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zoom RSS アンチセンス筋ジストロフィー治療薬の人への最初の治療

<<   作成日時 : 2007/12/27 23:46   >>

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画像 デュシャンヌ型の筋ジストロフィー症において欠損している筋肉に必須の蛋白を作ることを可能にする薬剤を、4人の少年に使用した、人への最初の試験である。
 一定の遺伝の変異の効果を相殺することによって、「アンチセンス」と呼ばれる実験的な薬は効果をあらわす。これらのタイプの薬は、ガン、心臓病、伝染、および他の病気を治療するために研究されている。10〜13才の4人の少年の足の筋肉に1回の注射したが、副作用はなかった。
 1回の治療には25万ドルかかり、数ヶ月ごとに必要である。
 デュシャンヌ型の筋ジストロフィー症は世界に約25万症例あり、最も頻度の高い子どもの筋ジストロフィーである。一般的には12才で車椅子生活となり、20〜35才で呼吸や心臓の問題から死亡に至る。欠失蛋白ジストロフィンには数百の変異が知られ様々な程度の症状を示し、全く欠失している場合に最も症状が重い。変異の中には、変異ないし短縮した多少働く蛋白を作り、症状が軽い場合もある。
 研究対象となった患者は遺伝子の一部が欠失してジストロフィンを全く作れない。改竄された遺伝子部分でRNAの上にロックするようにしたアンチセンス薬剤を投与して、スキップしてジストロフィンを作れるようにした。結果として生成される蛋白は100%正常ではないけれども、病状をかなり改善する可能性がある。
(図はhttp://www.rinshoken.or.jp/benefit/20040127.htmより借用)
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Promising Dystrophy Drug Clears Early Test
http://www.nytimes.com/2007/12/27/health/27drug.html?ref=health
By DENISE GRADY
Published: December 27, 2007

Researchers in the Netherlands have developed a drug that may eventually be used to treat children with a severe and fatal type of muscular dystrophy.

In its first test in humans, a safety study in just four boys, the drug enabled patients to produce an essential muscle protein that is missing in Duchenne’s muscular dystrophy, a genetic disease. Not enough of the protein was produced to help the boys, but the presence of any at all was considered “proof of concept,” meaning that the approach has the potential to work and is worth pursuing.

The experimental drug, called an “antisense” compound, works by canceling out the effects of certain genetic mutations. These types of drugs are being studied to treat cancer, heart disease, infections and other illnesses.

“I don’t think you could ask for a better result from a preliminary study like this,” said Sharon Hesterlee, the vice president for translational research at the Muscular Dystrophy Association, which was not involved in the study but helped pay for an earlier phase of the work.

Though promising, the research still has a long way to go. The four boys, ages 10 to 13, each received just one injection into a leg muscle. There were no adverse effects. But larger and longer trials with much higher doses, given systemically so that the drug reaches all muscles, are needed to test both safety and efficacy. If the treatment works, it will have to be given regularly, for life.

“We are still years from its first application,” said Gert-Jan B. van Ommen, head of human genetics at Leiden University Medical Center and an author of a report on the drug that is being published Thursday in The New England Journal of Medicine. The work was done by researchers from universities in The Netherlands and Belgium, and from a Dutch company, Prosensa, that makes the drug. Dr. van Ommen said the next round of studies would involve injections under the skin, which can deliver the drug to muscles all over the body.

Only one antisense drug, an antiviral, has made it to market. Antisense drugs act on RNA, a molecule that helps cells to make needed proteins. RNA is similar to the DNA that makes up genes, and helps carry out the instructions encoded in DNA.

Antisense drugs are actually a synthetic, chemically altered form of RNA that sticks to the real RNA and blocks parts of it from working.

An editorial accompanying the journal article said the study “might herald the dawn of personalized molecular medicine” ― if the new drug can be given systemically, and if different versions can be designed to treat the hundreds of mutations that cause the disease.

But Eric P. Hoffman, the author of the editorial and director of the research center for genetic medicine at Children’s National Medical Center in Washington, said antisense therapy was expensive. He said he and his colleagues were studying it in dogs with muscular dystrophy and finding it effective. However, the cost for each round of treatment is $250,000, with treatments needed every few months.

Dr. van Ommen said the research leading to the latest study had already cost more than $15 million.

Duchenne’s is the most common form of muscular dystrophy in children, with about 250,000 cases worldwide. The disease affects boys, who generally need wheelchairs by age 12 and die between 20 and 35 from breathing and heart problems.

The gene for the missing protein dystrophin is the largest known in humans, with 2.5 million DNA units. Hundreds of mutations can cause varying degrees of muscular dystrophy. The severest types occur when there is no dystrophin. But some mutations lead to an altered or shortened form of the protein molecule that still works somewhat, resulting in only mild disease.

The patients in the study were missing part of the gene and could not make dystrophin. They were given an antisense drug that locked onto a stretch of their RNA, near the garbled region.

The drug essentially hid or blocked a defect that prevented dystrophin from being made, allowing the cells to skip over the flaw and make dystrophin. The resulting protein was not 100 percent normal, but researchers think it may be good enough to make the disease significantly less severe.

Dr. van Ommen said that if the technique works, it would probably take 10 different antisense drugs to treat about half of all children with Duchenne’s. But he and Dr. Hoffman said that if each antisense drug had to go through the usual lengthy, expensive approval process, instead of being approved as a class, creating the drugs could be difficult or even impossible.

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http://content.nejm.org/cgi/content/short/357/26/2677
Volume 357:2677-2686 December 27, 2007 Number 26

Local Dystrophin Restoration with Antisense Oligonucleotide PRO051
Judith C. van Deutekom, Ph.D., Anneke A. Janson, B.S., Ieke B. Ginjaar, Ph.D., Wendy S. Frankhuizen, B.S., Annemieke Aartsma-Rus, Ph.D., Mattie Bremmer-Bout, B.S., Johan T. den Dunnen, Ph.D., Klaas Koop, M.D., Anneke J. van der Kooi, M.D., Ph.D., Nathalie M. Goemans, M.D., Ph.D., Sjef J. de Kimpe, Ph.D., Peter F. Ekhart, M.Sc., Edna H. Venneker, M.D., Gerard J. Platenburg, M.Sc., Jan J. Verschuuren, M.D., Ph.D., and Gert-Jan B. van Ommen, Ph.D.

ABSTRACT

Background Duchenne's muscular dystrophy is associated with severe, progressive muscle weakness and typically leads to death between the ages of 20 and 35 years. By inducing specific exon skipping during messenger RNA (mRNA) splicing, antisense compounds were recently shown to correct the open reading frame of the DMD gene and thus to restore dystrophin expression in vitro and in animal models in vivo. We explored the safety, adverse-event profile, and local dystrophin-restoring effect of a single, intramuscular dose of an antisense oligonucleotide, PRO051, in patients with this disease.

Methods Four patients, who were selected on the basis of their mutational status, muscle condition, and positive exon-skipping response to PRO051 in vitro, received a dose of 0.8 mg of PRO051 injected into the tibialis anterior muscle. A biopsy was performed 28 days later. Safety measures, composition of mRNA, and dystrophin expression were assessed.

Results PRO051 injection was not associated with clinically apparent adverse events. Each patient showed specific skipping of exon 51 and sarcolemmal dystrophin in 64 to 97% of myofibers. The amount of dystrophin in total protein extracts ranged from 3 to 12% of that found in the control specimen and from 17 to 35% of that of the control specimen in the quantitative ratio of dystrophin to laminin {alpha}2.

Conclusions Intramuscular injection of antisense oligonucleotide PRO051 induced dystrophin synthesis in four patients with Duchenne's muscular dystrophy who had suitable mutations, suggesting that further studies might be feasible.


Source Information

From the Departments of Human and Clinical Genetics (J.C.D., A.A.J., I.B.G., W.S.F., A.A.-R., M.B.-B., J.T.D., G.-J.B.O.), Pathology (K.K.), and Neurology (J.J.V.), Leiden University Medical Center; and Prosensa B.V. (J.C.D., S.J.K., P.F.E., G.J.P.) ― both in Leiden, the Netherlands; the Department of Neurology, Academic Medical Center, University of Amsterdam, Amsterdam (A.J.K.); the Department of Pediatric Neurology, University of Leuven, Leuven, Belgium (N.M.G.); and Afforce Healthcare, The Hague, the Netherlands (E.H.V.).

Address reprint requests to Dr. van Deutekom at Prosensa B.V., Wassenaarseweg 72, 2333 AL Leiden, the Netherlands, or at j.vandeutekom@prosensa.nl.

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2008/01/05 10:08

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