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PROPHYLACTIC OR AMELIORATING AGENT FOR GENETIC DISEASES

Foreign code F200010136
File No. 6172
Posted date May 25, 2020
Country WIPO
International application number 2011JP003655
International publication number WO 2012001941
Date of international filing Jun 27, 2011
Date of international publication Jan 5, 2012
Priority data
  • P2010-146699 (Jun 28, 2010) JP
Title PROPHYLACTIC OR AMELIORATING AGENT FOR GENETIC DISEASES
Abstract Disclosed is a prophylactic or ameliorating agent for a genetic disease which is induced by the mutation of an exon in a gene and in which an exon that contains the mutation is skipped so as to produce a functional truncated protein. Specifically disclosed is a prophylactic or ameliorating agent for a genetic disease which is induced by the mutation of an exon in a gene and in which an exon that contains the mutation is skipped so as to produce a functional truncated protein, wherein the prophylactic or ameliorating agent is characterized by comprising a compound having a molecular weight of 1500 or less.
Outline of related art and contending technology BACKGROUND ART
Muscular dystrophy, destruction of muscle fibers, and the reproducing are repeated to modified (muscle necrosis), muscle atrophy and muscle weakness gradually proceeds hereditary muscle disease is a general term of, among them, is well known in the progressive muscular dystrophy. Progressive muscular dystrophy of Duchenne muscular dystrophy (Duchenne muscular dystrophy type 1: DMD) is, one of the most common and muscular dystrophy, dystrophin gene on the chromosome X mutation (see non-patent document 1) develop. By early childhood onset progressive muscular atrophy, and the patient usually DMD 20 in decades, heart failure or respiratory failure and death by.
Dystrophin protein (hereinafter, simply referred to as' dystrophin ' and will be also displayed.) Is, the cellular membrane of the muscle cells present inside the area, caused by the contraction of muscle actin - myosin by mechanical energy, a cell membrane or a surrounding connective tissue, such as in a balanced manner and transmitted to the tendon, so that no excessive impact is applied by, the structure of the muscle cells play a role in maintaining or the like. In the case of patients DMD, due to mutation of the dystrophin gene, that no muscle fibers, since there is no or very little dystrophin, muscle contraction of muscle cell membrane is broken, in large amounts of calcium ions than normal flows into the muscle fibers. Excessive calcium, and a protease such as , destroying the muscle to activate the enzyme to induce apoptosis, as a result, activated fibroblasts fiberization occurs, scarred tissue, and is unlikely to regenerate muscle cells, muscle atrophy to proceed.
On the other hand, a type of progressive muscular dystrophy Becker muscular dystrophy (Becker muscular dystrophy 1: BMD) also, develops a mutation of the dystrophin gene, the onset time is typically an adult, as compared to the progress of a condition also slow DMD. Is BMD and DMD, dystrophin gene by mutation of both despite the onset, and the extent of the travel speed are different from each other. This difference between BMD and DMD, rule described by reading frame. Intermediate stop codon in the dystrophin mRNA (premature termination codon: PTC) in the occurring variant (nonsense mutations), severe DMD (Duchenne) results in a normal phenotype, the original reading frame of the dystrophin mRNA (an in-frame mutation) maintained in the mutant, more Mifepristone BMD (Becker) and phenotype (see non-patent document 2). However, it has been found surprisingly, some mild BMD patients, on the dystrophin gene in spite of the nonsense mutation, a nonsense mutations by skipping an exon is, novel in-frame dystrophin mRNA is being produced has been reported (see non-patent document 3-6). Of part of the exon skipping in the dystrophin mRNA lacking dystrophin (truncated dystrophin) is encoded, shorter than the normal dystrophin, muscle cell structure is maintained because the function remains to some extent, the symptoms of muscular dystrophy is relatively light, in addition, the moving speed is moderate and muscle wasting.
Of the underlying muscular dystrophy therapy is not yet been established, conventional, training or joint contracture prevention function as well as a stretch of, heart failure, symptomatic treatment has been performed for disordered breathing was only. However, in recent years, and the inventors of the present invention, other by researchers, new DMD treatment method has been developed, expected are collected. This treatment may be, dystrophin mRNA using antisense oligonucleotides to (AON), by inducing , phenotype DMD phenotype BMD from achieving the conversion to, reduce the symptoms (non-patent document 3) in the method. In the cells of the patient DMD to induce, promote splice sites or splicing element relative to any of the several types of different AON is designed. These AON is, the reading frame of dystrophin mRNA was able to repair. For example, with respect to exon 19 of AON (ESE) by , skipping of exon 19 in the above-described DMD patient cells occurs, the generation of the truncated dystrophin was observed (see non-patent document 3-5). In addition, with respect to exon 51 also used AON relative to patient cells, the current, these AON is clinical studies (see non-patent document 6-8) stage.
However, AON is, periodically must be given an intravenous injection or intramuscular injection, problems that the troublesome for the patient, for the preparation of a high cost for a large amount has a problem that it was. Further, mdx mice muscle AON in processing was performed, to some extent in skeletal muscle but not on the expression of dystrophin, dystrophin expression recovery in the heart (non-patent document 9) difficult. Therefore, a low molecular weight adjusted clinical are in great demand. Low molecular weight non- suppressor mutation (registered trademark) compound PTC124 (3-5 - (2 - fluorophenyl) - 1, 2, 4 - yl benzoic acid -3 -) is, in some DMD nonsense mutations that may be treated patients and has been reported (non-patent document 10 or 11), the current, and the United States in, which is performed in a phase 2b clinical trials. PTC124 Is, at the time of the translation stop codon in the middle of the ribosomal skip (PTC) (read-through) by inducing as, full-length functional dystrophin expression of a therapeutic agent in is recovered to a certain degree, nonsense-mediated mRNA of other genes is an effect of a cracking mechanism, yet unknown.
However, the inventors of the present invention, Cdc-like kinase (Clk) specific kinase as an inhibitor, TG003 (described below in the formulas (1), R1 and R2 represents a methyl group, R3 methoxy group compound) were identified. TG003 Is, in both in vitro or in vivo a compound splicing (see non-patent document 12 and 13), the present inventors (see Patent Document 1) related to the patent application, the phosphorylation of TG003 is via SR protein, has the effect or adjusted, such actions can be utilized to, to the prevention and treatment of diseases such as cancer can occur as described. However, the TG003, dystrophin gene exon skipping may facilitate is not known until now.
Scope of claims (In Japanese)[請求項1]
遺伝子のエクソンの変異に起し、かつ、該変異が含まれるエクソンをスキッピングさせて機能性トランケート型タンパク質を生成させ得る遺伝性疾患の予防・改善剤であって、分子量1500以下の化合物を含有することを特徴とする予防・改善剤。

[請求項2]
前記化合物が、スプライシング調節作用を有する化合物であることを特徴とする請求項1に記載の予防・改善剤。

[請求項3]
前記化合物が、変異が含まれるエクソンのスキッピングを誘導・促進させる効果を有する化合物であることを特徴とする請求項1又は2に記載の予防・改善剤。

[請求項4]
前記化合物が、Cdc-likeキナーゼ阻害化合物であることを特徴とする請求項1~3のいずれかに記載の予防・改善剤。

[請求項5]
前記Cdc-likeキナーゼ阻害化合物が、一般式(1)
[化1]
(省略)
[式中、R 1及びR 2は各々独立に、直鎖状、分岐鎖状のC 1-C 10炭化水素基を示し;R 3はメトキシ基、エトキシ基、アセトキシ基又はハロゲン原子を示す。]
で表される化合物であることを特徴とする請求項4に記載の予防・改善剤。

[請求項6]
前記変異が、ナンセンス変異であることを特徴とする請求項1~5のいずれかに記載の予防・改善剤。

[請求項7]
前記ナンセンス変異が、前記遺伝子におけるエクソンスプライシングエンハンサー活性を抑制し、及び/又は、前記遺伝子におけるエクソンスプライシングサイレンサー活性を上昇させる、ナンセンス変異であることを特徴とする請求項6に記載の予防・改善剤。

[請求項8]
前記遺伝子がジストロフィン遺伝子であり、前記機能性トランケート型タンパク質が機能性トランケート型ジストロフィンタンパク質であり、前記遺伝性疾患がデュシェンヌ型筋ジストロフィーであることを特徴とする請求項1~7のいずれかに記載の予防・改善剤。

[請求項9]
前記ジストロフィン遺伝子のエクソンが、ジストロフィン遺伝子のエクソン31又はエクソン27であることを特徴とする請求項8に記載の予防・改善剤。

[請求項10]
前記ジストロフィン遺伝子のエクソン31の変異が、配列番号1のポリヌクレオチド配列のヌクレオチド番号4303におけるグアニンのチミンへのナンセンス変異であり、エクソン27の変異が、配列番号1のポリヌクレオチド配列のヌクレオチド番号3613におけるグアニンが欠失したアウトオブフレーム変異であることを特徴とする請求項9に記載の予防・改善剤。
  • Applicant
  • ※All designated countries except for US in the data before July 2012
  • KYOTO UNIVERSITY
  • Inventor
  • HAGIWARA, Masatoshi
  • MATSUO, Masafumi
  • KATAOKA, Naoyuki
  • NISHIDA, Atsushi
IPC(International Patent Classification)
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