WO2023284380A1 - Application clinique de cellules en tant que vecteurs pour thérapie génique - Google Patents
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- WO2023284380A1 WO2023284380A1 PCT/CN2022/091281 CN2022091281W WO2023284380A1 WO 2023284380 A1 WO2023284380 A1 WO 2023284380A1 CN 2022091281 W CN2022091281 W CN 2022091281W WO 2023284380 A1 WO2023284380 A1 WO 2023284380A1
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- cell therapy
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- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
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Definitions
- the invention belongs to the field of cell therapy and relates to the clinical application of cells as gene therapy carriers.
- Gene therapy refers to the introduction of exogenous normal genes into appropriate recipient cells of patients through gene transfer technology, so that the products produced by exogenous genes can treat certain diseases to correct or compensate for diseases caused by defects and abnormal genes , in order to achieve the purpose of treatment.
- it can be divided into gene correction and gene replacement, that is, to correct the abnormal sequence of the defective gene, and to repair the defective gene accurately in situ without any other changes in the genome.
- the other type is gene augmentation and gene inactivation, which do not remove abnormal genes, but introduce foreign genes to make them express normal products, thereby compensating for the functions of defective genes, etc.; or specifically blocking certain The translation or transcription of genes to achieve the suppression of certain abnormal gene expression.
- the introduced gene can be mRNA, miRNA, ncRNA, shRNA, gRNA, etc.
- exosomes are used as the primary carrier to load mRNA, miRNA, ncRNA, shRNA, gRNA, etc. required for treatment.
- Use autologous or allogeneic adult cells with high clinical safety or adult cell precursor cells or stem cells with low immune origin, such as umbilical cord-derived, adipose-derived, bone marrow-derived mesenchymal stem cells (MSC), dental pulp stem cells (TpSC), myelin sheath Precursor cells (OPCs) etc. are used as secondary carriers to produce specific exosomes.
- the above cells are locally injected into the disease site or administered systemically through blood and lymphatic channels such as veins. Then adult cells or adult precursor cells are enriched around the disease through the mechanism of homing to the disease, and continuously produce and release exosomes. Exosomes enter target cells through specific targeting to achieve the introduction of therapeutic genes and achieve the purpose of treatment. Because the cells have a certain survival period in the body, they are finally cleared by the body's immune system to achieve safety. During the survival period, the cells can continuously produce exosomes, reaching an effective concentration in the local area of action without increasing the overall blood drug concentration of the body, while ensuring that the action lasts for a certain period of time.
- the present invention provides a cell therapy comprising administering therapeutic cells capable of secreting extracellular vesicles or a cell therapy agent comprising the same to a person in need.
- the therapeutic cells that secrete extracellular vesicles are derived from plants, microorganisms, animals, and humans.
- therapeutic cells that secrete extracellular vesicles are derived from humans.
- the therapeutic cells secreting extracellular vesicles include mature somatic cells or precursor cells of mature somatic cells.
- the precursor cells of the mature somatic cells include stem cells.
- the stem cells include totipotent stem cells, pluripotent stem cells, and unipotent stem cells.
- cells of origin for therapeutically useful cells capable of secreting extracellular vesicles mentioned in the present invention include, but are not limited to, primary cells, cell lines, cells present in multicellular organisms, or substantially any other type of cell source .
- Cells of the invention include cells that produce extracellular vesicles in vivo.
- Cells according to the invention can be selected from a wide range of cells and cell lines, such as mesenchymal stem cells, dental pulp stem cells or stromal cells (which can be obtained from, for example, bone marrow, adipose tissue, Wharton's jelly, perinatal tissue , placenta, dental buds, umbilical cord blood, skin tissue, etc.), fibroblasts, amnion cells and more specifically amnion epithelial cells optionally expressing various early markers, myeloid suppressor cells, M2 polarized macrophages cells, adipocytes, endothelial cells, fibroblasts, etc.
- mesenchymal stem cells such as mesenchymal stem cells, dental pulp stem cells or stromal cells (which can be obtained from, for example, bone marrow, adipose tissue, Wharton's jelly, perinatal tissue , placenta, dental buds, umbilical cord blood, skin tissue, etc.), fibroblasts, amn
- Cell lines of particular interest include human umbilical cord endothelial cells (HUVEC), human embryonic kidney (HEK) cells, endothelial cell lines such as microvascular endothelial cells or lymphatic endothelial cells, erythrocytes, erythroid progenitors, chondrocytes, MSCs of various origins, amnion cells, amnion epithelial (AE) cells, any cells obtained by amniocentesis or from placenta, airway or alveolar epithelial cells, fibroblasts, endothelial cells, etc.
- HEVEC human umbilical cord endothelial cells
- HEK human embryonic kidney
- endothelial cell lines such as microvascular endothelial cells or lymphatic endothelial cells
- erythrocytes erythroid progenitors
- chondrocytes chondrocytes
- MSCs of various origins amnion cells
- extracellular vesicles can be derived from essentially any cellular source, whether primary or immortalized cell lines.
- Extracellular vesicle-derived cells can be any embryonic, fetal, and adult somatic stem cell type, including induced pluripotent stem cells (iPSCs) and other stem cells derived by any method.
- iPSCs induced pluripotent stem cells
- the cells may be allogeneic, autologous, or even xenogeneic in nature to the patient to be treated, ie the cells may be from the patient himself or from an unrelated, matched or mismatched donor.
- extracellular vesicles include exosomes, vesicles, microvesicles, microparticles, endosome-derived vesicles, multivesicular bodies, apoptotic bodies, and combinations thereof.
- extracellular vesicles are exosomes. The same applies to the following.
- extracellular vesicles contain a therapeutic substance or a test substance for treating a disease suffered by a person in need thereof.
- the extracellular vesicle also includes a recognition motif for an RNA-binding polypeptide or an RNA-binding polypeptide that directs the therapeutic substance or detection substance into the extracellular vesicle.
- the recognition motif of the RNA-binding polypeptide is linked to the therapeutic substance or detection substance.
- the recognition motif of the RNA-binding polypeptide is directly or indirectly linked to the therapeutic substance or detection substance.
- RNA-binding polypeptide recognizes RNA through the recognition motif of the RNA-binding polypeptide.
- RNA-binding polypeptide includes MS2 protein, hnRNPA2B1 protein or extracellular vesicle polypeptide.
- RNA-binding polypeptide includes extracellular vesicle polypeptide and MS2 protein, and the extracellular vesicle polypeptide is linked to MS2 protein.
- the C-terminal or N-terminal of the extracellular vesicle polypeptide is connected with MS2 protein.
- the C-terminus of the extracellular vesicle polypeptide is connected with MS2 protein.
- extracellular vesicle polypeptides include extracellular vesicle membrane proteins or fragments thereof, proteins in extracellular vesicles or fragments thereof.
- the extracellular vesicle polypeptide includes the following proteins or fragments thereof: CD9, CD53, CD63, CD81, CD54, CD50, FLOT1, FLOT2, CD49d, CD71, CD133, CD138, CD235a, ALIX, AARDC1, Syntenin-1, Syntenin-2, Lamp2b, TSPAN8, syndecan-1, syndecan-2, syndecan-3, syndecan-4, TSPAN14, CD37, CD82, CD151, CD231, CD102, NOTCH1, NOTCH2, NOTCH3, NOTCH4, DLL1, DLL4, JAG1, JAG2, CD49d/ITGA4, ITGB5, ITGB6, ITGB7, CD11a, CD11b, CD11c, CD18/ITGB2, CD41, CD49b, CD49c, CD49e, CD51, CD61, CD104, Fc receptors, interleukin receptors, immunoglobulins, MHC- I or MHC-II components, CD2, CD3 ⁇ , CD3 ⁇ , CD13,
- the recognition motif of the RNA-binding polypeptide includes the following sequence: G-X-Y-G, wherein X is G, A, U, and Y is A, U.
- the recognition motif of the RNA-binding polypeptide includes the following sequence: M-G-X-Y-G, wherein, M is A, U; X is G, A, U, and Y is A, U.
- the recognition motif of the RNA-binding polypeptide includes the following sequence: N-M-G-X-Y-G, wherein, M is A, U; N is A, C, G, U; X is G, A, U, and Y is A, U.
- the recognition motif of the RNA-binding polypeptide includes the following sequence: N-M-G-X-Y-G, wherein, M is A, C, G, U; N is A, C, G, U; X is G, A, U, and Y is A, U.
- the recognition motif of the RNA-binding polypeptide includes the following sequence: L-N-M-G-X-Y-G, wherein, M is A, C, G, U; N is A, C, G, U; L is A, C, G, U; X is G, A, U, Y is A, U.
- the recognition motif of the RNA-binding polypeptide includes the sequence shown in SEQ ID NO.8.
- the above-mentioned therapeutic substance of the present invention changes the phenotype and physiological state of diseased cells in the body of a person in need.
- the aforementioned therapeutic substances of the present invention include polynucleotides, proteins, polypeptides, and small molecules.
- polynucleotides include coding RNA, non-coding RNA, and DNA.
- non-coding RNA includes ncRNA, shRNA, siRNA, miRNA, gRNA.
- polynucleotides, proteins, polypeptides, and small molecules of the present invention are contained or not contained in naturally occurring extracellular vesicles.
- polynucleotides, proteins, polypeptides, and small molecules of the present invention are not contained in naturally occurring extracellular vesicles.
- Therapeutic proteins that can be used in the present invention include the following: antibodies, intrabodies, single chain variable fragments (scFv), affibodies, bispecific and multispecific antibodies or conjugates, receptors, ligands , enzymes for e.g.
- enzyme replacement therapy or gene editing tumor suppressors, viral or bacterial inhibitors, cellular component proteins, DNA and/or RNA binding proteins, DNA repair inhibitors, nucleases, proteases, integrases, transcription Factors, growth factors, apoptosis inhibitors and inducers, toxins (such as Pseudomonas exotoxin), structural proteins, neurotrophic factors (such as NT3/4), brain-derived neurotrophic factor (BDNF), and nerve growth factors (NGF) and its individual subunits (such as 2.5S ⁇ subunit), ion channels, membrane transporters, protein homeostasis factors, proteins involved in cell signaling, translation and transcription-related proteins, nucleotide-binding proteins, protein-binding proteins , lipid-binding proteins, glycosaminoglycans (GAG) and GAG-binding proteins, metabolic proteins, cellular stress regulatory proteins, inflammation and immune system regulatory proteins, mitochondrial proteins, and heat shock proteins, etc.
- toxins such as Pseudom
- the detection substances include fluorescent labels, colorimetric labels, photochromic compounds, magnetic particles or other chemical labels.
- the detection substance can be biotin or His tag.
- the fluorescent label can be a fluorophore.
- the extracellular vesicle of the present invention also includes a targeting polypeptide, and the targeting polypeptide recognizes a target cell membrane protein.
- the targeting polypeptide includes proteins, peptides, single-chain antibodies or any other derivatives of antibodies.
- targeting polypeptide is linked to extracellular vesicle membrane protein or its transmembrane domain or membrane-associated domain.
- the sequential manner may be direct connection, or various linkers, release domains or release sites, cleavage sites or cleavage domains may be used to connect and/or attach to each other.
- a cleavage linker is introduced such that it is possible to cleave (eg, by enzymatic activity) the cleavage linker and thereby separate the two ligated parts.
- Suitable examples of cleavage linkers are TEV linkers or SUMO linkers, which can be cleaved by two different types of proteases, respectively.
- the release domain enables the release of the therapeutic substance once it has been loaded into extracellular vesicles such as exosomes.
- a suitable example of such a release linker is an intron.
- Suitable extracellular vesicle membrane proteins or their transmembrane domains or membrane-associated domains may be selected from the group comprising: CD63, CD81, CD9, CD82, CD44, CD47, CD55, LAMP2B, ICAM, integrins, ARRDC1, Annexin, and any other extracellular vesicle polypeptide, and any combination, derivative, domain or region thereof.
- one of the methods for obtaining therapeutic cells that secrete extracellular vesicles includes the following steps:
- step 2) contacting the extracellular vesicles obtained in step 1) with cells;
- step 2) Cultivate and purify the cells in step 2) to obtain cells that secrete extracellular vesicles containing therapeutic substances or test substances, and obtain therapeutic cells that secrete extracellular vesicles.
- Polynucleotides can be introduced directly into exosomes or other vesicular structures described herein by using any suitable technique, examples of which include, but are not limited to, electroporation, incubation, cell activation and transfection, lipotransfer transfection, lipid delivery, liposome delivery, polymer transfection, polymer delivery, delivery by peptides (i.e. but not limited to cationic peptides, amphiphilic peptides, cell penetrating peptides), calcium or magnesium precipitation and ionic precipitation ( Also known as DNA-calcium phosphate precipitation).
- peptides i.e. but not limited to cationic peptides, amphiphilic peptides, cell penetrating peptides
- calcium or magnesium precipitation and ionic precipitation also known as DNA-calcium phosphate precipitation.
- one of the two methods for obtaining therapeutic cells that secrete extracellular vesicles includes the following steps:
- the step of introducing it into cells that secrete extracellular vesicles includes;
- RNA polynucleotide comprising the aforementioned RNA-binding polypeptide recognition motif into a cell
- Step i) and step ii) are in no particular order.
- the step of introducing it into cells that secrete extracellular vesicles includes;
- Step I) and step I) are in no particular order.
- Extracellular vesicle-producing cells can be genetically modified with at least one polynucleotide construct using essentially any non-viral or viral method for introducing polynucleotides into cells.
- a polynucleotide can be introduced into an extracellular vesicle-producing cell using essentially any non-viral or viral method for introducing a polynucleotide into a cell.
- Suitable methods for introducing polynucleotides include transfection using polycations such as PEI, lipid-based transfection reagents such as liposomes (RTM), lentiviral transduction, CRISPR-Cas guided insertion , Flp-In system, transposon system, electroporation, DEAE-dextran transfection and calcium phosphate transfection.
- polycations such as PEI
- lipid-based transfection reagents such as liposomes (RTM)
- lentiviral transduction such as liposomes (RTM)
- CRISPR-Cas guided insertion CRISPR-Cas guided insertion
- Flp-In system Flp-In system
- transposon system transposon system
- electroporation DEAE-dextran transfection and calcium phosphate transfection.
- DEAE-dextran transfection calcium phosphate transfection.
- linear DNA polynucleotide or mRNA linear DNA polynucleotide or mRNA
- desired level of compliance and control production of extracellular vesicles can be achieved using techniques well known in the field of cell line development, including hTERT-mediated immortalization, transcription factor immortalization, E1/E2 immortalization, or other virus-mediated immortalization techniques Immortalization of cells to generate stable cell lines.
- the cell therapeutic agent of the present invention comprises the therapeutic cells and a pharmaceutically acceptable carrier.
- the therapeutic cells that secrete extracellular vesicles can be formulated in a suitable form together with a carrier that is a pharmaceutically acceptable carrier commonly used in cell therapy. Therefore, the above-mentioned cell therapy agent of the present invention comprises therapeutic cells secreting extracellular vesicles and a pharmaceutically acceptable carrier.
- pharmaceutically acceptable refers to a composition that is physiologically acceptable and generally does not cause allergic reactions such as gastrointestinal disorders, dizziness, or similar reactions when administered to humans.
- pharmaceutically acceptable carriers include water, suitable oils, physiological saline, water-soluble glucose, ethylene glycol, and other parenteral administration carriers, and may further include stabilizers and preservatives.
- Suitable stabilizers are antioxidants such as sodium bisulfite, sodium sulfite or ascorbic acid.
- Suitable preservatives are benzalkonium chloride, methyl or propyl paraben, chlorobutanol.
- the cell therapy agent of the present invention is usually used in the form of parenteral preparations such as injections.
- carriers that can be used in parenteral preparations include aqueous carriers such as physiological saline, isotonic solutions containing glucose, D-sorbitol, and the like.
- the injections of the present invention include injections, such as physiological saline, lactated Ringer's solution, compound electrolyte injection, 5% glucose injection, 20% HSA injection, succinylated gelatin injection, succinylated gelatin MIX injection, MZJ Injection 1, MZJ Injection 2, MZJ Injection 3, Human Serum Protein Injection, Bomaili A, Potassium Chloride Injection, Magnesium Sulfate Injection, Sodium Bicarbonate Injection, Glucose Sodium Chloride Injection, Compound sodium chloride injection (Ringer's solution), dextran 20 glucose injection (small molecule), amino acid injection, hydroxyethyl starch 40 sodium chloride injection, hydroxyethyl starch 40 sodium chloride injection, hydroxy Ethyl Starch 40 Sodium Chloride Injection, Low Molecular Weight Heparin Calcium for Injection, Heparin Sodium Injection, Coenzyme A for Injection, Cytidine Triphosphate Disodium, Lysine Hydro
- the injection contains an isotonic or hypertonic solution; preferably, the solution is selected from NaCl injection (such as 0.9% to 2.7% NaCl injection), glucose injection (such as 4% to 5% glucose injection), Sodium lactate Ringer injection, compound electrolyte injection, HSA injection (eg 10%-20% HSA injection), succinylated gelatin injection (eg 4%-5% succinylated gelatin injection) and any combination thereof.
- NaCl injection such as 0.9% to 2.7% NaCl injection
- glucose injection such as 4% to 5% glucose injection
- Sodium lactate Ringer injection compound electrolyte injection
- HSA injection eg 10%-20% HSA injection
- succinylated gelatin injection eg 4%-5% succinylated gelatin injection
- the cell therapy agent of the present invention can also contain one or more injection additives in addition to the injection, for example selected from solubilizers, wetting agents, emulsifiers, buffers, suspending agents, chelating agents, antioxidants, pH Antimicrobial agents, local anesthetics, isotonicity regulators, fillers, protective agents and any combination thereof.
- injection additives for example selected from solubilizers, wetting agents, emulsifiers, buffers, suspending agents, chelating agents, antioxidants, pH Antimicrobial agents, local anesthetics, isotonicity regulators, fillers, protective agents and any combination thereof.
- the cell therapeutic agent is a mixture of the therapeutic cells and physiological saline.
- the cell therapy agent is an intravenous injection.
- the dosage of the cell therapy agent is positively correlated with the body weight of the subject.
- the administration method of the therapeutic agent is:
- the therapeutic cells of each therapeutic dose are dissolved in 100 ml of physiological saline; 0.1-0.2 ml of the cell therapy agent is intravenously injected at a rate of 60 drops per minute.
- the cell therapy agent also includes any one or more of the following functional components:
- the functional components include serum substitutes, non-essential amino acids, glutamine, stabilized dipeptides of L-alanyl-L-glutamine, growth factors and any combination thereof.
- the cell therapy agent of the present invention can be administered via any conventional route so long as it reaches the target tissue.
- cellular therapeutics can be administered by any device capable of delivering the active ingredient to target cells.
- the cell therapy agent of the present invention is a parenteral preparation, for example, local administration such as intravascular administration (preferably intravenous administration), intraperitoneal administration, enteral administration, subcutaneous administration, subcapsular administration, etc. Medicine (capsule means membrane tissue covering various organs), intrathecal administration.
- the cell therapy agent of the present invention is administered to a living body by intravenous administration.
- the cellular therapeutic agents of the present invention may be administered in a therapeutically effective amount, as used herein, the phrase "therapeutically effective amount” means an amount sufficient to treat a disease with a reasonable benefit/risk ratio applicable to any medical treatment. Effective dosage levels may vary depending on a variety of factors including the type, severity, age and sex of the individual, drug activity, drug sensitivity, time of administration, route of administration, discharge ratio, Treatment period and co-administered drugs and other factors well known in the medical art.
- the dose of the cell therapy agent is not less than 1 ⁇ 10 4 cells/mL (for example, not less than 1 ⁇ 10 4 cells/ml, not less than 3 ⁇ 10 4 cells/ml, Not less than 5 ⁇ 10 4 /ml, not less than 7 ⁇ 10 4 /ml, not less than 1 ⁇ 10 5 /ml, not less than 3 ⁇ 10 5 /ml, not less than 5 ⁇ 10 5 pieces/ml, not less than 7 ⁇ 10 5 pieces/ml, not less than 1 ⁇ 10 6 pieces/ml, not less than 3 ⁇ 10 6 pieces/ml, not less than 5 ⁇ 10 6 pieces/ml, no Less than 7 ⁇ 10 6 /ml, not less than 1 ⁇ 10 6 /ml, not less than 3 ⁇ 10 6 /ml, not less than 5 ⁇ 10 6 /ml, not less than 7 ⁇ 10 6 pcs/ml, not less than 1 ⁇ 10 6 pcs/ml, not less than 3 ⁇ 10 6 pcs/ml, not
- the dose of the cell therapy agent is not less than 1 ⁇ 10 3 cells/kg (for example, not less than 1 ⁇ 10 3 cells/kg, not less than 3 ⁇ 10 3 cells/kg, Not less than 5 ⁇ 10 3 pieces/kg, not less than 7 ⁇ 10 3 pieces/kg, not less than 1 ⁇ 10 4 pieces/kg, not less than 3 ⁇ 10 4 pieces/kg, not less than 5 ⁇ 10 4 pieces/kg, not less than 7 ⁇ 10 4 pieces/kg, not less than 1 ⁇ 10 5 pieces/kg, not less than 3 ⁇ 10 5 pieces/kg, not less than 5 ⁇ 10 5 pieces/kg, no Less than 7 ⁇ 10 5 pieces/kg, not less than 1 ⁇ 10 6 pieces/kg, not less than 3 ⁇ 10 6 pieces/kg, not less than 5 ⁇ 10 6 pieces/kg, not less than 7 ⁇ 10 6 pieces/kg pieces/kg, not less than 1 ⁇ 107 pieces/kg, not less than 3 ⁇ 107 pieces/kg, not less than 5 ⁇ 107 pieces/kg, not less than 7 ⁇ 107 pieces/kg, not less Less
- the cellular therapeutics of the invention can be administered alone or in combination with other therapies. Co-administration of a therapeutic agent of the invention with other therapies can be performed simultaneously or sequentially. Single or multiple doses are possible. It is important to use the smallest possible amount sufficient to obtain maximum benefit without side effects, all factors considered.
- the diseases applicable to the cell therapy of the present invention include but not limited to: hereditary diseases, tumors, autoimmune diseases, nervous system diseases, cardiovascular diseases or gastrointestinal diseases.
- Non-limiting examples of diseases of the invention include: Crohn's disease, ulcerative colitis, ankylosing spondylitis, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, sarcoidosis, idiopathic pulmonary fibrosis psoriasis, tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS), interleukin-1 receptor antagonist deficiency (DIRA), endometriosis, autoimmune hepatitis, scleroderma, myositis , stroke, acute spinal cord injury, vasculitis, Guillain-Barré syndrome, acute myocardial infarction, acute respiratory distress syndrome (ARDS), sepsis, meningitis, encephalitis, liver failure, nonalcoholic steatohepatitis (NASH) , nonalcoholic fatty liver disease (NAFLD), renal failure, heart failure, or any acute or chronic organ failure and related underlying etiologie
- ALL acute lymphoblastic leukemia
- acute myeloid leukemia acute myeloid leukemia
- adrenocortical carcinoma AIDS-related cancer
- AIDS-related lymphoma anal cancer
- appendix cancer astrocytoma Cytoma, cerebellar or brain cancer
- basal cell carcinoma cholangiocarcinoma, bladder cancer, bone tumor, brainstem glioma, brain cancer, brain tumor (cerebellar astrocytoma, cerebral astrocytoma/malignant glioma, Ependymoma, medulloblastoma, supratentorial primitive neuroectodermal tumor, visual pathway hypothalamic glioma), breast cancer, bronchial adenoma/carcinoid, Burkitt lymphoma, carcinoid tumor (children, Gastrointestinal tract), unknown primary tumor, central nervous system lymphoma, cerebellar astrocytoma/gli
- the "person in need” mentioned herein is the subject to be treated, which can be any animal or human being.
- the subject is preferably a mammal, more preferably a human.
- the subject may be a non-human mammal, but is more preferably a human.
- the subject can be male or female.
- the subject can be a patient.
- Therapeutic use can be in humans or animals (veterinary use).
- Target cells as used herein depend on the disease to be treated.
- Fig. 1 shows the result graph of the infection efficiency of EGFP lentivirus once infected MSC cells
- Figure 2 shows the results of the infection efficiency of EGFP lentivirus once infected dental pulp stem cells
- Figure 3 shows the results of infection efficiency of MSC cells infected with EGFP lentivirus for three times
- Fig. 4 shows the infection efficiency result diagram of EGFP lentivirus infection of dental pulp stem cells for three times
- Figure 5 shows the result graph of infection efficiency after MSC passage three times
- Figure 6 shows the result graph of the infection efficiency of dental pulp stem cells after passage three times
- Figure 7 shows the statistical diagram of the ratio of EGFP mRNA in dental pulp stem cells and MSC cell exosomes to cytoplasm
- Figure 8 shows the statistical results of the expression levels of EGFP mRNA in various tissues and organs of animals after injection of dental pulp stem cells
- Figure 9 shows the statistical results of the expression levels of EGFP mRNA in various tissues and organs of animals after MSC injection
- Figure 10 shows a schematic diagram of the structure of the pLenti-EF1 ⁇ -Lamp2b-MS2 vector
- Figure 11 shows a schematic diagram of the structure of the pLenti-EF1 ⁇ -MS2-Neo vector
- Figure 12 shows a schematic diagram of the structure of the pLenti-EF1 ⁇ -RVG-Lamp2b-MS2 vector
- Figure 13 shows the fluorescence image after exosomes infect cells
- Figure 14 shows a schematic diagram of the structure of the pLKO.1-miR-151a-5p-puro lentiviral vector
- Figure 15 shows a schematic diagram of the structure of the pLKO.1-miR-155-5p-puro lentiviral vector
- Figure 16 shows a schematic diagram of the structure of the pLV-EF1a-HNRNPA2B1-IRES-Hygro lentiviral vector
- Figure 17 shows the expression level results of miR-151a-5p and miR-155-5p in exosomes
- Figure 18 shows the results of expression levels of miR-155-5p and its mutants in exosomes.
- the present disclosure includes all polynucleotide and amino acid sequences described herein. Every RNA sequence includes its DNA equivalent, and every DNA sequence includes its RNA equivalent. Complementary and antiparallel polynucleotide sequences are included. This disclosure encompasses every DNA and RNA sequence that encodes a polypeptide disclosed herein. The present disclosure includes polynucleotide consensus sequences and motifs.
- the backbone vector pCDH-MSCV-MCS-EF1-Puro was purchased from SBI (article number: CD710B-1);
- the lentiviral vector constructed in this example was named pCDH-MSCV-EGFP-T2A-CD63-MS2-EF1-Puro.
- the gene sequence is as follows:
- the medium used for MSC and dental pulp stem cells is the same, and the medium formula is shown in Table 1.
- 1Resuscitation Take out the frozen MSCs and dental pulp stem cells from the liquid nitrogen tank, place them in a 37°C water bath to thaw quickly, add 1ml MEM ⁇ medium to the cryopreservation tube to resuspend, centrifuge at 1300r/min for 5min, and remove the supernatant , resuspended with MEM ⁇ medium and plated in a 10cm cell culture dish, cultured at 37°C, 5% CO 2 .
- RNA Isolation Mini Kit Use the Cell Culture Media Exosome Purification and RNA Isolation Mini Kit (norgenbiotek, Cat. No.: Cat. 60700) to extract the exosomes in the above cell supernatant, and extract the total RNA, and take an appropriate amount of total RNA for reverse transcription.
- the reverse transcription kit is II Reverse Transcriptase (full gold, AH101-02), reverse transcription was performed according to the manufacturer's instructions.
- PCR SuperMix whole gold, AS111-11 was used for PCR, and the reaction system described in Table 3 was premixed.
- Reverse primer 5'-CTTGTAGTTGCCGTCGTCCTTGAA-3' (SEQ ID NO.7).
- the experimental group was administered at the rate of 2 million cells/kg body weight (resuspended cells were prepared with physiological saline), and the experimental group was reinfused with the same volume of normal saline.
- the main organs (heart, liver, spleen, lung, kidney, brain, testis, ovary, small intestine, stomach) were collected, total RNA was extracted, and the expression of EGFP mRNA in the organs was detected by qPCR.
- Fig. 9 After the injection of mesenchymal stem cells, the expression levels of EGFP mRNA in various tissues and organs of the animals at different time points are shown in Fig. 9 .
- autologous or allogeneic mature somatic cells or precursor cells of mature somatic cells are infected by lentivirus to load target therapeutic genes in exosomes, including mRNA, miRNA, ncRNA, shRNA, gRNA, etc.
- the cells are cultured for one generation and then infused intravenously into the body.
- the test found that the introduced gene can be detected in different tissues and organs in the animal body.
- the amount of EGFP-containing mRNA produced by dental pulp stem cells and MSCs at different time points was measured, which proved that using cells as carriers can continuously and effectively target cells. Delivery of the introduced gene.
- This embodiment involves two vectors, one vector (as shown in Figure 10) expresses proteins including Lamp2b (or PDGFT), and its N-terminus (inserted by the BsmBI restriction site) can express proteins including but not limited to recognizing neuronal cells RVG protein, or GE11 protein that recognizes EGFR receptors, or other specific single-chain antibodies, etc., its C-terminus expresses MS2 protein, which is used to recognize mRNA containing acaugaggaucacccaug (SEQ ID NO.8) sequence; another vector expresses mRNA containing For the mRNA of acaugaggaucacccaug sequence, take GFP as an example, as shown in Figure 11, GFP is inserted by BsiWI and NheI restriction sites, and can be replaced with other target genes or RNA sequences.
- Lamp2b or PDGFT
- N-terminus inserted by the BsmBI restriction site
- MS2 protein which is used to recognize mRNA containing acaugaggaucaccc
- the exosome membrane protein vector pLenti-EF1 ⁇ -Lamp2b-MS2 (nucleotide sequence shown in SEQ ID NO.9) is expressed.
- This vector can be used to package lentivirus and contains puromycin selection marker, vector Contains EF1 ⁇ promoter to promote the expression of Lamp2b-MS2 fusion protein.
- the N-terminal membrane signal of Lamp2b protein is designed with a BsmBI restriction site, which can be seamlessly connected to, for example, the RVG protein that recognizes neuron cells.
- the vector contains WPRE components, Can increase the corresponding protein expression.
- the target mRNA carrier containing the MS2 recognition sequence (acaugaggaucacccaug) (taking EGFP as an example, pLenti-EF1 ⁇ -EGFP-MS2-Neo carrier, the nucleotide sequence is shown in SEQ ID NO.10), which can be The mRNA sequence of other target genes can be connected into other target gene mRNA sequences for protein expression through BsiWI and NheI restriction sites.
- miRNA200cluster (miRNA200, miRNA200b, miRNA200c, miRNA141, miRNA429)
- the vector contains NeoR resistance gene
- G418 can be used for resistance screening
- the vector can also be used to package lentivirus.
- RVG protein vector containing the recognition of neuron cells as shown in Figure 12, pLenti-EF1 ⁇ -RVG-Lamp2b-MS2, the nucleotide sequence of RVG is shown in SEQ ID NO.11
- infect HEK293T Cells were screened with puromycin to obtain a stably transfected cell line (referred to as 293T-RVG-Lamp2b-MS2).
- step 2) Pick the monoclonal in step 2) and expand the culture of 293T-RVG-Lamp2b-MS2-EGFP cells, collect the supernatant, concentrate the exosomes, use the concentrated exosomes to infect the cells, and observe the fluorescence.
- the pLKO.1-puro plasmid (sigma, Cat. No. SHC001) is used as the backbone vector for miRNA expression, and the restriction sites are AgeI and EcoRI.
- hsa-miR-151a-5p is UCGAGGAGCUCACAGUCUAGU (SEQ ID NO: 12), GGAG sequence exists in hsa-miR-151a-5;
- hsa-miR-155-5p The sequence of hsa-miR-155-5p is UUAAUGCUAAUCGUGAUAGGGGUU (SEQ ID NO: 13), and there is no GGAG sequence in hsa-miR-155-5p.
- shRNA structural sequence of hsa-miR-151a-5p is:
- shRNA structural sequence of hsa-miR-155-5p is:
- HNRNPA2B1 Gene synthesis of the HNRNPA2B1 sequence (its nucleotide sequence is shown in SEQ ID NO: 16, and its amino acid sequence is shown in SEQ ID NO: 17), the synthesis company is Anhui General Biotechnology Co., Ltd., and the HNRNPA2B1 sequence is inserted into pLV-EF1a - Between EcoRI and Hpa1 of the IRES-Hygro plasmid, the vector is named pLV-EF1a-HNRNPA2B1-IRES-Hygro (the schematic diagram of the vector is shown in Figure 16).
- Cell inoculation inoculate 1.5 ⁇ 10 7 293T cells in a 10cm dish. Add 10ml of DMEM (Thermo Fisher Scientific, 11965084) medium containing 10% FBS (hyclone, SH30084.03), culture overnight at 37°C in a 5% CO 2 incubator, and transfect after 16-24 hours;
- DMEM Thermo Fisher Scientific, 11965084
- FBS hyclone, SH30084.03
- Transfection medium After 16-18 hours, remove the medium containing the transfection reagent, add 10ml of DMEM containing 10% FBS, 5% CO 2 , and continue to culture at 37°C (at this time, the cell supernatant will produce virus).
- the second virus harvest Harvest the cell supernatant, transfer it to a 50ml centrifuge tube, centrifuge at 3,000rpm for 10min, filter the supernatant with a 0.45 ⁇ m filter membrane, and store at 4°C. Cells were discarded after being treated with 10% disinfectant (84 disinfectant).
- Virus concentration filter the collected lentivirus components with a 0.45 ⁇ m filter to remove bacterial contamination, mix the filtered components with Lenti-XTM Concentrator (clonetech, 631232) at a volume ratio of 3:1, and gently invert to mix .
- exosome isolation reagent After centrifugation, remove the supernatant and resuspend with total exosome isolation reagent to obtain exosomes, which can be stored at 2-8 degrees for 1 week.
- the shRNA structural sequence of mutant 1 is:
- the shRNA structural sequence of mutant 2 is:
- the shRNA structural sequence of mutant 3 is:
- the shRNA structural sequence of mutant 4 is:
- the shRNA structural sequence of mutant 5 is:
- the shRNA structural sequence of mutant 6 is:
- the shRNA structural sequence of mutant 7 is:
- the shRNA structural sequence of mutant 8 is:
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Abstract
L'invention concerne une application clinique de cellules en tant que vecteurs pour la thérapie génique. Les exosomes sont utilisés en tant que vecteurs primaires pour charger des ARN nécessaires au traitement, des cellules somatiques matures autologues ou allogéniques ayant une innocuité clinique élevée ou des cellules précurseurs de cellules somatiques matures ayant une faible immunogénicité sont utilisées en tant que vecteurs secondaires pour charger des exosomes spécifiques, et les cellules sont injectées dans un corps pour un traitement. Selon le procédé de thérapie cellulaire, des cellules peuvent être enrichies autour d'une maladie, générer et libérer en continu des exosomes, et les exosomes entrent dans des cellules cibles au moyen d'une fonction de ciblage spécifique, de manière à obtenir l'objectif d'introduction de gènes thérapeutiques pour obtenir un traitement. Le procédé de thérapie cellulaire présente de bonnes perspectives d'application clinique en raison de son innocuité et de son efficacité.
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CN114874990A (zh) * | 2021-02-05 | 2022-08-09 | 中国科学院苏州纳米技术与纳米仿生研究所 | 一种功能化外泌体及其制备方法和应用 |
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