (SS-OCTA), which uses decorrelation signal generated from moving erythrocytes.
Both methods have been shown to have the capability to image the choriocapillaris.
See, e.g., Wang Q, Chan S, Yang JY, et al. Vascular density in retina and choriocapillaris as measured by optical coherence tomography angiography. Am J Ophthalmol. 2016;
168:
95-109.; Zhang Q, Zheng F, Motu!sky EH, et al. A novel strategy for quantifying choriocapillaris flow voids using swept-source OCT angiography. Invest Opthalmology Vis Sci. 2018; 59: 203-211; and Lane M, Moult EM, Novais EA, et al.
Visualizing the choriocapillaris under drusen: comparing 1050-nm swept-source versus 840-nm spectral-domain optical coherence tomography angiography. Invest Opthalmology Vis Sci. 2016; 57 (9): 0CT585-0CT590, all of which are incorporated herein by reference in their entireties. See also a recent comparison between the methods in Wang, J.C., et al. Visualization of Choriocapillaris and Choroidal Vasculature in Healthy Eyes With En Face Swept-Source Optical Coherence Tomography Versus Angiography, Translational Vision Science & Technology December 2018, Vol.7, 25. doi:10.1167/tvst.7.6.25.

[0088] Various manufacturers offer commercially available OCTA devices.
Currently, the predominant devices on the market are AngioVueTM (Optovue Inc., PATENT
Attorney Docket No.: 14002.6004-00000 Fremont, CA, USA), Angioplex and PLEX Elite 9000 (Carl Zeiss Meditec Inc., Dublin, CA, USA), Swept-Source Optical Coherence Tomography AngioTM (Topcon Corp., Japan), Heidelberg Spectralis OCTA (Heidelberg, Germany), and Canon OCT-HS100 (Canon, Japan).

[0089] A recent improvement in methods for visualizing the choriocapillaris has also been described. Chu, Z. et al. Improving visualization and quantitative assessment of choriocapillaris with swept source OCTA through registration and averaging applicable to clinical systems. Scientific Reports volume 8, Article number:

(2018). The use of these methods in visualizing the choriocapillaris is another embodiment of the disclosure.

[0090] The following are non-limiting exemplary embodiments of VE-PTP
inhibitors and other Tie2 activators, as well as VEGF inhibitors, that can be used in the methods of the disclosure. In certain embodiments, references where the compounds are either used or described are provided and are incorporated herein by reference in their entireties.

[0091] Recombinant Angiopoietin-1 Proteins as Tie2 Activators

[0092] BowAng1

[0093] Int J Oncol. 2009 Jan;34(1):79-87. Angiopoietin-1/Tie-2 activation contributes to vascular survival and tumor growth during VEGF blockade. Huang J, Bae PATENT
Attorney Docket No.: 14002.6004-00000 JO, Tsai JP, Kadenhe-Chiweshe A, Papa J, Lee A, Zeng S, Komfeld ZN, Ullner P, Zaghloul N, loffe E, Nandor S, Burova E, Holash J, Thurston G, Rudge J, Yancopoulos GD, Yamashiro DJ, Kandel JJ. PMID: 19082480 PMCID: PMC3160826

[0094] Nat Struct Biol. 2003 Jan;10(1):38-44. Angiopoietins have distinct modular domains essential for receptor binding, dimerization and superclustering. Davis S, Papadopoulos N, Aldrich TH, Maisonpierre PC, Huang T, Kovac L, Xu A, Leidich R, Radziejewska E, Rafique A, Goldberg J, Jain V, Bailey K, Karow M, Fandl J, Samuelsson SJ, loffe E, Rudge JS, Daly TJ, Radziejewski C, Yancopoulos GD.
PMID:
12469114 DOI: 10.1038/nsb880. BowAng1

[0095] COMP-Angl

[0096] Sci Rep. 2015 Oct 19;5:15291. A Designed Angiopoietin-1 Variant, Dimeric CMP-Ang1 Activates Tie2 and Stimulates Angiogenesis and Vascular Stabilization in N-glycan Dependent Manner.Oh N, Kim K, Kim SJ, Park I, Lee JE, Seo YS, An HJ, Kim HM, Koh GY.PMID: 26478188 PMCID: PMC4609988 DOI:
10.1038/srep15291

[0097] Mol Cancer Res. 2009 Dec;7(12):1920-7. Epub 2009 Dec 1.COMP-Ang1 potentiates the antitumor activity of 5-fluorouracil by improving tissue perfusion in murine Lewis lung carcinoma.Hwang JA, Lee EH, Kim HW, Park JB, Jeon BH, Cho CH.PMID: 19952114 DOI: 10.1158/1541-7786.MCR-09-0041.

[0098] Biochem Biophys Res Commun. 2009 Apr 17;381(4):592-6. Epub 2009 Feb 24.COMP-Ang1 ameliorates leukocyte adhesion and reinforces endothelial tight PATENT
Attorney Docket No.: 14002.6004-00000 junctions during endotoxemia.Hwang JA, Lee EH, Lee SD, Park JB, Jeon BH, Cho CH.PMID: 19245790 DOI: 10.1016/j.bbrc.2009.02.096

[0099] Proc Natl Acad Sci U S A. 2004 Apr 13;101(15):5553-8. Epub 2004 Apr 1.Designed angiopoietin-1 variant, COMP-Ang1, protects against radiation-induced endothelial cell apoptosis.Cho CH, Kammerer RA, Lee HJ, Yasunaga K, Kim KT, Choi HH, Kim W, Kim SH, Park SK, Lee GM, Koh GY.PMID: 15060280 PMCID: PMC397421 DOI: 10.1073/pnas.0307575101

[0100] Proc Natl Acad Sci U S A. 2004 Apr 13,101(15):5547-52. Epub 2004 Apr 1.COMP-Ang1: a designed angiopoietin-1 variant with nonleaky angiogenic activity.Cho CH, Kammerer RA, Lee HJ, Steinmetz MO, Ryu YS, Lee SH, Yasunaga K, Kim KT, Kim I, Choi HH, Kim W, Kim SH, Park SK, Lee GM, Koh GY.PMID: 15060279 PMCID:
PMC397420 001: 10.1073/pnas.0307574101

[0101] Synthetic Angiopoietin-1 Mimetic Ligands as Tie2 Activators

[0102] TSL1

[0103] Mol Pharm. 2018 Sep 4;15(9):3962-3968. Epub 2018 Aug 6.

[0104] Development of an Orthogonal Tie2 Ligand Resistant to Inhibition by Ang2.Issa E, Moss AJ, Fischer M, Kang M, Ahmed S, Farah H, Bate N, Giakomidi D, Brindle NP.PMID: 30036484 DOI: 10.1021/acs.molpharmaceut.8b00409.

[0105] Vasculotide

[0106] Cell Transplant. 2018 Dec;27(12):1744-1752. Epub 2018 Aug 20.Angiopoietin-1 Mimetic Peptide Promotes Neuroprotection after Stroke in Type 1 PATENT
Attorney Docket No.: 14002.6004-00000 Diabetic Rats.Venkat P, Yan T, Chopp M, Zacharek A, Ning R, Van Slyke P, Dumont D, Landschoot-Ward J, Liang L, Chen J.PMID: 30124060 PMCID: PMC6300775 DOI:
10.1177/0963689718791568

[0107] Br J Anaesth. 2018 Nov;121(5):1041-1051. Epub 2018 Jun 19.Vasculotide, an angiopoietin-1 mimetic, reduces pulmonary vascular leakage and preserves microcirculatory perfusion during cardiopulmonary bypass in rats.
Dekker NAM, van Meurs M, van Leeuwen ALI, Hofland HM, van Slyke P, Vonk ABA, Boer C, van den Brom CE.PMID: 30336848 DOI: 10.1016/j.bja.2018.05.049

[0108] Anesthesiology. 2018 Feb;128(2):361-374. Vasculotide, an Angiopoietin-1 Mimetic, Restores Microcirculatory Perfusion and Microvascular Leakage and Decreases Fluid Resuscitation Requirements in Hemorrhagic Shock.Trieu M, van Meurs M, van Leeuwen ALI, Van Slyke P, Hoang V, Geeraedts LMG Jr, Boer C, van den Brom CE.PMID: 28968277 001: 10.1097/ALN.0000000000001907

[0109] Crit Care. 2017 Nov 13;21(1):274. Vasculotide reduces pulmonary hyperpermeability in experimental pneumococcal pneumonia.Gutbier B, Jiang X, Dietert K, Ehrler C, Lienau J, Van Slyke P, Kim H, Hoang VC, Maynes JT, Dumont DJ, Gruber AD, Weissmann N, Mitchell TJ, Suttorp N, Witzenrath M.PMID: 29132435 PMCID:
PMC5683375 DOI: 10.1186/s13054-017-1851-6

[0110] BMC Res Notes. 2016 May 28;9:289.Vasculotide, an Angiopoietin-1 mimetic, ameliorates several features of experimental atopic dermatitis-like PATENT
Attorney Docket No.: 14002.6004-00000 disease.Bourdeau A, Van Slyke P, Kim H, Cruz M, Smith T, Dumont DJ.PMID:
27236199 PMCID: PMC4884390 DOI: 10.1186/s13104-015-1817-1

[0111] Sci Rep. 2016 Feb 25;6:22111. The Synthetic Tie2 Agonist Peptide Vasculotide Protects Renal Vascular Barrier Function In Experimental Acute Kidney Injury.RUbig E, Stypmann J, Van Slyke P, Dumont DJ, Spieker T, Buscher K, Reuter S, Goerge T, Pavenstadt H, Kumpers P.PMID: 26911791 PMCID: PMC4766468 DOI:
10.1038/srep22111

[0112] Sci Rep. 2015 Jun 5;5:11030. The Tie2-agonist Vasculotide rescues mice from influenza virus infection.Sugiyama MG, Armstrong SM, Wang C, Hwang D, Leong-Poi H, Advani A, Advani S, Zhang H, Szaszi K, Tabuchi A, Kuebler WM, Van Slyke P, Dumont DJ, Lee WL.PMID: 26046800 PMCID: PMC4457136 DOI:
10.1038/srep11030

[0113] EMBO Mol Med. 2015 Jun;7(6):770-87. Vasculotide reduces endothelial permeability and tumor cell extravasation in the absence of binding to or agonistic activation of Tie2.Wu FT, Lee CR, Bogdanovic E, Prodeus A, Gariepy J, Kerbel RS.PMID: 25851538 PMCID: PMC4459817 DOI: 10.15252/emmm.201404193

[0114] BMC Cancer. 2014 Aug 26,14:614.Vasculotide, an Angiopoietin-1 mimetic, reduces acute skin ionizing radiation damage in a preclinical mouse model.Korpela E, Yohan D, Chin LC, Kim A, Huang X, Sade S, Van Slyke P, Dumont DJ, Liu SK.PMID: 25159192 PMCID: PMC4159535 DOI: 10.1186/1471-2407-14-614 PATENT
Attorney Docket No.: 14002.6004-00000

[0115] Tissue Eng Part A. 2009 Jun;15(6):1269-80.Acceleration of diabetic wound healing by an angiopoietin peptide mimetic.Van Slyke P, Alami J, Martin D, Kuliszewski M, Leong-Poi H, Sefton MV, Dumont D.PMID: 18939935 DOI:
10.1089/ten.tea.2007.0400

[0116] Anti-Angiopoietin-2 Binding and Oligomerizing Antibody as Tie2 Activator

[0117] Any anti-angiopoietin 2 antibody can be used with the methods of the disclosure and one of ordinary skill in the art would be aware of the same.
Non-limiting examples include those described inSci Adv. 2019 Feb 13;5(2):eaau6732.Tie2 activation promotes choriocapillary regeneration for alleviating neovascular age-related macular degeneration.Kim J, Park JR, Choi J, Park!, Hwang Y, Bae H, Kim Y, Choi W, Yang JM, Han S, Chung TY, Kim P, Kubota Y, Augustin HG, Oh WY, Koh GY.PMID:
30788433 PMCID: PMC6374104 DOI: 10.1126/sciadv.aau6732

[0118] J Clin Invest. 2017 Oct 2;127(10):3877-3896.Impaired angiopoietinfrie2 signaling compromises Schlemm's canal integrity and induces glaucoma.Kim J, Park DY, Bae H, Park DY, Kim D, Lee CK, Song S, Chung TY, Lim DH, Kubota Y, Hong YK, He Y, Augustin HG, Oliver G, Koh GYPMID: 28920924 PMCID: PMC5617682 DOI:
10.1172/JCI94668

[0119] Cancer Cell. 2016 Dec 12;30(6):953-967. Normalization of Tumor Vessels by Tie2 Activation and Ang2 Inhibition Enhances Drug Delivery and Produces a Favorable Tumor Microenvironment.Park JS, Kim IK, Han S, Park 1, Kim C, Bae J, Oh PATENT
Attorney Docket No.: 14002.6004-00000 SJ, Lee S, Kim JH, Woo DC, He Y, Augustin HG, Kim 1, Lee D, Koh GY.PMID:
27960088 DOI: 10.1016/j.cce11.2016.10.018

[0120] Sci Transl Med. 2016 Apr 20;8(335):335ra55.Amelioration of sepsis by TIE2 activation-induced vascular protection.Han S, Lee SJ, Kim KE, Lee HS, Oh N, Park I, Ko E, Oh SJ, Lee YS, Kim D, Lee S, Lee DH, Lee KH, Chae SY, Lee JH, Kim SJ, Kim HC, Kim S, Kim SH, Kim C, Nakaoka Y, He Y, Augustin HG, Hu J, Song PH, Kim YI, Kim P, Kim I, Koh GY.PMID: 27099174 DOI: 10.1126/scitranslmed.aad9260

[0121] Anti-Tie2 Receptor Agonistic Antibody as Tie2 Activator

[0122] Any anti-Tie2 antibody can be used with the methods of the disclosure and one of ordinary skill in the art would be aware of the same. Non-limiting examples include those described inBionnaterials. 2015 May;51:119-128.Stimulation of angiogenesis and survival of endothelial cells by human monoclonal Tie2 receptor antibody. Hwang B, Lee SH, Kim JS, Moon JH, Jeung IC, Lee NG, Park J, Hong HJ, Cho YL, Jung H, Park YJ, Lee SJ, Lee HG, Kim WK, Han BS, Bae KH, Chung SJ, Kwon YG, Lee SC, Kim SJ and Min JK. PMID: 25771003 DOI:
10.1016/j.biomaterials.2015.01.062.
VE-PTP INHIBITORS.

[0123] Anti-VE-PTP Antibody as Tie2 Activator

[0124] Any antibody against VE-PTP can be used with the methods of the disclosure and one of ordinary skill in the art would be aware of the same.
Non-limiting PATENT
Attorney Docket No.: 14002.6004-00000 examples include those described inJ Exp Med. 2015 Dec 14;212(13):2267-87.
Epub 2015 Dec 7.Interfering with VE-PTP stabilizes endothelial junctions in vivo via Tie-2 in the absence of VE-cadherin Frye M, Dierkes M, Kiippers V, Vockel M, Tomm J, Zeuschner D, Rossaint J, Zarbock A, Koh GY, Peters K, Nottebaum AF, Vestweber D.PMID: 26642851 PMCID: PMC4689167 DOI: 10.1084/jem.20150718

[0125] J Clin Invest. 2014 Oct;124(10):4564-76. Epub 2014 Sep 2.Targeting VE-PTP activates TIE2 and stabilizes the ocular vasculature.Shen J, Frye M, Lee BL, Reinardy JL, McClung JM, Ding K, Kojima M, Xia H, Seidel C, Lima e Silva R, Dong A, Hackett SF, Wang J, Howard BW, Vestweber D, Kontos CD, Peters KG, Campochiaro PA.PMID: 25180601 PMCID: PMC4191011 DOI: 10.1172/JCI74527

[0126] J Cell Biol. 2009 May 18;185(4):657-71. VE-PTP controls blood vessel development by balancing Tie-2 activity.Winderlich M, Keller L, Cagna G, Broermann A, Kamenyeva 0, Kiefer F, Deutsch U, Nottebaum AF, Vestweber D.PMID: 19451274 PMCID: PMC2711575 DOI: 10.1083/jcb.200811159

[0127] Small Molecule VE-PTP Inhibitors as Tie2 Activators

[0128] Any small molecule agent that inhibits VE-PTP can be used with the methods of the disclosure and one of ordinary skill in the art would be aware of the same. Non-limiting examples include those described in: Bioorg Chem. 2018 Dec;81:270-277. Epub 2018 Jun 6. Zhang W, Wei Z, et al.; Microsurgery. 2017 Sep;37(6):624-631. Epub 2016 Nov 17.Zor F, Meric C et al.;J Infect Dis. 2017 Mar 1;215(5):813-817.0ehlers SH et al. ; Curr Diab Rep. 2016 Dec;16(12):126.
Review.

PATENT
Attorney Docket No.: 14002.6004-00000 Campochiaro PA et al.; Ophthalmology. 2016 Aug;123(8):1722-1730. Epub 2016 May 26Campochiaro PA et al.; Acta Neuropathol. 2016 May;131(5):753-73. Epub 2016 Mar 1.Gurnik S, et al.; J Exp Med. 2015 Dec 14;212(13):2267-87. Epub 2015 Dec 7Frye M, et al.; Ophthalmology. 2015 Mar;122(3):545-54. Epub 2014 Nov 12.Campochiaro PA
et al.; J Clin Invest. 2014 Oct;124(10):4564-76. Epub 2014 Sep 2.; Shen J et al.Targeting VE-PTP activates TIE2 and stabilizes the ocular vasculature. et al.; Antioxid Redox Signal. 2014 May 10;20(14):2130-40. Epub 2014 Feb 4.Zeng LF et al; J Natl Cancer Inst. 2013 Aug 21;105(16):1188-201. Epub 2013 Jul 30. Goel S et al.;J Biol Chem. 2012 Mar 16;287(12):9322-6. Epub 2012 Jan 24.Wilson M et al.; Angiogenesis.
2009;12(1):25-33. Epub 2009 Jan 1.Yacyshyn OK et al.; Acta Crystallogr D Biol Crystallogr. 2006 Dec;62(Pt 12):1435-45. Epub 2006 Nov 23. Evdokinnov AG et al.;
Bioorg Med Chem Lett. 2006 Aug 15;16(16):4252-6. Epub 2006 Jun 12.Amarasinghe KK et al.; Proc Natl Acad Sci U S A. 2006 Jul 11;103(28):10606-11. Epub 2006 Jun 29.Ntiren-Miiller A et al.: Am J Physiol Heart Circ Physiol. 2004 Jul;287(1):H268-76.
Epub 2004 Feb 26. Carr AN et al.; J Biol Chem. 2004 Jun 4;279(23):24226-35.
Epub 2004 Mar 15. ; Lund IK, et al.; J lnorg Biochem. 2003 Aug 1;96(2-3):321-30.;
Peters KG
et at.
ANTI-VEGF TREATMENTS.

[0129] Any agent that inhibits VEGF can be used with the methods of the disclosure and one of ordinary skill in the art would be aware of the same.
Non-limiting PATENT
Attorney Docket No.: 14002.6004-00000 examples include: Affibercept, trade name Eylea and Zaltrap, is a recombinant fusion protein.; Bevacizumab, trade name Avastin, is a humanized recombinant monoclonal IgG1 antibody.; Pegaptanib sodium, trade name Macugen, is a pegylated synthetic RNA
aptamer.; Ranibizumab, trade name Lucentis, is a humanized IgG1 monoclonal antibody fragment.; Brolucizumab is a humanized single chain antibody fragment;
Conbercept is a fusion protein that acts as a VEGF receptor decoy; Ramucirumab is a novel human IgG1 monoclonal antibody that selectively inhibits the VEGFR2 and blocks the VEGFR2-related signaling and activating pathways; Faricimab (RG7716), is a bispecific anti-VEGF/ANG2 monoclonal antibody capable of binding, neutralizing, and depleting VEGF-A and ANG-2.; Nesvacumab-Affibercept is Ang-2NEGF-A co-formulation of two monoclonal antibodies.; Designed ankyrin repeat proteins (DARPins) are various formulations of genetically engineered small recombinant non-immunoglobulin proteins that mimic antibodies in their ability to bind specific proteins with high affinity and specificity; biosimilars of all of the listed antibodies; Gene-therapy-targeting VEGF; small molecules, etc.
METHODS OF ASSESSING CHORIOCAPILLARIS PERFUSION

[0130] One of ordinary skill in the art would be familiar with methods to assess choriocapillaris perfusion. In one embodiment, choriocapillaris perfusion is assessed PATENT
Attorney Docket No.: 14002.6004-00000 through the use of passive fluorescent dyes. In one embodiment, choriocapillaris perfusion is assessed through fluorescent dye angiography.
METHODS OF ASSESSING PROTECTION OF THE CHORIOCAPILLARIS
One of ordinary skill in the art would be familiar with methods to assess protection of the choriocapillaris. In one embodiment, the choriocapillaris is visualized as described above in METHODS OF ASSESSING CHORIOCAPILLARIS VASCULARIZATION. In one embodiment, the choriocapillaris is visualized prior to treatment, at different stages during treatment, and at different stages after a treatment that damages the choriocapillaris. In one embodiment, the treatment is anti-VEGF treatment. In one embodiment, a Tie2 activator is administered in combination with the anti-VEGF

treatment in order to protect the choriocapillaris from anti-VEGF treatment-induced/related damage. Exemplary embodiments of different combination treatment regimens are exemplified below.
METHODS OF ASSESSING CHORIOCAPILLARIS DROPOUT

[0131] The term "choriocapillaris dropout" refers to the loss of functional capillaries supplying blood to the choroid (e.g. could be physical loss due to rarefaction or it could be to non-functional vessels). Methods for assessing this parameter are known in the art and described elsewhere in this application.

PATENT
Attorney Docket No.: 14002.6004-00000 METHODS OF ASSESSING IMPROVEMENTS IN VISION

[0132] In one embodiment, improvements in vision are measured by a subject's uncorrected distance and near visual acuity, which may be taken using a standard acceptable eye chart.

[0133] In another embodiment, improvements in vision are measured by clinical evaluation of the depth of field, which may be obtained either using standard wavefront aberrometry or according to other methods well known to one of ordinary skill in the art.

[0134] In yet another embodiment, improvements in vision are measured by change of pupil size, which may be evaluated by the infrared imaging system used for checking alignment during auto-refractometry. The pupil size can also be measured by Aberronneter and pupilometer.

[0135] In yet another embodiment, improvements in vision are measured by pupil appearance, which can include inspecting the pupils for equal size (1 mm or less of difference may be normal), regular shape, reactivity to light, and direct and consensual accommodation.

[0136] In yet another embodiment, improvements in vision are measured by non-invasive objective assessments of the 3rd, 4th and 5th ocular higher order PATENT
Attorney Docket No.: 14002.6004-00000 aberrations (such as coma, spherical aberration, and trefoil), which may be conducted using standard wavefront aberrometry.
METHODS OF ADMINISTRATION

[0137] The Tie2 activators, VE-PTP inhibitors, and anti-VEGF treatments, can be administered in unit forms of administration to mammalian subjects, including human beings. Suitable unit forms of administration include, as non-limiting examples, forms administered orally and forms administered via a parenteral/systemic route, non-limiting examples of which including inhalation, subcutaneous administration, intramuscular administration, intravenous administration, intradermal administration, intravitreal administration, as well as topical and local ocular (i.e, subconjunctival, intravitreal, retrobulbar, intracameral) modes of administration. In one embodiment, the treatment is injected into the eye (intraocular injection). Can we add in nanoparticle -mediated delivery?

[0138] In some embodiments, pharmaceutical compositions for parenteral administration can be in the form of aqueous solutions, non¨aqueous solutions, suspensions, emulsions, drops (including, as a non-limiting example, eye drops), or any combination(s) thereof. In some embodiments, such pharmaceutical compositions may comprise one or more of water, pharmaceutically acceptable glycol(s), pharmaceutically acceptable oil(s), pharmaceutically acceptable organic esters, or other pharmaceutically acceptable solvents. A variety of vehicles suitable for administering compounds to the eye are known in the art. Specific non-limiting examples are described in U.S.
Pat. No.

PATENT
Attorney Docket No.: 14002.6004-00000 6,261,547; U.S. Pat. No. 6,197,934; U.S. Pat. No. 6,056,950; U.S. Pat. No.
5,800,807;
U.S. Pat. No. 5,776,445; U.S. Pat. No. 5,698,219; U.S. Pat. No. 5,521,222;
U.S. Pat.
No. 5,403,841; U.S. Pat. No. 5,077,033; U.S. Pat. No. 4,882,150; and U.S. Pat.
No.
4,738,851, all of which are incorporate herein by reference in their entirety.

[0139] With regard to these treatments, the mode (or modes) of administration, dosage (or dosages), and optimized pharmaceutical form (or forms) can be determined according to criteria generally considered during the establishment of a treatment of a patient, such as, by way of non-limiting examples, the potency of the compound(s) and/or pharmaceutically acceptable salts of the compound(s), the age of the patient, the body weight of the patient, the severity of the patient's condition (or conditions), the patient's tolerance to the treatment, and secondary effects observed in treatment.
Determination of dosages effective to provide therapeutic benefit for specific modes and frequency of administration is within the capabilities of those skilled in the art.
COMBINATION TREATMENTS

[0140] In one embodiment, the disclosure provides combination treatments for use in the treatment of choriocapillaris disorders such as, for example, AMD.

[0141] Each therapeutic agent in a combination therapy of the invention may be administered simultaneously (i.e., in the same medicament), concurrently (i.e., in separate medicaments administered one right after the other in any order) or sequentially in any order. Sequential administration is particularly useful when the PATENT
Attorney Docket No.: 14002.6004-00000 therapeutic agents in the combination therapy are in different dosage forms (one agent is a tablet or capsule and another agent is a sterile liquid) and/or are administered on different dosing schedules, e.g., a Tie2 activator that is administered at least daily and a anti-VEGF treatment that is administered less frequently, such as once weekly, once every two weeks, or once every three weeks.

[0142] In some embodiments, at least one of the therapeutic agents in the combination therapy is administered using the same dosage regimen (dose, frequency and duration of treatment) that is typically employed when the agent is used as monotherapy for treating the same disease or another disease. In other embodiments, the patient receives a lower total amount of at least one of the therapeutic agents in the combination therapy than when the agent is used as monotherapy, e.g., smaller doses, less frequent doses, and/or shorter treatment duration.

[0143] In some embodiments, a combination therapy of the invention is administered to a patient who has not been previously treated with either one or both of the individual treatments, i.e., is treatment-naïve. In other embodiments, the combination therapy is administered to a patient who failed to achieve a sustained response after prior therapy with one of the agents, i.e., is treatment-experienced.

[0144] In one embodiment, the Tie2 activator and/or the VE-PTP
inhibitors are administered together with the anti-VEGF treatment to a treatment-naïve patient. In another embodiment, the Tie2 activator and/or the VE-PTP inhibitors are administered PATENT
Attorney Docket No.: 14002.6004-00000 after the patient has started the anti-VEGF treatment and the treatment is either not sufficient or there are side effects (e.g., choriocapillaris dropout).

[0145] Selecting a dosage regimen (also referred to herein as an administration regimen) for a combination therapy of the invention depends on several factors, including the serum or tissue turnover rate of the entity, the level of symptoms, the immunogenicity of the entity, and the accessibility of the target cells, tissue or organ in the subject being treated. Optionally, a dosage regimen maximizes the amount of each therapeutic agent delivered to the patient consistent with an acceptable level of side effects. Accordingly, the dose amount and dosing frequency of each biotherapeutic and chemotherapeutic agent in the combination depends in part on the particular therapeutic agent, the severity of the choriocapillaris disorder being treated, and patient characteristics. Determination of the appropriate dosage regimen may be also made by the clinician, e.g., using parameters or factors known or suspected in the art to affect treatment or predicted to affect treatment, and will depend, for example, the patient's clinical history (e.g., previous therapy), and the severity of the choriocapillaris disorder.

[0146] Regardless of the treatment indication, there are essentially two regimens for administering anti-VEGF drugs: continuous and intermittent/as required (or pro re nata, PRN for short).

[0147] The following non-limiting examples and data illustrate various aspects and features relating to the methods and uses of compounds of the present invention. In some embodiments, the present methods and uses of compounds provide results and PATENT
Attorney Docket No.: 14002.6004-00000 data which are surprising, unexpected and contrary thereto. While the utility of this invention is illustrated through the use of several compounds and moieties/groups which can be used therewith, it will be understood by those skilled in the art that comparable results are obtainable with various other compounds, moieties and/or groups, as are commensurate with the scope of this invention.
EXAMPLES

Angiopoietin-Tie2 signaling is a key regulator of choriocapillaris development

[0148] Data presented herein indicate, for the first time, that Angpt-Tie2 signaling is essential throughout choroid development and that mice lacking Angptl from the entire body or only in their neural-crest derived cells including melanocytes of the choroid, exhibit dramatic choriocapillaris attenuation. This term refers to a reduction of capillary density in the choroid. It is visible on flat mount, histologic sections through the choroid and by immunohistochemical analysis. It results in loss of blood flow and delivery of nutrients to key cells of the choroid including the RPEs. Indeed, experiments using whole-body Angptl knockout mice deleted at E13.5, after the first stage of choriocapillaris development, revealed sparse choriocapillaris by postnatal day (P) 0 (FIG. 2 A), highlighting the critical role of Angpt-Tie2 signaling in late-stage development. Importantly, given the expression pattern of Angptl (FIG. 3 A) in choroidal melanocytes, and the fact that melanocytes have recently been reported as an important regulator of choriocapillaris development, we developed a mouse deficient PATENT
Attorney Docket No.: 14002.6004-00000 in Angptl in melanocytes. Importantly, the mechanisms and growth factors produced by choroidal melanocytes needed for choroid development have not been identified.
The data suggest that Angptl may be one such¨if not the¨melanocyte-secreted factor responsible for this regulation. To investigate this possibility, and to understand the role of Angptl in early choroid development, a novel neural-crest specific Angptl knockout mouse was generated using WntlCre (53, 54). Angptl ANC mice lack Angptl in the choroidal melanocytes and other non-endothelial cells of the choroid and sclera but retain expression in the RPE. Compared to littermate controls, AngptlANC
mice show a markedly attenuated choriocapillary network at P1 (FIG. 2 B), confirming the importance of choroidal Angptl.

Deficits in Angpt-TIE2 signaling lead to choriocapillaris dysfunction, including capillary rarefaction and PCV-like disorganized vascular networks

[0149] Angptl knockout mice induced at E13.5, after completion of initial choriocapillaris development (16), exhibit reduced choriocapillary density (FIG. 2A), suggesting that Angpt-Tie2 signaling is essential for late-stage choriocapillaris development, growth or maintenance. Using neural crest-specific Angptl knockout mice, it was discovered that by P11, while the capillary sparsity seen at P1 was still observed, a branched network of large, disorganized vessels had formed in the choriocapillaris of mutant mice, suggesting a continued role for Angpt signaling after PATENT
Attorney Docket No.: 14002.6004-00000 birth (FIG. 4). These abnormal vessels were positive for the endothelial marker PODXL, but EMCN negative, suggesting either loss of the choriocapillary phenotype or encroachment of intermediate or large choroidal vessels into the choriocapillaris. This finding is strikingly similar to the disorganized networks commonly observed by indocyanine green angiography in eyes with polypoidal choroidal vasculopathy (PCV), a little understood group of adult-onset AMD-like diseases including pachychoroid vasculopathy (62) which are characterized by a disorganized network of dilated choroidal vessels and polypoid lesions (24-26).

[0150] The data suggest that Angpt-TIE2 signaling plays an important role in choriocapillaris homeostasis and deletion of Angpt ligands or TIE2 leads to dysfunction.
Identification of PCV-like vascular networks in AngptlANC mice provides an important proof-of-concept, and characterization of these mice provides mechanistic insights on the unusual encroachment of large disorganized vessels into the choriocapillaris¨a key aspect of this poorly understood disease.

VE-PTP deletion leads to TIE2 activation and choriocapillary growth, and will protect the choriocapillaris during geographic atrophy and anti-VEGF therapy

[0151] VE-PTP is an endothelial receptor-type phosphatase which specifically dephosphorylates TIE2, reducing its signaling activity (41, 48). Loss of VE-PTP activity, either by genetic deletion or pharmacological inhibition, results in increased TIE2 activity PATENT
Attorney Docket No.: 14002.6004-00000 in vivo even in the absence of ANGPT1, leading to elevated signaling through and eNOS ((41). Results presented herein indicate that Ve-ptp is strongly expressed by the adult mouse choriocapillaris (FIG. 5 A,B), highlighting its role in the choriocapillary endothelium. In addition to regulating vascular stability, TIE2 activation can cause venous widening (47, 68) and data presented herein suggest that embryonic deletion of Ve-ptp at E13.5 leads to increased choriocapillaris vascular density by PO
(FIG. 5 C,D).
Thus, the results indicate that Ve-ptp is strongly expressed in the adult mouse choriocapillaris, and that knockout mice have dramatically increased choriocapillary area. Importantly, we have recently demonstrated that elevated VE-PTP
expression can worsen micro-vascular disease outcomes. Renal VE-PTP expression is upregulated by hypertension and hyperglycemia (Carota et al. JEM 2019, in press), leading to reduced TIE2 signaling and enhancing a cycle of microvascular dysfunction in diabetes.
VE-PTP
knockout mice have dramatically increased choriocapillary area, suggesting that this protein could provide an effective target for therapy aimed at increasing choriocapillaris function in early AMD or preventing capillary dropout during anti-VEGF
therapy.

[0152] As choriocapillaris rarefaction is a component of AMD, this suggests that VE-PTP inhibition may provide an effective pro-choriocapillaris therapy. In vivo, VE-PTP
inhibition leads to increased activation of PI3K/AKT and ENOS signaling, pro-survival pathways which are also activated by VEGF. Therefore, VE-PTP inhibition as combination therapy may protect the choriocapillaris during treatment with anti-VEGF

PATENT
Attorney Docket No.: 14002.6004-00000 agents, preventing choriocapillaris rarefaction and limiting potential side effects of anti-VEGF treatment.

Generation of the Mice Used in the Examples

[0153] Angptl, Angpt2 and Tie2 knockout mice have been previously described (39, 40, 55). As global deletion of Angptl before E13.5 is incompatible with life, specific deletion in the periocular mesenchyme is essential for study of the choriocapillaris during early embryogenesis. While periocular endothelial cells arise from the mesoderm, non-endothelial cells and melanocytes are neural crest-derived (54, 56).
Therefore, the well-characterized WntlCre line (53, 54) was used to achieve deletion of Angptl in the neural crest lineage.

[0154] A novel neural-crest specific Angptl knockout mouse using Wnt/Cre (53, 54) was generated. AngptlANC mice lack Angptl in the choroidal melanocytes and other non-endothelial cells of the choroid and sclera but retain expression in the RPE.
Compared to littermate controls, Angpti ANC mice show a markedly attenuated choriocapillary network at P1 (FIG. 2 B), confirming the importance of choroidal Angptl.
These mice are a good model of for AMD and for Polypoidal choroidal vasculopathy, which is an AMD-like disease that predominantly affects patients of African-American and Asian descent and has no existing animal model.

[0155] Inducible VE-PTP knockout mice (Vete"; Rosa261frA; TetOnCre) are described in Carota et al. JEM 2019, published.

PATENT
Attorney Docket No.: 14002.6004-00000 INCORPORATION BY REFERENCE

[0156] Various publications, articles and patents are cited or described in the background and throughout the specification; each of these references is herein incorporated by reference in its entirety. Discussion of documents, acts, materials, devices, articles or the like which has been included in the present specification is for the purpose of providing context for the invention. Such discussion is not an admission that any or all of these matters form part of the prior art with respect to any inventions disclosed or claimed.

[0157] REFERENCES CITED AND OTHER SUPPORTING REFERENCES.
1. Bird AC. Therapeutic targets in age-related macular disease. J Clin Invest.
2010;120(9):3033-41.
2. Wong WL, Su X, Li X, Cheung CMG, Klein R, Cheng C-Y, and Wong TY. Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040: A systematic review and meta-analysis. The Lancet Global Health.
2014;2(2):e106-e16.
3. Stefansson E, GeirsdOttir A, and Sigurdsson H. Metabolic physiology in age related macular degeneration. Prog Retin Eye Res. 2011;30(1):72-80.
4. Dietzel M, Pauleikhoff D, Holz FG, and Bird AC. In: Holz FG, Pauleikhoff D, Spaide RF, and Bird AC eds. Age-related macular degeneration. Berlin, Heidelberg:
Springer Berlin Heidelberg; 2013:101-9.
5. Pauleikhoff D, Spital G, Radermacher M, Brumm GA, Lommatzsch A, and Bird AC. A
fluorescein and indocyanine green angiographic study of choriocapillaris in age-related macular disease. Arch Ophthalmol. 1999;117(10):1353-8.
6. Lutty G, Grunwald J, Majji AB, Uyama M, and Yoneya S. Changes in choriocapillaris and retinal pigment epithelium in age-related macular degeneration. Mol Vis.
1999;5(35.
7. Metelitsina TI, Grunwald JE, Dupont JC, Ying G-S, Brucker AJ, and Dunaief JL.
Foveolar choroidal circulation and choroidal neovascularization in age-related macular degeneration. Invest Ophthalmol Vis ScL 2008;49(1):358-63.
8. Fleckenstein M, Schmitz-Valckenberg S, Sunness JS, and Holz FG. In: Holz FG, Pauleikhoff D, Spaide RF, and Bird AC eds. Age-related macular degeneration.
Berlin, Heidelberg: Springer Berlin Heidelberg; 2013:121-38.
9. Spilsbury K, Garrett KL, Shen W-Y, Constable IJ, and Rakoczy PE.
Overexpression of vascular endothelial growth factor (vegf) in the retinal pigment epithelium leads to the PATENT
Attorney Docket No.: 14002.6004-00000 development of choroidal neovascularization. The American Journal of Pathology.
2000;157(1):135-44.
10. Inoue Y, Yanagi Y, Matsuura K, Takahashi H, Tamaki Y, and Araie M.
Expression of hypoxia-inducible factor 1a and 2a in choroidal neovascular membranes associated with age-related macular degeneration. Br J Ophthalmol. 2007;91(12):1720-1.
11. Sheridan CM, Pate S, Hiscott P, Wong D, Pattwell DM, and Kent D.
Expression of hypoxia-inducible factor-1a and -2a in human choroidal neovascular membranes.
Graefe's Archive for Clinical and Experimental Ophthalmology.
2009;247(10):1361-7.
12. Mendrinos E, and Pournaras CJ. Topographic variation of the choroidal watershed zone and its relationship to neovascularization in patients with age-related macular degeneration. Acta Ophthalmol (Copenh). 2009;87(3):290-6.
13. Mcleod DS, Grebe R, Bhutto I, Merges C, Baba T, and Lutty GA.
Relationship between rpe and choriocapillaris in age-related macular degeneration. Invest Ophthalmol Vis 2009;50(10):4982-91.
14. Seddon JM, Mcleod D, Bhutto IA, and Et Al. Histopathological insights into choroidal vascular loss in clinically documented cases of age-related macular degeneration. JAMA
Ophthalmology. 2016;134(11):1272-80.
15. Young M, Chui L, Fallah N, Or C, Merkur AB, Kirker AW, Albiani DA, and Forooghian F.
Exacerbation of choroidal and retinal pigment epithelial atrophy after anti-vascular endothelial growth factor treatment in neovascular age-related macular degeneration.
Retina. 2014;34(7):1308-15.
16. Marneros AG, Fan J, Yokoyama Y, Gerber HP, Ferrara N, Crouch RK, and Olsen BR.
Vascular endothelial growth factor expression in the retinal pigment epithelium is essential for choriocapillaris development and visual function. The American Journal of Pathology.167(5):1451-9.
17. Peters S, Heiduschka P, Julien S, Ziemssen F, Fietz H, Bartz-Schmidt KU, and Schraermeyer U. Ultrastructural findings in the primate eye after intravitreal injection of bevacizumab. Am J Ophtha/mo/.143(6):995-1002.e2.
18. Shimomura Y, Hirata A, Ishikawa S, and Okinami S. Changes in choriocapillaris fenestration of rat eyes after intravitreal bevacizumab injection. Graefe's Archive for Clinical and Experimental Ophthalmology. 2009;247(8):1089-94.
19. Kurihara T, Westenskow PD, Bravo S, Aguilar E, and Friedlander M.
Targeted deletion of vegfa in adult mice induces vision loss. J Clin Invest. 2012;122(11):4213-7.
20. Grunwald JE, Daniel E, Huang J, Ying G-S, Maguire MG, Toth CA, Jaffe GJ, Fine SL, Blodi B, Klein ML, et al. Risk of geographic atrophy in the comparison of age-related macular degeneration treatments trials. Ophthalmology.121(1):150-61.
21. Chakravarthy U, Harding SP, Rogers CA, Downes SM, Lotery AJ, Culliford LA, and Reeves BC. Alternative treatments to inhibit vegf in age-related choroidal neovascularisation: 2-year findings of the ivan randomised controlled trial.
The Lancet.382(9900):1258-67.
22. Sho K, Takahashi K, Yamada H, Wada M, Nagai Y, Otsuji T, Nishikawa M, Mitsuma Y, Yamazaki Y, Matsumura M, et al. Polypoidal choroidal vasculopathy: Incidence, demographic features, and clinical characteristics. Arch Ophthalmol.
2003;121(10):1392-6.

PATENT
Attorney Docket No.: 14002.6004-00000 23. Yannuzzi LA, Sorenson J, Spaide RF, and Lipson B. Idiopathic polypoidal choroidal vasculopathy (ipcv). Retina. 1990;10(1):1-8.
24. Nakajima M, Yuzawa M, Shimada H, and Mori R. Correlation between indocyanine green angiographic findings and histopathology of polypoidal choroidal vasculopathy.
Jpn J Ophthalmol. 2004;48(3):249-55.
25. Laude A, Cackett PD, Vithana EN, Yeo IY, Wong D, Koh AH, Wong TY, and Aung T.
Polypoidal choroidal vasculopathy and neovascular age-related macular degeneration:
Same or different disease? Prog Retin Eye Res. 2010;29(1):19-29.
26. Yuzawa M, Mori R, and Kawamura A. The origins of polypoidal choroidal vasculopathy.
Br J Ophthalmol. 2005;89(5):602-7.
27. Hatz K, and Prunte C. Polypoidal choroidal vasculopathy in caucasian patients with presumed neovascular age-related macular degeneration and poor ranibizumab response. Br J Ophthalmol. 2014;98(2):188-94.
28. Stangos AN, Gandhi JS, Nair-Sahni J, Heimann H, Pournaras CJ, and Harding SP.
Polypoidal choroidal vasculopathy masquerading as neovascular age-related macular degeneration refractory to ranibizumab. Am J Ophthalmol. 2010;150(5):666-73.
29. Kawashima Y, Oishi A, Tsujikawa A, Yamashiro K, Miyake M, Ueda-Arakawa N, Yoshikawa M, Takahashi A, and Yoshimura N. Effects of aflibercept for ranibizumab-resistant neovascular age-related macular degeneration and polypoidal choroidal vasculopathy. Graefe's Archive for Clinical and Experimental Ophthalmology.
2015;253(9):1471-7.
30. Koh A, Lee WK, Chen L-J, Chen S-J, Hashad Y, Kim H, Lai TY, Pilz S, Ruamviboonsuk P, Tokaji E, et al. Everest study: Efficacy and safety of verteporfin photodynamic therapy in combination with ranibizumab or alone versus ranibizumab monotherapy in patients with symptomatic macular polypoidal choroidal vasculopathy. Retina.
2012;32(8):1453-64.
31. Tan CS, Ngo WK, Chen JP, Tan NW, and Lim TH. Everest study report 2:
Imaging and grading protocol, and baseline characteristics of a randomised controlled trial of polypoidal choroidal vasculopathy. Br J Ophthalmol. 2015;99(5):624-8.
32. Koh A, Lai TYY, Takahashi K, Wong TY, Chen L-J, Ruamviboonsuk P, Tan CS, Feller C, Margaron P, Lim TH, et al. Efficacy and safety of ranibizumab with or without verteporfin photodynamic therapy for polypoidal choroidal vasculopathy: A randomized clinical trial.
JAMA ophthalmology. 2017;135(11):1206-13.
33. Ma L, Brelen ME, Tsujikawa M, Chen H, Chu WK, Lai TYY, Ng DSC, Sayanagi K, Hara C, Hashida N, et al. Identification of angpt2 as a new gene for neovascular age-related macular degeneration and polypoidal choroidal vasculopathy in the chinese and japanese populationsangpt2 in amd and pcv. Invest Ophthalmol Vis Sci.
2017;58(2):1076-83.
34. Lutty GA, Hasegawa T, Baba T, Grebe R, Bhutto I, and Mcleod DS.
Development of the human choriocapillaris. Eye. 2010;24(408.
35. Hasegawa T, Mcleod DS, Bhutto IA, Prow T, Merges CA, Grebe R, and Lutty GA. The embryonic human choriocapillaris develops by hemo-vasculogenesis. Dev Dyn.
2007;236(8):2089-100.

PATENT
Attorney Docket No.: 14002.6004-00000 36. Saint-Geniez M, Kurihara T, Sekiyama E, Maldonado AE, and D'amore PA.
An essential role for rpe-derived soluble vegf in the maintenance of the choriocapillaris.
Proceedings of the National Academy of Sciences. 2009;106(44):18751-6.
37. Augustin HG, Young Koh G, Thurston G, and Alitalo K. Control of vascular morphogenesis and homeostasis through the angiopoietin-tie system. Nat Rev Mol Cell Biol. 2009;10(3):165-77.
38. Kim J, Park JR, Choi J, Park I, Hwang Y, Bae H, Kim Y, Choi W, Yang JM, Han S, et al.
Tie2 activation promotes choriocapillary regeneration for alleviating neovascular age-related macular degeneration. Science Advances. 2019;5(2):eaau6732.
39. Gale NW, Thurston G, Hackett SF, Renard R, Wang Q, Mcclain J, Martin C, Witte C, Witte MH, Jackson D, et al. Angiopoietin-2 is required for postnatal angiogenesis and lymphatic patterning, and only the latter role is rescued by angiopoietin-1.
Dev Cell.
2002;3(3):411-23.
40. Davis S, Aldrich TH, Jones PF, Acheson A, Compton DL, Jain V, Ryan TE, Bruno J, Radziejewski C, Maisonpierre PC, et al. Isolation of angiopoietin-1, a ligand for the tie2 receptor, by secretion-trap expression cloning. Cell. 1996;87(7):1161-9.
41. Souma T, Thomson BR, Heinen S, Carota IA, Yamaguchi S, Onay T, Liu P, Ghosh AK, Li C, Eremina V, et al. Context-dependent functions of angiopoietin 2 are determined by the endothelial phosphatase veptp. Proceedings of the National Academy of Sciences.
2018.
42. Thomson BR, Heinen S, Jeansson M, Ghosh AK, Fatima A, Sung H-K, Onay T, Chen H, Yamaguchi S, Economides AN, et al. A lymphatic defect causes ocular hypertension and glaucoma in mice. J Clin Invest. 2014;124(10).
43. Souma T, Tompson SW, Thomson BR, Siggs OM, Kizhatil K, Yamaguchi S, Feng L, Limviphuvadh V, Whisenhunt KN, Maurer-Stroh S, et al. Angiopoietin receptor tek mutations underlie primary congenital glaucoma with variable expressivity. J
Clin Invest.126(7):2575-87.
44. Thomson BR, Souma T, Tompson SW, Onay T, Kizhatil K, Siggs OM, Feng L, Whisenhunt KN, Yanovitch TL, Kalaydjieva L, et al. Angiopoietin-1 is required for schlemm's canal development in mice and humans. J Clin Invest.
2017;127(12):4421-36.
45. Nambu H, Nambu R, Oshima Y, Hackett SF, Okoye G, Wiegand S, Yancopoulos G, Zack DJ, and Campochiaro PA. Angiopoietin 1 inhibits ocular neovascularization and breakdown of the blood¨retinal barrier. Gene Ther. 2004;11(865.
46. Lee J, Park D-Y, Park DY, Park I, Chang W, Nakaoka Y, Komuro I, Yoo 0-J, and Koh GY. Angiopoietin-1 suppresses choroidal neovascularization and vascular leakage.
Invest Ophthalmol Vis ScL 2014;55(4):2191-9.
47. Thurston G, Wang Q, Baffert F, Rudge J, Papadopoulos N, Jean-Guillaume D, Wiegand S, Yancopoulos GD, and Mcdonald DM. Angiopoietin 1 causes vessel enlargement, without angiogenic sprouting, during a critical developmental period.
Development.
2005;132(14):3317.
48. Winderlich M, Keller L, Cagna G, Broermann A, Kamenyeva 0, Kiefer F, Deutsch U, Nottebaum AF, and Vestweber D. Ve-ptp controls blood vessel development by balancing tie-2 activity. The Journal of Cell Biology. 2009;185(4):657-71.

PATENT
Attorney Docket No.: 14002.6004-00000 49. Shen J, Frye M, Lee BL, Reinardy JL, Mcclung JM, Ding K, Kojima M, Xia H, Seidel C, Silva RLE, et al. Targeting ve-ptp activates t1e2 and stabilizes the ocular vasculature. J
Clin Invest. 2014;124(10):4564-76.
50. Campochiaro PA, Khanani A, Singer M, Patel S, Boyer D, Dugel P, Kherani S, Withers B, Gambino L, Peters K, et al. Enhanced benefit in diabetic macular edema from akb-9778 tie2 activation combined with vascular endothelial growth factor suppression.
Ophthalmology. 2016;123(8):1722-30.
51. Kenig-Kozlovsky Y, Scott RP, Onay T, Carota IA, Thomson BR, Gil HJ, Ramirez V, Yamaguchi S, Tanna CE, Heinen S, et al. Ascending vasa recta are angiopoietin/tie2-dependent lymphatic-like vessels. J Am Soc Nephrol. 2017.
52. Shibuya H, Watanabe R, Maeno A, Ichimura K, Tamura M, Wakana S, Shiroishi T, Ohba K, Takeda K, Tomita H, et al. Melanocytes contribute to the vasculature of the choroid.
Genes Genet Syst. 2018;advpub( 53. Snedeker J, Schock EN, Struve JN, Chang OF, Cionni M, Tran PV, Brugmann SA, and Stottmann RW. Unique spatiotemporal requirements for intraflagellar transport genes during forebrain development. PLoS One. 2017;12(3):e0173258.
54. Gage PJ, Rhoades W, Prucka SK, and Hjalt T. Fate maps of neural crest and mesoderm in the mammalian eye. Invest Ophthalmol Vis ScL 2005;46(11):4200-8.
55. Dumont DJ, Gradwohl G, Fong GH, Puri MC, Gertsenstein M, Auerbach A, and Breitman ML. Dominant-negative and targeted null mutations in the endothelial receptor tyrosine kinase, tek, reveal a critical role in vasculogenesis of the embryo.
Genes Dev.
1994;8(16):1897-909.
56. Etchevers HC, Vincent C, Le Douarin NM, and Couly GF. The cephalic neural crest provides pericytes and smooth muscle cells to all blood vessels of the face and forebrain. Development. 2001;128(7):1059-68.
57. Zhou BO, Ding L, and Morrison SJ. Hematopoietic stem and progenitor cells regulate the regeneration of their niche by secreting angiopoietin-1. Elife. 2015;4(e05521.
58. Kim J, Park D-Y, Bae H, Park DY, Kim D, Lee C-K, Song S, Chung T-Y, Lim DH, Kubota Y, et al. Impaired angiopoietin/tie2 signaling compromises schlemm's canal integrity and induces glaucoma. J Clin Invest. 2017;127(10):3877-96.
59. Chu M, Li T, Shen B, Cao X, Zhong H, Zhang L, Zhou F, Ma W, Jiang H, and Xie P.
Angiopoietin receptor tie2 is required for vein specification and maintenance via regulating coup-tfii. Elife. 2016;5(e21032.
60. Baba T, Grebe R, Hasegawa T, Bhutto I, Merges C, Mcleod DS, and Lutty GA.
Maturation of the fetal human choriocapillaris. Invest Ophthalmol Vis Sci.
2009;50(7):3503-11.
61. Chu M, Li T, Shen B, Cao X, Zhong H, Zhang L, Zhou F, Ma W, Jiang H, Xie P, et al.
Angiopoietin receptor tie2 is required for vein specification and maintenance via regulating coup-thi. eLife. 2016;5(e21032.
62. Akkaya S. Spectrum of pachychoroid diseases. Int Ophthalmol.
2018;38(5):2239-46.
63. Jeansson M, Gawlik A, Anderson G, Li C, Kerjaschki D, Henkelman M, and Quaggin SE.
Angiopoietin-1 is essential in mouse vasculature during development and in response to injury. J Clin Invest. 2011;121(6):2278-89.

PATENT
Attorney Docket No.: 14002.6004-00000 64. Thomson Br. CI, Souma T., Kizhatil K., Feng L., Liu X., John Sw., Young TI., Quaggin., Se. Defects in angiopoietin-tie2 signaling lead to dose-dependent glaucoma in mice ARVO. Seattle, WA; May 5, 2016, 2016.
65. Mcmenamin PG. Optimal methods for preparation and immunostaining of iris, ciliary body, and choroidal wholemounts. Invest Ophthalmol Vis ScL 2000;41(10):3043-8.
66. Terasaki H, Miyake Y, Suzuki T, Nakamura M, and Nagasaka T. Polypoidal choroidal vasculopathy treated with macular translocation: Clinical pathological correlation. Br J
Ophthalmol. 2002;86(3):321-7.
67. Thurston G, Rudge JS, loffe E, Zhou H, Ross L, Croll SD, Glazer N, Holash J, Mcdonald DM, and Yancopoulos GD. Angiopoietin-1 protects the adult vasculature against plasma leakage. Nat Med. 2000;6(4):460-3.
68. Limaye N, Wouters V, Uebelhoer M, Tuominen M, Wirkkala R, Mulliken JB, Eklund L, Boon LM, and Vikkula M. Somatic mutations in angiopoietin receptor gene tek cause solitary and multiple sporadic venous malformations. Nat Genet. 2009;41(11:118-24.
69. Bhutto IA, Ogura S, Baldeosingh R, Mcleod DS, Lutty GA, and Edwards MM.
An acute injury model for the phenotypic characteristics of geographic atrophy. Invest Ophthalmol Vis Sci. 2018;59(4):AMD143-AMD51.
70. Keir LS, Firth R, Aponik L, Feitelberg D, Sakimoto S, Aguilar E, Welsh GI, Richards A, Usui Y, Satchell SC, et al. Vegf regulates local inhibitory complement proteins in the eye and kidney. J Clin Invest. 2017;127(11:199-214.
71. Mullins RF, Dewald AD, Streb LM, Wang K, Kuehn MH, and Stone EM.
Elevated membrane attack complex in human choroid with high risk complement factor h genotypes. Exp Eye Res. 2011;93(4):565-7.
72. Clark SJ, Perveen R, Hakobyan S, Morgan BP, Sim RB, Bishop PN, and Day AJ.
Impaired binding of the age-related macular degeneration-associated complement factor h 402h allotype to bruch's membrane in human retina. The Journal of Biological Chemistry. 2010;285(39):30192-202.
73. Kannan R, and Hinton DR. Sodium iodate induced retinal degeneration:
New insights from an old model. Neural regeneration research. 2014;9(23):2044-5.
74. Zieger M, and Punzo C. Improved cell metabolism prolongs photoreceptor survival upon retinal-pigmented epithelium loss in the sodium iodate induced model of geographic atrophy. Oncotarget. 2016;7(9):9620-33.

Claims (44)

We claim:

1. A method of treating age-related macular degeneration (AMD) or PCV in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a Tie2 activator, optionally in combination with anti-VEGF therapy.

2. A method of treating AMD or PCV in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a VE-PTP
inhibitor, optionally in combination with anti-VEGF therapy.

3. A method of improving vision in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a Tie2 activator and/or a VE-PTP inhibitor, optionally in combination with anti-VEGF
therapy, wherein the subject has AMD, preferably variants of choroid polypoid vasculopathy, geographic atrophy associated with anti-VEGF therapy, and any other loss of choroid perfusion (e.g. diabetic eye disease).

4. A method of increasing and/or improving choriocapillaris vascularization in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a Tie2 activator, optionally in combination with anti-VEGF therapy, wherein choriocapillaris vascularization is increased and/or improved in the subject.

5. A method of increasing and/or improving choriocapillaris vascularization in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a VE-PTP inhibitor optionally in combination with anti-VEGF therapy, wherein choriocapillaris vascularization is increased and/or improved in the subject.

6. A method of reducing choriocapillaris dropout during anti-VEGF therapy in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a Tie2 activator optionally in combination with anti-VEGF therapy, wherein choriocapillaris dropout is reduced

7. A method of reducing choriocapillaris dropout during anti-VEGF therapy in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a VE-PTP inhibitor optionally in combination with anti-VEGF therapy, wherein choriocapillaris dropout is reduced.

8. A method of improving choroidal perfusion in a subject in need thereof having age-related macular degeneration (AMD), the method comprising administering to the subject a therapeutically effective amount of a Tie2 activator, wherein choroidal perfusion is increased; and optionally wherein the subject is being treated with anti-VEGF therapy.

9. A method of improving choroidal perfusion in a subject in need thereof having age-related macular degeneration (AMD), the method comprising administering to the subject a therapeutically effective amount of a VE-PTP
inhibitor, wherein choroidal perfusion is increased; and optionally wherein the subject is being treated with anti-VEGF therapy.

10.A method of protecting the choriocapillaris vasculature in a subject in need thereof having AMD, the method comprising administering to the subject a therapeutically effective amount of a Tie2 activator, wherein the choriocapillaris vasculature is protected; and optionally wherein the subject is being treated with anti-VEGF therapy.

11.A method of protecting the choriocapillaris vasculature in a subject in need thereof having AMD, the method comprising administering to the subject a therapeutically effective amount of a VE-PTP inhibitor, wherein the choriocapillaris vasculature is protected; and optionally wherein the subject is being treated with anti-VEGF therapy

12.The method of any one of claims 1 through 11, wherein the choriocapillaris is manipulated in the context of AMD.

13. The method of any one of claims 1 through 11, wherein the choriocapillaris is manipulated in the context of polypoidal choroidal vasculopathy (PCV).

14.The method of claim 13, wherein the PCV is pachychoroid vasculopathy.

15.The method of any one of claims 1 through 13, wherein the Tie2 activator is selected from recombinant angiopoietin, BowANG1, COMP-ANG1 , TSL1, Vasculotide, an Anti-Angiopoietin-2 Binding and Oligomerizing Antibody, an Anti-Tie2 Receptor Agonistic Antibody, an Anti-VE-PTP Antibody, a Small Molecule VE-PTP Inhibitor, and the like.

16.The method of claim 15, wherein the VE-PTP inhibitor is selected from the small molecule VE-PTP inhibitors as Tie2 activators described in the specification.

17.The method of any one of claims 1 through 16, wherein the Tie2 activator and/or the VE-PTP inhibitor are administered to the eye.

18.The method of any one of claims 1 through 17, wherein the anti-VEGF
therapy is selected from Aflibercept, Bevacizumab, Pegaptanib sodium, Ranibizumab, Brolucizumab, Conbercept, Ramucirumab, Faricimab ,Nesvacumab-Aflibercept, Designed ankyrin repeat proteins, Gene-therapy-targeting VEGF, and biosimilar versions thereof.

19.The method of claim 11, wherein the anti-VEGF therapy is administered to the eye.

20. A mouse carrying at least one angiopoietin 1 null allele and at least one wnt1-Cre allele.

21.The use of a therapeutically effective amount of a Tie2 activator, optionally in combination with anti-VEGF therapy, for treating AMD or PCV in a subject in need thereof.

22.The use of a therapeutically effective amount of a Tie2 activator for treating AMD or PCV in a subject in need thereof.

23.The use of a therapeutically effective amount of a VE-PTP inhibitor, optionally in combination with anti-VEGF therapy, for treating AMD or PCV in a subject in need thereof.

24.The use of a therapeutically effective amount of a VE-PTP inhibitor for treating AMD or PCV in a subject in need thereof.

25.The use of a therapeutically effective amount of a Tie2 activator and/or a VE-PTP inhibitor, optionally in combination with anti-VEGF therapy, for improving vision in a subject having any one or more of a group of choriocapillaris disorders comprising AMD, PCV, variants of choroid polypoid vasculopathy, geographic atrophy associated with anti-VEGF therapy, and any other loss of choroid perfusion (e.g. diabetic eye disease).

26. The use of a therapeutically effective amount of a Tie2 activator and/or a VE-PTP inhibitor for improving vision in a subject having any one or more of a group of choriocapillaris disorders comprising AMD, PCV, variants of choroid polypoid vasculopathy, geographic atrophy associated with anti-VEGF
therapy, and any other loss of choroid perfusion (e.g. diabetic eye disease).

27.The use of a therapeutically effective amount of a Tie2 activator, optionally in combination with anti-VEGF therapy, for increasing and/or improving choriocapillaris vascularization in a subject in need thereof.

28.The use of a therapeutically effective amount of a Tie2 activator for increasing and/or improving choriocapillaris vascularization in a subject in need thereof.

29.The use of a therapeutically effective amount of a VE-PTP inhibitor, optionally in combination with anti-VEGF therapy, for increasing and/or improving choriocapillaris vascularization in a subject in need thereof.

30.The use of a therapeutically effective amount of a VE-PTP inhibitor for increasing and/or improving choriocapillaris vascularization in a subject in need thereof.

31.The use of a therapeutically effective amount of a Tie2 activator for reducing choriocapillaris dropout during anti-VEGF therapy in a subject in need thereof.

32.The use of a therapeutically effective amount of a VE-PTP inhibitor for reducing choriocapillaris dropout during anti-VEGF therapy in a subject in need thereof.

33.The use of a therapeutically effective amount of a Tie2 activator, optionally in combination with anti-VEGF therapy, for improving choroidal perfusion in a subject in need thereof having AMD.

34.The use of a therapeutically effective amount of a Tie2 activator for improving choroidal perfusion in a subject in need thereof having AMD.

35.The use of a therapeutically effective amount of a VE-PTP inhibitor, optionally in combination with anti-VEGF therapy, for improving choroidal perfusion in a subject in need thereof having AMD.

36.The use of a therapeutically effective amount of a VE-PTP inhibitor for improving choroidal perfusion in a subject in need thereof having AMD.

37.The use of a therapeutically effective amount of a Tie2 activator, optionally in combination with anti-VEGF therapy, for protecting the choriocapillaris vasculature in a subject in need thereof having AMD.

38.The use of a therapeutically effective amount of a Tie2 activator for protecting the choriocapillaris vasculature in a subject in need thereof having AMD.

39.The use of a therapeutically effective amount of a VE-PTP inhibitor, optionally in combination with anti-VEGF therapy, for protecting the choriocapillaris vasculature in a subject in need thereof having AMD.

40.The use of a therapeutically effective amount of a VE-PTP inhibitor protecting the choriocapillaris vasculature in a subject in need thereof having AMD.

41.The use in any one of claims 21 through 40, wherein the choriocapillaris is manipulated in the context of one or more choriocapillaris disorders comprising AMD, PCV, pachychoroid vasculopathy, variants of choroid polypoid vasculopathy, geographic atrophy associated with anti-VEGF
therapy, and any other loss of choroid perfusion (e.g. diabetic eye disease)..

42.The use in any one of claims 21 through 41, wherein the Tie2 activator is selected from recombinant angiopoietin, BowAng1, COMP-Ang1 , TSL1, Vasculotide, an Anti-Angiopoietin-2 Binding and Oligomerizing Antibody, an Anti-Tie2 Receptor Agonistic Antibody, an Anti-VE-PTP Antibody, a Small Molecule VE-PTP Inhibitor, and the like.

43.The use in any one of claims 21 through 41, wherein the VE-PTP inhibitor is selected from the small molecule VE-PTP inhibitors as Tie2 activators described in the specification.

44.The use in any one of claims 21 through 41, wherein the anti-VEGF therapy is selected from Aflibercept, Bevacizumab, Pegaptanib sodium, Ranibizumab, Brolucizumab, Conbercept, Ramucirumab, Faricimab ,Nesvacumab-Aflibercept, Designed ankyrin repeat proteins, Gene-therapy-targeting VEGF, and biosimilar versions thereof.