JP2012062312A - Agent for treatment of hunter syndrome - Google Patents

Agent for treatment of hunter syndrome Download PDF

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JP2012062312A
JP2012062312A JP2011186533A JP2011186533A JP2012062312A JP 2012062312 A JP2012062312 A JP 2012062312A JP 2011186533 A JP2011186533 A JP 2011186533A JP 2011186533 A JP2011186533 A JP 2011186533A JP 2012062312 A JP2012062312 A JP 2012062312A
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brain
hi2s
sulfatase
therapeutic agent
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Yoshikatsu Eto
義勝 衞藤
Takashi Higuchi
孝 樋口
Juya Ohashi
十也 大橋
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JCR Pharmaceuticals Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/46—Hydrolases (3)
    • A61K38/465—Hydrolases (3) acting on ester bonds (3.1), e.g. lipases, ribonucleases
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Y—ENZYMES
    • C12Y301/00—Hydrolases acting on ester bonds (3.1)
    • C12Y301/06—Sulfuric ester hydrolases (3.1.6)
    • C12Y301/06013—Iduronate-2-sulfatase (3.1.6.13)

Abstract

PROBLEM TO BE SOLVED: To provide a method for supplying human iduronate-2-sulphatase into the brain of a patient in order to prevent the progression of brain damage in patients with Hunter syndrome.SOLUTION: A treatment agent contains the human iduronate-2-sulphatase being administered into the brain of the patient with Hunter syndrome.

Description

本発明は，ハンター症候群の治療剤に関し，より詳しくは，ハンター症候群に伴う脳障害の進行を防止するためのヒトイズロン酸２−スルファターゼを含有する治療剤に関する。  The present invention relates to a therapeutic agent for Hunter syndrome, and more particularly to a therapeutic agent containing human iduronic acid 2-sulfatase for preventing progression of brain damage associated with Hunter syndrome.

ハンター症候群（ムコ多糖症ＩＩ型）は，イズロン酸２−スルファターゼ（Ｉ２Ｓ）の遺伝子変異を原因とする遺伝病であり，リソソーム病の一種である。Ｉ２Ｓは，グリコサミノグリカンに属するヘパラン硫酸及びデルマタン硫酸の硫酸エステル結合を加水分解する活性を有する。ハンター症候群の患者では，本酵素の遺伝子変異により，その基質であるヘパラン硫酸及びデルマタン硫酸の代謝異常が起こり，これらの不完全な分解産物が全身組織に蓄積し，その結果，骨格異常，心拡大等の諸症状を呈する。また，患者の尿中にヘパラン硫酸及びデルマタン硫酸が多く排出される。ハンター症候群には，臨床経過が比較的短く進行の速い重症型（ＩＩＡ型）と極めて経過の長い軽症型（ＩＩＢ型）がある。重症型（ＩＩＡ型）と軽症型（ＩＩＢ型）の２つ型は，Ｉ２Ｓ遺伝子の変異タイプの違いにより生じる。前者は予後不良で１５〜１６歳までに死亡する。  Hunter syndrome (mucopolysaccharidosis type II) is a genetic disease caused by a gene mutation of iduronic acid 2-sulfatase (I2S), and is a kind of lysosomal disease. I2S has an activity of hydrolyzing the sulfate ester bond of heparan sulfate and dermatan sulfate belonging to glycosaminoglycan. In patients with Hunter syndrome, metabolic mutations in the enzymes, heparan sulfate and dermatan sulfate, cause accumulation of these incomplete degradation products in systemic tissues, resulting in skeletal abnormalities and cardiac enlargement. Symptoms such as A large amount of heparan sulfate and dermatan sulfate is excreted in the patient's urine. Hunter syndrome includes a severe type (IIA type) with a relatively short clinical course and a rapid progression, and a mild type (IIB type) with a very long course. Two types, severe (type IIA) and mild (type IIB), are caused by differences in the mutation type of the I2S gene. The former has a poor prognosis and dies by the age of 15-16.

ハンター症候群の患者ではＩ２Ｓの活性が低いことは１９７０年代には既に知られており，本疾患がＩ２Ｓの先天的な欠損によるものであることは予想されていた。また，Ｉ２Ｓ遺伝子がＸ染色体上に存在することは，本疾患が伴性遺伝することから古くから予想されていたが，１９９０年に豪州のウィメンズアンドチルドレンズホスピタルのＨｏｐｗｏｏｄらのグループが本酵素をコードする遺伝子の単離に成功し，本酵素の変異がハンター症候群の原因であることをあらためて証明した（非特許文献１参照）。  It was already known in the 1970s that the activity of I2S was low in Hunter syndrome patients, and it was expected that this disease was due to a congenital deficiency of I2S. The presence of the I2S gene on the X chromosome has long been predicted because this disease is inherited, but in 1990, the group of Hopwood et al. Of Women's and Children's Hospital in Australia We succeeded in isolating the encoded gene and proved again that the mutation of this enzyme is the cause of Hunter syndrome (see Non-patent Document 1).

上述したように，ハンター症候群はＩ２Ｓの欠損に起因することが予想されたことから，１９７０年代にはハンター症候群患者に対する本酵素の補充による療法が開始されており，本酵素を発現するマクロファージの移植（非特許文献２参照）や正常血清の点滴注入による本酵素の補充（非特許文献３参照）が患者を対象に試みられた。その結果，これらの補充療法により，患者の症状改善までには至らなかったが，ヘパラン硫酸等の尿中***の減少が観察され，その有効性が示唆された。しかし酵素自体を補充する補充療法（酵素補充療法）は，必要量の酵素の確保が困難なこともあり実施はされていなかった。  As mentioned above, since Hunter syndrome was expected to be caused by I2S deficiency, therapy by supplementation of this enzyme for Hunter syndrome patients was started in the 1970s, and transplantation of macrophages expressing this enzyme was started. Replenishment of this enzyme by instillation of normal serum (see Non-Patent Document 2) and non-patent document 3 (see Non-Patent Document 3) has been attempted for patients. As a result, these replacement therapies did not improve the patient's symptoms, but a decrease in urinary excretion of heparan sulfate was observed, suggesting its effectiveness. However, replacement therapy that replaces the enzyme itself (enzyme replacement therapy) has not been implemented due to difficulties in securing the required amount of enzyme.

酵素補充療法を実施するためには，大量の酵素の確保が不可欠と考えられていたが，本酵素をコードする遺伝子が１９９０年に単離されたことは（非特許文献１参照），遺伝子組換え技術による本酵素の大量合成を可能とし，それによる酵素補充療法の道を拓くものとして大きな意義を有した。  In order to carry out enzyme replacement therapy, it was considered indispensable to secure a large amount of enzyme, but the gene encoding this enzyme was isolated in 1990 (see Non-Patent Document 1). It was of great significance as a means of synthesizing the enzyme in large quantities using a replacement technique and opening the way for enzyme replacement therapy.

現在，遺伝子組み換え技術により製造されたＩ２Ｓを有効成分として含有する製剤が日本で販売されているが，その用法用量は，１回体重１ｋｇあたり０．５ｍｇを週１回点滴静脈内投与することとなっている。  Currently, a preparation containing I2S produced by genetic engineering as an active ingredient is sold in Japan. The dosage is 0.5 mg / kg body weight once a week by intravenous infusion. It has become.

ハンター症候群は，知能障害を伴うことがあり，脳の萎縮，水頭症等の重篤な脳障害が観察されることもある。しかし，高分子物質のタンパク質であるＩ２Ｓは，静脈内投与した場合，血液脳関門により，ほとんど脳内に到達できない。従って，Ｉ２Ｓの点滴静脈内投与では，ハンター症候群患者の脳障害に対する有効な治療は期待できないという問題点があった。リソソーム病に伴う脳障害に対処するため，ハーラー症候群（ムコ多糖症Ｉ型）の患者の髄腔内にヒトα−Ｌ−イズロニダーゼを投与する方法（特許文献１参照），ニーマン−ピック病の患者の脳室内にヒト酸スフィンゴミエリナーゼを投与する方法（特許文献２参照）が報告されている。しかし，ハンター症候群患者の脳障害に対処する具体的な方法に関する報告はない。  Hunter syndrome may be associated with intellectual disability, and severe brain disorders such as brain atrophy and hydrocephalus may be observed. However, I2S, which is a high molecular weight protein, can hardly reach the brain due to the blood-brain barrier when administered intravenously. Therefore, the intravenous administration of I2S has a problem that an effective treatment for a brain disorder of a Hunter syndrome patient cannot be expected. A method of administering human α-L-iduronidase into the medullary cavity of a patient with Hurler's syndrome (mucopolysaccharidosis type I) in order to cope with a brain disorder associated with lysosomal disease (see Patent Document 1), a patient with Niemann-Pick disease A method of administering human acid sphingomyelinase into the cerebral ventricle (see Patent Document 2) has been reported. However, there are no reports on specific ways of dealing with brain damage in Hunter syndrome patients.

特表２００７−５０４１６６号公報Special table 2007-504166 特表２００９−５２５９６３号公報Special table 2009-525963

Ｗｉｌｓｏｎ ＰＪ ｅｔ ａｌ．，Ｐｒｏｃ Ｎａｔｌ Ａｃａｄ Ｓｃｉ ＵＳＡ（１９９０）８７，８５３１−５Wilson PJ et al. Proc Natl Acad Sci USA (1990) 87, 8531-5. Ｄｅａｎ ＭＦ ｅｔ ａｌ．，Ｊ Ｃｌｉｎ Ｉｎｖｅｓｔ．（１９７９）６３，１３８−４５Dean MF et al. , J Clin Invest. (1979) 63, 138-45 Ｂｒｏｗｎ ＦＲ ３▲ｒｄ▼ ｅｔ ａｌ．，Ａｍ Ｊ Ｍｅｄ Ｇｅｎｅｔ．（１９８２）１３，３０９−１８Brown FR 3 <rd> et al. , Am J Med Genet. (1982) 13, 309-18

上記背景の下で，本発明の目的は，ハンター症候群の患者の脳障害の進行を防止するためにヒトイズロン酸２−スルファターゼ（ｈＩ２Ｓ）を患者の脳内に供給する方法を提供することである。  In view of the above background, an object of the present invention is to provide a method of supplying human iduronic acid 2-sulfatase (hI2S) into a patient's brain to prevent progression of brain damage in a patient with Hunter syndrome.

上記目的に向けた研究において，本発明者らは，ｈＩ２Ｓを，Ｉ２Ｓ遺伝子を欠失するノックアウトマウス脳室内に投与することにより，脳内におけるＩ２Ｓ活性を上昇させ且つ維持できることを見出し，本発明を完成した。すなわち，本発明は以下を提供する。
（１）ヒトの脳室内に投与されることを特徴とする，ヒトイズロン酸２−スルファターゼを有効成分として含有する，ハンター症候群の治療剤。
（２）ハンター症候群が，脳障書を伴うものである，上記（１）に記載の治療剤。
（３）留置カニューレ，留置カテーテル，又は留置針を用いて投与される，上記（１）又は（２）に記載の治療剤。
（４）ヒトイズロン酸２−スルファターゼが，１回当たり１０〜８００μｇ／ｋｇ体重の量を３週〜２ヶ月毎に投与される，上記（１）〜（３）のいずれかに記載の治療剤。
（５）ヒトイズロン酸２−スルファターゼが，１回当たり１００〜６００μｇ／ｋｇ体重の量を３週毎に投与される，上記（１）〜（３）のいずれかに記載の治療剤。
（６）上記（１）〜（５）のいずれかに記載の治療剤と、該治療剤を投与するためのカテラン針とを含む、キット製剤。In a study aimed at the above purpose, the present inventors have found that by administering hI2S into the ventricle of the knockout mouse lacking the I2S gene, the I2S activity in the brain can be increased and maintained. completed. That is, the present invention provides the following.
(1) A therapeutic agent for Hunter syndrome comprising human iduronic acid 2-sulfatase as an active ingredient, which is administered into the human ventricle.
(2) The therapeutic agent according to (1) above, wherein the Hunter syndrome is accompanied by a encephalopathy book.
(3) The therapeutic agent according to (1) or (2) above, which is administered using an indwelling cannula, an indwelling catheter, or an indwelling needle.
(4) The therapeutic agent according to any one of (1) to (3) above, wherein human iduronic acid 2-sulfatase is administered at a dose of 10 to 800 μg / kg body weight every 3 weeks to 2 months.
(5) The therapeutic agent according to any one of (1) to (3) above, wherein human iduronic acid 2-sulfatase is administered at a dose of 100 to 600 μg / kg body weight every 3 weeks.
(6) A kit preparation comprising the therapeutic agent according to any one of (1) to (5) above and a catalan needle for administering the therapeutic agent.

本発明によれば，ヒトの脳室内にヒトイズロン酸２−スルファターゼを投与することにより，脳内のＩ２Ｓ活性を上昇させ且つ維持することができ，脳内に蓄積したヘパラン硫酸及びデルマタン硫酸を分解，排除できる。  According to the present invention, by administering human iduronic acid 2-sulfatase into the human ventricle, I2S activity in the brain can be increased and maintained, and heparan sulfate and dermatan sulfate accumulated in the brain are decomposed. Can be eliminated.

本発明において，「ヒトイズロン酸２−スルファターゼ」というときは，野生型のヒトイズロン酸２−スルファターゼのみならず，生物学的な活性を有する限り，ヒトイズロン酸２−スルファターゼを構成する１つ又は複数のアミノ酸残基を，置換，欠失，挿入させたヒトイズロン酸２−スルファターゼの類似物も含む。ｈＩ２Ｓも同義である。ヒトイズロン酸２−スルファターゼ（ｈＩ２Ｓ）は遺伝子組換え技術を用いて製造することができる。例えば，ｈＩ２Ｓをコードする遺伝子を発現ベクターに組み込み，これを用いて形質転換させた宿主細胞を培養することにより，培養液中又は宿主細胞内にｈＩ２Ｓが生産される。このとき宿主細胞として用いられる細胞には特に限定はないが，哺乳動物細胞，昆虫細胞，酵母が好適に用いられる。哺乳動物細胞を用いる場合，ヒト，マウス，ハムスター由来の細胞が好適であり，特にチャイニーズハムスター卵巣細胞由来のＣＨＯ細胞が好適に用いられる。  In the present invention, the term “human iduronic acid 2-sulfatase” means not only wild-type human iduronic acid 2-sulfatase but also one or more amino acids constituting human iduronic acid 2-sulfatase as long as it has biological activity. Also included are analogs of human iduronic acid 2-sulfatase with residues substituted, deleted, or inserted. hI2S is also synonymous. Human iduronic acid 2-sulfatase (hI2S) can be produced using genetic recombination techniques. For example, hI2S is produced in a culture solution or in a host cell by incorporating a gene encoding hI2S into an expression vector and culturing the transformed host cell. There are no particular limitations on the cells used as host cells at this time, but mammalian cells, insect cells, and yeast are preferably used. When using mammalian cells, cells derived from humans, mice, and hamsters are preferred, and CHO cells derived from Chinese hamster ovary cells are particularly preferred.

ｈＩ２Ｓを発現ベクターに組込み，ＣＨＯ細胞を形質転換し，形質転換細胞を培養することにより，生物学的に活性なｈＩ２Ｓを製造する方法は，当業者に周知である（米国特許公報５９３２２１１）。  Methods for producing biologically active hI2S by incorporating hI2S into an expression vector, transforming CHO cells, and culturing the transformed cells are well known to those skilled in the art (US Pat. No. 5,932,211).

本発明において，治療対象とされるハンター症候群の患者は，特に限定はないが，特に脳障害を伴う患者である。脳障害には，知的障害，脳の萎縮，水頭症等が含まれる。知的障害等の発生を未然に防止するうえで，脳障害が引き起こされる前に治療を開始することも，非常に重要である。従って，脳障害が未発生の患者であっても，将来脳障害を引き起こすおそれがあると診断された患者も特に対象となる。脳障害を引き起こすか否かを予測するための診断は，患者のみならず全乳幼児に対して実施することが，脳障害の未然防止の観点から望まれる。そのような診断方法として遺伝子診断を用いることができる。遺伝子診断によりヒトイズロン酸２−スルファターゼの変異を特定することにより，脳障害の発生を予測できる。遺伝子診断と本発明の治療剤とを組み合わせることにより，ハンター症候群の患者の治療をより有効に実施できる。  In the present invention, a patient with Hunter syndrome to be treated is not particularly limited, but is particularly a patient with a brain disorder. Brain disorders include intellectual disability, brain atrophy, hydrocephalus and the like. In order to prevent the occurrence of intellectual disability, it is also very important to start treatment before brain damage is caused. Therefore, patients who have been diagnosed as having a possibility of causing brain damage in the future even for patients who have not suffered from brain damage are of particular interest. Diagnosis to predict whether or not it will cause brain damage should be performed not only on patients but also on all infants from the viewpoint of preventing brain damage. Genetic diagnosis can be used as such a diagnostic method. By identifying the mutation of human iduronic acid 2-sulfatase by genetic diagnosis, the occurrence of brain damage can be predicted. By combining genetic diagnosis and the therapeutic agent of the present invention, treatment of patients with Hunter syndrome can be carried out more effectively.

本発明の治療剤は，頭部から脳室内に投与される。例えば，頭皮を切開し，次いで頭蓋骨に穴を開けて，当該穴に，長い注射針，例えばカテラン針を挿入して脳室内に投与される。持続的に複数回に渡って投与する必要がある場合，当該穴に，留置針，留置用のカニューレ，又は留置カテーテルを設置することにより，これらを通じて所望のタイミングで脳室内に投与できる。  The therapeutic agent of the present invention is administered into the ventricle from the head. For example, the scalp is incised, then a hole is made in the skull, and a long injection needle, such as a catalan needle, is inserted into the hole and administered into the ventricle. When it is necessary to administer a plurality of times continuously, an indwelling needle, a cannula for indwelling, or an indwelling catheter can be installed in the hole, and can be administered into the ventricle at a desired timing through them.

脳室内に投与されるヒトイズロン酸２−スルファターゼの１回当たりの量は，好ましくは１０〜８００μｇ／ｋｇ体重であり，より好ましくは１００〜８００μｇ／ｋｇ体重であり，更に好ましくは１００〜６００μｇ／ｋｇ体重である。持続的に複数回に渡って投与される場合，その投与間隔は，好ましくは３週〜２ヶ月毎であり，より好ましくは３週である。しかし，患者の症状に合わせて，投与間隔は２週〜６ヶ月毎に１回と適宜調整できる。  The amount of human iduronic acid 2-sulfatase administered into the ventricle is preferably 10 to 800 μg / kg body weight, more preferably 100 to 800 μg / kg body weight, still more preferably 100 to 600 μg / kg. It is weight. When administered continuously multiple times, the dosing interval is preferably every 3 weeks to 2 months, more preferably 3 weeks. However, the dosing interval can be adjusted as appropriate once every 2 weeks to 6 months according to the patient's symptoms.

本発明の治療剤は，凍結乾燥品として，又は水性液剤として医療機関に供給することができる。水性液剤の場合，ヒトイズロン酸２−スルファターゼを，安定化剤，緩衝剤，等張化剤を含有する溶液に予め溶解したものを，バイアル又は注射器に封入した製剤として供給できる。注射器に封入された製剤は，一般にプレフィルドシリンジ製剤と呼称される。  The therapeutic agent of the present invention can be supplied to a medical institution as a lyophilized product or as an aqueous liquid. In the case of an aqueous solution, human iduronic acid 2-sulfatase dissolved in a solution containing a stabilizer, a buffer, and an isotonic agent can be supplied as a preparation sealed in a vial or a syringe. A preparation enclosed in a syringe is generally called a prefilled syringe preparation.

水性液剤として供給される場合，水性液剤に含有されるヒトイズロン酸２−スルファターゼの濃度は，好ましくは１〜４ｍｇ／ｍＬであり，より好ましくは２〜３ｍｇ／ｍＬである。また，水性液剤に含有される安定化剤は，薬剤学的に許容し得るものである限り特に限定はないが，非イオン性界面活性剤が好適に使用できる。このような非イオン性界面活性剤としては，ポリソルベート，ポロキサマー等を単独で又はこれらを組合せて使用できる。ポリソルベートとしてはポリソルベート２０，ポリソルベート８０が，ポロキサマーとしてはポロキサマー１８８（ポリオキシエチレン（１６０）ポリオキシプロピレン（３０）グリコール）が特に好適である。また，水性液剤に含有される非イオン性界面活性剤の濃度は，０．０１〜１ｍｇ／ｍＬであることが好ましく，０．０１〜０．５ｍｇ／ｍＬであることがより好ましく，０．１〜０．５ｍｇ／ｍＬであることが更に好ましい。水性液剤に含有される緩衝剤は，薬剤学的に許容し得るものである限り特に限定はないが，リン酸塩緩衝剤が好ましく，特にリン酸ナトリウム緩衝剤が好ましい。リン酸ナトリウムの濃度は，好ましくは０．０１〜０．０４Ｍである。また，緩衝剤によって調整される水性液剤のｐＨは，好ましくは５．５〜７．２である。水性液剤に含有される等張化剤は，薬剤学的に許容し得るものである限り特に限定はないが，塩化ナトリウム，マンニトールを単独で又は組み合わせて好適に使用できる。  When supplied as an aqueous liquid, the concentration of human iduronic acid 2-sulfatase contained in the aqueous liquid is preferably 1 to 4 mg / mL, more preferably 2 to 3 mg / mL. The stabilizer contained in the aqueous liquid is not particularly limited as long as it is pharmaceutically acceptable, but a nonionic surfactant can be preferably used. As such a nonionic surfactant, polysorbate, poloxamer, etc. can be used alone or in combination. Polysorbate 20 and polysorbate 80 are particularly suitable as the polysorbate, and poloxamer 188 (polyoxyethylene (160) polyoxypropylene (30) glycol) is particularly suitable as the poloxamer. Further, the concentration of the nonionic surfactant contained in the aqueous liquid is preferably 0.01 to 1 mg / mL, more preferably 0.01 to 0.5 mg / mL, More preferably, it is -0.5 mg / mL. The buffer contained in the aqueous liquid is not particularly limited as long as it is pharmaceutically acceptable, but a phosphate buffer is preferable, and a sodium phosphate buffer is particularly preferable. The concentration of sodium phosphate is preferably 0.01 to 0.04M. Moreover, the pH of the aqueous liquid preparation adjusted with a buffering agent becomes like this. Preferably it is 5.5-7.2. The isotonic agent contained in the aqueous solution is not particularly limited as long as it is pharmaceutically acceptable, but sodium chloride and mannitol can be used preferably alone or in combination.

本発明の治療剤は，その投与に使用する専用の注射針、例えばカテラン針と共に包装したキット製剤として流通させることにより，医療機関における利便性を向上することができる。  The therapeutic agent of the present invention can improve convenience in a medical institution by distributing it as a kit preparation packaged together with a dedicated injection needle used for its administration, for example, a cattelan needle.

以下，実施例を参照して本発明を更に詳細に説明するが，本発明が実施例に限定されることは意図しない。なお，全ての動物実験は，東京慈恵会医科大学の学内ガイドラインに従って実施した。  Hereinafter, the present invention will be described in more detail with reference to examples. However, it is not intended that the present invention be limited to the examples. All animal experiments were conducted according to the internal guidelines of Jikei University School of Medicine.

〔ヒトイズロン酸２−スルファターゼ（ｈＩ２Ｓ）の脳室内投与〕
イズロン酸２−スルファターゼ遺伝子を破壊しイズロン酸２−スルファターゼを完全に欠失したノックアウトマウスを，水とエサを自由に摂取させて飼育した。エサは通常食を与えた。ノックアウトマウスを２群に分け，そのうちの１群をｈＩ２Ｓを投与するｈＩ２Ｓ投与群（３匹），他の群を生理食塩水を投与するコントロール群（４匹）とした。また，野生型マウスに生理食塩水を投与する群（４匹，野生型群）をおいた。[Intraventricular administration of human iduronic acid 2-sulfatase (hI2S)]
Knockout mice in which the iduronic acid 2-sulfatase gene was disrupted and iduronic acid 2-sulfatase was completely deleted were bred with free access to water and food. The food was usually fed. Knockout mice were divided into two groups, one of which was an hI2S administration group (3 mice) administered with hI2S, and the other group was a control group (4 mice) administered with physiological saline. In addition, a group (4 mice, wild type group) in which physiological saline was administered to wild type mice was placed.

ｈＩ２Ｓは，ｈＩ２Ｓ遺伝子で形質転換させたＣＨＯ細胞を培養する周知の方法を参考にして作成したものを用いた（米国特許公報５９３２２１１）。  hI2S was prepared by referring to a well-known method for culturing CHO cells transformed with the hI2S gene (US Pat. No. 5,932,211).

２１週齢の雄マウスをジエチルエーテルで満たした麻酔瓶に入れて吸入麻酔させた後，１０倍希釈した２００〜３００μＬのネンブタール注射液（大日本製薬）を３０ゲージの注射針を用いてマウスの皮下に投与して完全に麻酔させた。麻酔したマウスの頭部に脳定位固定装置（株式会社成茂科学器機研究所，Ｔｙｐｅ ＳＲ−５）の付属部材である脳固定具を取り付けてから，マウスを当該脳定位固定装置に固定した。  A 21-week-old male mouse was placed in an anesthesia bottle filled with diethyl ether and anesthetized by inhalation, and then 200-300 μL of Nembutal Injection (Dainippon Pharmaceutical) diluted 10-fold was added to the mouse using a 30-gauge needle. It was administered subcutaneously and completely anesthetized. After attaching a brain fixing tool, which is an accessory member of the brain stereotaxic apparatus (Narumo Scientific Instruments Laboratory, Type SR-5), to the anesthetized mouse head, the mouse was fixed to the brain stereotaxic apparatus.

マウス頭部の体毛を鋏で切り取り頭皮を露出させた。頭皮をイソジンで消毒した後，拡大ルーぺ存在下，頭皮を鋏で切開し冠状縫合と失状縫合の交点（ブレグマ）を露出させた。マウスを正面から見てプレグマから奥３ｍｍ，左２ｍｍの位置の頭蓋骨にカテラン針１８Ｇ（テルモ株式会社）を用いて直径０．５ｍｍの穴を開け，これをアクセスポイントとした。脳定位固定装置の目盛りガイドに従って，アクセスポイントから深さ３ｍｍの位置に，２０μｇ（６．７μＬ）のｈＩ２Ｓを，約３０秒かけて投与した。投与は，マイクロシリンジ（イトーマイクロシリンジ１０μＬ用：型番ＩＴＳ ＭＳ−ＮＧ１０，株式会社伊藤製作所）に注射針（互換針イトーマイクロシリンジ用３０Ｇ ２０ｍｍ ２２度，株式会社伊藤製作所）を取り付けたものを用いて行った。投与後，注射針を１分間固定し，その後ゆっくりと１．５ｍｍ抜いてそこで更に１分間固定し，次いでゆっくりと完全に抜き取った。コントロール群には６．７μＬの生理食塩水を同様にして投与した。イソジンを用いて切開部を消毒した後，瞬間接着剤（アロンアルファＡ，第一三共）を用いて頭皮を張り合わせた。投与は，３週毎に４回，すなわち２１週齢時，２４週齢時，２７週齢時及び３０週齢時に行った。  The hair of the mouse head was cut off with a scissors to expose the scalp. After the scalp was disinfected with isodine, in the presence of a magnifier, the scalp was incised with a scissors to expose the intersection (bregma) of the coronal suture and the deformed suture. When the mouse was viewed from the front, a hole with a diameter of 0.5 mm was drilled in the skull at a position 3 mm deep and 2 mm left from the pegma using a catalan needle 18G (Terumo Corporation), and this was used as an access point. According to the scale guide of the stereotaxic apparatus, 20 μg (6.7 μL) of hI2S was administered to a position 3 mm deep from the access point over about 30 seconds. For administration, a microsyringe (for Ito microsyringe 10 μL: model number ITS MS-NG10, Ito Seisakusho Co., Ltd.) attached with an injection needle (for compatible needle Ito microsyringe 30G 20 mm 22 degrees, Ito Seisakusho Co., Ltd.) went. After administration, the needle was fixed for 1 minute, then slowly pulled out 1.5 mm, where it was fixed for another 1 minute, and then slowly and completely removed. 6.7 μL of physiological saline was administered to the control group in the same manner. After disinfecting the incision with isodine, the scalp was pasted together with an instantaneous adhesive (Aron Alpha A, Daiichi Sankyo). The administration was performed 4 times every 3 weeks, that is, at 21 weeks of age, 24 weeks of age, 27 weeks of age and 30 weeks of age.

ｈＩ２Ｓの投与前に，マウスを計量し，体重１ｋｇ当たりのｈＩ２Ｓの投与量を算出した。ｈＩ２Ｓの投与量は，ｈＩ２Ｓ投与群３匹の平均で，１回目（２１週齢時）が６９８．７μｇ／ｋｇ体重，２回目（２４週齢時）が６６１．２μｇ／ｋｇ体重，３回目（２７週齢時）が６８１．８μｇ／ｋｇ体重，４回目（３０週齢時）が６４５．２μｇ／ｋｇ体重であった。  Prior to administration of hI2S, mice were weighed and the dose of hI2S per kg body weight was calculated. The dose of hI2S was the average of 3 animals in the hI2S administration group, the first time (at 21 weeks of age) 698.7 μg / kg body weight, the second time (at 24 weeks of age) 661.2 μg / kg body weight, the third time ( 27 weeks old) was 681.8 μg / kg body weight, and the fourth time (30 weeks old) was 645.2 μg / kg body weight.

最終投与から３週間後（３３週齢）に，マウスを解剖して組織を摘出した。マウスをジエチルエーテルで満たした麻酔瓶に入れて吸入麻酔させた後，マウスの胸部を切開して右心耳を切断し，次いで右心室に翼状注射針（テルモ翼状注射針２７Ｇ Ｘ １／２，テルモ）を挿入し５０ｍＬのシリンジ（テルモシリンジ５０ｍＬ，テルモ）を用いてゆっくり１ＸＤ−ＰＢＳ（−）（和光純薬工業）を還流させた。還流後，脳，目，肺，心臓，肝臓，腎臓，脾臓及び精巣を摘出した。脳は摘出後，大脳前部，大脳後部及び小脳に分割した。各組織は，重量を測定した後，サンプルチューブに封入して液体窒素中で保存した。  Three weeks after the final administration (33 weeks of age), the mouse was dissected and the tissue was removed. The mouse was placed in an anesthesia bottle filled with diethyl ether and inhaled and anesthetized. Then, the chest of the mouse was incised, the right atrial appendage was cut, and then a winged needle (Terumo winged needle 27G X 1/2, Terumo was placed in the right ventricle. 1XD-PBS (-) (Wako Pure Chemical Industries) was slowly refluxed using a 50 mL syringe (Terumo syringe 50 mL, Terumo). After reflux, the brain, eyes, lungs, heart, liver, kidney, spleen and testis were removed. After removal, the brain was divided into anterior cerebrum, posterior cerebrum and cerebellum. Each tissue was weighed and then enclosed in a sample tube and stored in liquid nitrogen.

〔ヒトイズロン酸２−スルファターゼ活性の測定〕
凍結した臓器を解凍し，それぞれ２０ｍｇずつはかり取り，１．５ｍＬのサンプリングチューブに入れた。各サンプリングチューブに純水を４００μＬ加えて卓上ホモジナイザー（Ｈａｎｄｙ ｍｉｃｒｏ ｈｏｍｏｇｅｎｉｚｅｒ Ｐｈｙｓｃｏｔｒｏｎ：型番Ｃｅｎｔｒｉｆｕｇｅ ＮＳ−３１０ ＥＩＩ，ＭｉｃｒｏＴｅｃ社）を用いてホモジネートし，次いで卓上小型冷却遠心機（Ｃｅｎｔｒｉｆｕｇｅ ５４１５Ｒ，エッペンドルフ社）を用いて１３２００ｒｐｍ，１０分間，４℃で遠心し，上清を回収した。[Measurement of human iduronic acid 2-sulfatase activity]
Frozen organs were thawed, 20 mg each was weighed and placed in a 1.5 mL sampling tube. 400 μL of pure water was added to each sampling tube and homogenized using a tabletop homogenizer (Handy micro homogenizer Physcotron: model number Centrifuge NS-310 EII, MicroTec), and then a tabletop small refrigerated centrifuge (Centrifuge Pen 15 Rendezvous Pen 54). The supernatant was collected by centrifugation at 13200 rpm for 10 minutes at 4 ° C.

上清中に含まれるタンパク質の濃度をＢＣＡ Ｐｒｏｔｅｉｎ Ａｓｓａｙ Ｋｉｔ（Ｔｈｅｒｍｏ社）を用いて，当該キットに添付のプロトコールに従って測定した。すなわち，９６穴マイクロプレート（ヌンク社）中で上清２５μＬとＢＣＡ混合液（Ａ液：Ｂ液＝５０：１）２００μＬを混ぜ，３７℃で３０分間反応させた後，マイクロプレートリーダー（１４２０ Ｍｕｌｔｉｌａｂｅｌ Ｃｏｕｎｔｅｒ ＡＲＶＯ ＭＸ，パーキンエルマー）を用いて吸光度（５６０ｎｍ）を測定し，この測定値を同時に作成した検量線に内挿して定量を行った。なお、蛋白質の濃度の測定に際しては，Ｓｍｉｔｈ ＰＫ ｅｔ ａｌ．，Ａｎａｌ Ｂｉｏｃｈｅｍ．（１９８５）１５０，７６−８５に記載の方法を参考にした。  The concentration of the protein contained in the supernatant was measured using BCA Protein Assay Kit (Thermo) according to the protocol attached to the kit. Specifically, 25 μL of supernatant and 200 μL of BCA mixed solution (A solution: B solution = 50: 1) were mixed in a 96-well microplate (Nunk), reacted at 37 ° C. for 30 minutes, and then microplate reader (1420 Multilabel). Absorbance (560 nm) was measured using a Counter ARVO MX (Perkin Elmer), and this measurement value was interpolated into a calibration curve created at the same time for quantification. In measuring the protein concentration, Smith PK et al. , Anal Biochem. (1985) 150, 76-85.

タンパク質の濃度の測定値から，各上清についてタンパク質１５μｇを含む液量を算出し，その液量を各々０．２ｍＬチューブに採取した。各チューブに基質液（１．２５ｍＭ ４−ｍｅｔｈｙｌｕｍｂｅｌｌｉｆｅｒｙｌ−α−Ｌ−ｉｄｕｒｏｎｉｄｅ−２−ｓｕｌｐｈａｔｅ（ＭＵ−α Ｉｄｕ−２Ｓ，Ｍｏｓｃｅｒｄａｍ Ｓｕｂｓｔｒａｔｅｓ社）を基質バファー（０．１Ｍ Ｎａ−ａｃｅｔａｔｅ／ａｃｅｔｉｃ ａｃｉｄ ｂｕｆｆｅｒ，１０ｍＭ Ｐｂ−ａｃｅｔａｔｅ（ｐＨ５．０））に溶解したもの）を２０μＬ加え，更に純水を加えて３０μＬとした。これを３７℃で４時間静置した（第１反応）。次いでＰｉ／Ｃｉバファー（０．４Ｍ Ｎａ２ＨＰＯ４，０．２Ｍ Ｃ６Ｈ５Ｎａ３Ｏ７．２Ｈ２Ｏ，０．０２％（ｗ／ｖ）ＮａＮ３（ｐＨ４．５））を４０μＬ加えて攪拌し，更にＬＥＢＴ（ウシ精巣由来精製リソソーム酵素，Ｍｏｓｃｅｒｄａｍ Ｓｕｂｓｔｒａｔｅｓ社）を１０μＬ加えて攪拌した後，３７℃で２４時間静置して反応させた（第２反応）。静置後，反応液の全量をＲＩＡチューブ（ＲＩＡチューブ３，梁瀬産業）に移し，これにストップバファー（０．５Ｍ ＮａＨＣＯ３／Ｎａ２ＣＯ３ ｂｕｆｆｅｒ，０．０２５％ Ｔｒｉｔｏｎ Ｘ−１００（ｐＨ１０．７））を３．９２ｍＬ加えて反応を停止させた。反応停止後，各溶液の吸光度（励起波長３６０ｎｍ，測定波長４４８ｎｍ）を，紫外可視吸光光度計（ＲＦ−５３００ＰＣ，島津製作所）を用いて測定した。イズロン酸２−スルファターゼ活性を、４時間の第１反応中に分解された基質量を、上清中のタンパク質量で除した値（ｎｍｏｌ／４ｈ／ｍｇタンパク質）として算出した。なお，ヒトイズロン酸２−スルファターゼ活性の測定は，Ｆｒｉｓｏ Ａ ｅｔ ａｌ．，Ｊ Ｇｅｎｅ Ｍｅｄ．（２００５）７，１４８２−９１に記載の方法を参考にして実施した。From the measured value of the protein concentration, the amount of liquid containing 15 μg of protein was calculated for each supernatant, and the amount of liquid was collected in 0.2 mL tubes. In each tube, a substrate solution (1.25 mM 4-methylbelliferyl-α-L-iduronide-2-sulfate (MU-α Idu-2S, Moscerdam Substrates)) was used as a substrate buffer (0.1 M Na-acetate / acetic acid buffer, 10 mM). 20 μL of Pb-acetate (pH 5.0)) was added, and pure water was added to make 30 μL. This was allowed to stand at 37 ° C. for 4 hours (first reaction). Then Pi / Ci Bafa (0.4M Na 2 HPO 4, 0.2M C 6 H 5 Na 3 O 7 .2H 2 O, 0.02% (w / v) NaN 3 (pH4.5)) and 40μL is added Further, 10 μL of LEBT (bovine testis-derived purified lysosomal enzyme, Moscerdam Substrates) was added and stirred, and the mixture was allowed to stand at 37 ° C. for 24 hours for reaction (second reaction). After standing, the entire amount of the reaction solution was transferred to an RIA tube (RIA tube 3, Yanase Sangyo), to which a stop buffer (0.5 M NaHCO 3 / Na 2 CO 3 buffer, 0.025% Triton X-100 (pH 10. The reaction was stopped by adding 3.92 mL of 7)). After the reaction was stopped, the absorbance (excitation wavelength: 360 nm, measurement wavelength: 448 nm) of each solution was measured using an ultraviolet-visible absorptiometer (RF-5300PC, Shimadzu Corporation). The iduronic acid 2-sulfatase activity was calculated as a value (nmol / 4h / mg protein) obtained by dividing the base mass decomposed during the first reaction for 4 hours by the amount of protein in the supernatant. The measurement of human iduronic acid 2-sulfatase activity was carried out by Friso A et al. , J Gene Med. (2005) 7, 1482-91.

測定値を表１に示す。ｈＩ２Ｓ投与群と生理食塩水を投与したコントロール群で脳内のイズロン酸２−スルファターゼ活性を比較すると，ｈＩ２Ｓ投与群ではコントロール群と比較して小脳で約６０倍，前脳と後脳で約５００〜１０００倍の活性を示した。酵素活性の測定は酵素の最終投与から３週間経過後に行われているので，この結果は，脳室内に投与されたｈＩ２Ｓが，投与後も３週間以上脳内でその酵素活性を持続することを示す。また，ｈＩ２Ｓ投与群と生理食塩水を投与した野生型群で脳内のイズロン酸２−スルファターゼ活性を比較すると，小脳では同等レベルであったが，前脳と後脳ではｈＩ２Ｓ投与群が野生型群と比較して３倍以上の酵素活性を示した。この結果は，ｈＩ２Ｓ活性を完全に欠失するマウスに，１回当たり６００〜７００μｇ／ｋｇ体重の量で，３週毎にｈＩ２Ｓを投与することにより，脳内，特に前脳と後脳のｈＩ２Ｓの酵素活性を，野生型と同等，若しくはそれ以上に維持することができることを示す。ｈＩ２Ｓは，動物種に拘わらず体内で同一の酵素活性を示すことを考慮すると，１回当たり６００〜７００μｇ／ｋｇ体重の量で３週毎に投与するｈＩ２Ｓの投与スケジュールは，ヒトにもそのまま適用できる。また，ｈＩ２Ｓ投与群で前脳と後脳の酵素活性が野生型の３倍を示すこと，及びｈＩ２Ｓが治療効果を発揮するには，脳内における酵素活性が野生型レベルにまで上昇すれば十分であることを考慮すると，１回当たりの投与量を１０〜６００μｇ／ｋｇ体重程度としても，十分な治療効果を得ることが可能である。また，投与３週間後も脳内での酵素活性が高値に維持されていることから，投与間隔を３週間以上，例えば，１ヶ月〜２ヶ月毎とすることも可能である。  The measured values are shown in Table 1. When comparing the iduronic acid 2-sulfatase activity in the brain between the hI2S administration group and the control group administered with physiological saline, the hI2S administration group is about 60 times more in the cerebellum than the control group, and about 500 in the forebrain and hindbrain. It showed ˜1000-fold activity. Since the measurement of enzyme activity is performed 3 weeks after the last administration of the enzyme, this result shows that hI2S administered into the ventricle continues its enzyme activity in the brain for more than 3 weeks after administration. Show. Moreover, when comparing the iduronic acid 2-sulfatase activity in the brain between the hI2S-administered group and the wild-type group administered with physiological saline, the level was comparable in the cerebellum, but the hI2S-administered group was wild-type in the forebrain and hindbrain. The enzyme activity was more than 3 times that of the group. This result shows that hI2S in the brain, especially in the forebrain and hindbrain, was administered to mice completely deficient in hI2S by administering hI2S every 3 weeks in an amount of 600 to 700 μg / kg body weight per dose. It is shown that the enzyme activity of can be maintained equal to or higher than that of the wild type. Considering that hI2S shows the same enzyme activity in the body regardless of the animal species, the dosage schedule of hI2S administered at a dose of 600 to 700 μg / kg body weight every 3 weeks is applied to humans as it is. it can. In addition, the enzyme activity in the forebrain and hindbrain is three times that of the wild type in the hI2S administration group, and it is sufficient that the enzyme activity in the brain rises to the wild type level in order for hI2S to exert a therapeutic effect. In view of this, even if the dose per administration is about 10 to 600 μg / kg body weight, a sufficient therapeutic effect can be obtained. In addition, since the enzyme activity in the brain is maintained at a high level even after 3 weeks of administration, the administration interval can be 3 weeks or more, for example, every 1 to 2 months.

脳以外の組織についてみると，ｈＩ２Ｓ投与群の酵素活性は，概ね野生型と比較して０．７〜１．７倍の値の酵素活性を示しており，ｈＩ２Ｓを脳室内に投与することにより，他の臓器にもｈＩ２Ｓが効率良く取り込まれることがわかった。このことは，ハンター症候群の患者へｈＩ２Ｓを全身投与する手段としても，ｈＩ２Ｓの脳室内投与が極めて優れていることを示す。  As for the tissues other than the brain, the enzyme activity of the hI2S administration group is approximately 0.7 to 1.7 times that of the wild type, and by administering hI2S into the ventricle , HI2S was found to be efficiently taken up by other organs. This indicates that the intraventricular administration of hI2S is extremely excellent as a means for systemically administering hI2S to patients with Hunter syndrome.

Figure 2012062312
Figure 2012062312

本発明によれば，脳障害を伴うハンター症候群に用いるためのヒトイズロン酸２−スルファターゼ含有医薬品を提供することができる。  ADVANTAGE OF THE INVENTION According to this invention, the human iduronic acid 2-sulfatase containing pharmaceutical for using for the Hunter syndrome with a brain disorder can be provided.

Claims (6)

ヒトの脳室内に投与されることを特徴とする，ヒトイズロン酸２−スルファターゼを有効成分として含有する，ハンター症候群の治療剤。  A therapeutic agent for Hunter syndrome comprising human iduronic acid 2-sulfatase as an active ingredient, which is administered into a human ventricle. ハンター症候群が，脳障害を伴うものである，請求項１に記載の治療剤。  The therapeutic agent according to claim 1, wherein the Hunter syndrome is associated with a brain disorder. 留置カニューレ，留置カテーテル，又は留置針を用いて投与される，請求項１又は２に記載の水性液剤。  The aqueous liquid preparation according to claim 1 or 2, which is administered using an indwelling cannula, an indwelling catheter, or an indwelling needle. ヒトイズロン酸２−スルファターゼが，１回当たり１０〜８００μｇ／ｋｇ体重の量を３週〜２ヶ月毎に投与される，請求項１〜３のいずれかに記載の治療剤。  The therapeutic agent according to any one of claims 1 to 3, wherein human iduronic acid 2-sulfatase is administered at a dose of 10 to 800 µg / kg body weight every 3 weeks to 2 months. ヒトイズロン酸２−スルファターゼが，１回当たり１００〜６００μｇ／ｋｇ体重の量を３週毎に投与される，請求項１〜３のいずれかに記載の治療剤。  The therapeutic agent according to any one of claims 1 to 3, wherein human iduronic acid 2-sulfatase is administered at a dose of 100 to 600 µg / kg body weight every 3 weeks. 請求項１〜５のいずれかに記載の治療剤と、該治療剤を投与するためのカテラン針とを含む、キット製剤。  A kit preparation comprising the therapeutic agent according to any one of claims 1 to 5 and a catalan needle for administering the therapeutic agent.
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