福山型筋ジストロフィーを含めた糖鎖合成異常症の系統的な解明・治療に関する研究

Research on systematic elucidation and treatment of glycosylation disorders, including Fukuyama muscular dystrophy

抄録

　福山型筋ジストロフィー（Fukuyama type congenital muscular dystrophy：FCMD）は，筋ジストロフィー，眼疾患，Ⅱ型滑脳症を特徴とする常染色体潜性遺伝病であり，起立・歩行機能を獲得することが無い最重症型で，日本に特異的に多いが，治療法もなく原因も不明であった．筋疾患でありながら中枢系の異常を伴うという病型の認知まで長時間を要した謎に満ちた疾患であった．

　本研究によりFCMDを含めた糖鎖合成異常症の系統的な解明と新しい糖鎖の発見がなされ，日本発の学術的な貢献がなされた．我々は，FCMDの原因遺伝子フクチンを，患者集めから始め分子遺伝学的手法により同定し，本疾患の遺伝子診断，出生前診断，そして正確な病型分類を可能にした．その後遺伝子異常の発生するメカニズム，スプライシング異常の詳細が明らかにされた．一方，遠藤博士によって発見された新規糖鎖O-マンノース型糖鎖（O-Man型糖鎖）の糖鎖生合成の解明を目指した研究の過程で共同研究により，「糖鎖と筋ジス」の関係を明らかにした．これは神経内科，筋疾患分野，および糖鎖科学分野，いずれの研究者も全く想像しなかった結びつきであった．この共同研究は，FCMDおよびその類縁疾患は糖鎖合成の異常による疾患ではないか，とのパラダイムシフトを引き起こし，FCMDの病態解明への道を切り拓いた．その結果，これまで人体で報告のないリビトールリン酸のタンデム構造の形成不全が，FCMDおよび類縁疾患（肢帯型筋ジストロフィーなど）の本態であるという驚嘆すべき発見に至った．そして，これら疾患群は，中枢-末梢神経系，眼，骨格筋に共通して存在するO-Man型糖鎖の合成異常症であることが解明された．

　本研究は，基礎レベルから糖鎖合成異常症について系統的な疾患の謎を解き明かすという学術的に大きな貢献をした．また，リビトールなどの新しい糖鎖の発見およびその生理的な意義の確立は，生体物質である糖鎖の存在意義を一段と高めたといえる．さらに本成果は，アンチセンス療法，糖薬物治療等，不治の難病，筋ジストロフィーに対する根本的な治療法開発に寄与することが期待されるものであり，実際に薬事承認を目指してアンチセンス核酸NS035の臨床試験中であり，学術的意義のみならず臨床的意義も高い．

　福山型は我が国で初めて記載された疾患であり，患者数も多く，我が国の研究により，治療法開発をすすめることは我々の責務である，と考える．これら一連の本研究は，ゲノム医学の手法を用いて，難治疾患の遺伝子同定，「糖鎖と筋ジス」という病態機序を明らかにし，治療法のない疾患の治療法を開発した．まさにゲノム医学・医療のテーマに合った独創性の高い研究である．

Abstract

　Fukuyama muscular dystrophy（FCMD）is an autosomal recessive genetic disease characterized by muscular dystrophy, eye disease, and type Ⅱ lissencephaly, the most severe form of muscular dystrophy, which has never acquired the ability to stand or walk. It is a muscle disease with central nervous system abnormalities, and it took a long time before the disease type was recognized as a mystery.

　This research has led to the systematic elucidation of glycosylation disorders including FCMD and the discovery of new glycans, making an academic contribution originating in Japan. We identified the causative gene for FCMD, fukutin, by molecular genetic methods, starting with the collection of patients, which enabled genetic diagnosis, prenatal diagnosis, and accurate classification of the disease type. Subsequently, the mechanism underlying the genetic abnormality and the details of the splicing abnormality were clarified. On the other hand, in the course of research aimed at elucidating the glycan biosynthesis of the novel O-mannose-type glycan chain（O-Man-type glycan chain）discovered by Dr. Endo, the relationship between “glycans and muscular dystrophy” was clarified through collaborative research. This was a link that neither researchers in the fields of neurology, muscular diseases, nor glycoscience had ever imagined. This joint research has triggered a paradigm shift to the hypothesis that FCMD and related diseases may be caused by abnormalities in glycan synthesis, and has paved the way to elucidating the pathophysiology of FCMD. This led to the astonishing discovery that a tandem structural deficiency of ribitol phosphate, which has never been reported in the human body, is the true pathogenesis of FCMD and related diseases（e.g., limb-girdle muscular dystrophy）. These diseases were found to be disorders of O-Man-type sugar chain synthesis common to the central and peripheral nervous systems, the eye, and skeletal muscle.

　This research has made a major academic contribution in unraveling the mysteries of systematic diseases related to glycosylation disorders from the basic level. In addition, the discovery of new glycans such as ribitol and the establishment of their physiological significance have further raised the significance of the existence of glycans as biological substances. Furthermore, these results are expected to contribute to the development of fundamental treatments for incurable intractable diseases and muscular dystrophy, such as antisense therapy and glycopharmacotherapy, and clinical trials for antisense nucleic acid NS035 are underway with the aim of obtaining regulatory approval.

　Fukuyama type is the first disease described in Japan and has a large number of patients. We believe that it is our responsibility to promote the development of treatments for this disease through research in Japan. This series of research has used genomic medicine to identify genes for intractable diseases, clarify the pathomechanism of “glycosylation and muscular dystrophy,” and develop treatments for diseases for which there is no cure. This is truly highly original research that fits the theme of genomic medicine and medical care.