Symposium
From bench to bedside: Seamless development of therapy for neurological diseases
シンポジウム
ベンチからベッドサイドへシームレスに展開する神経疾患の治療法開発研究 |
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| 7月28日（日）10:50～11:20 第5会場（朱鷺メッセ 3F 302）
4S05a-1
スプライシング異常に起因する遺伝病に対する創薬
Masatoshi Hagiwara（萩原 正敏）
京都大院医形態形成
Patients of congenital diseases have abnormalities in their chromosomes and/or genes. Therefore, it has been considered that drug treatments can do little for these patients than to patch over each symptom temporarily when it arises. Although we cannot normalize their chromosomes and genes with chemical drugs, we may be able to manipulate the amounts and patterns of mRNAs transcribed from patients' DNAs with small chemicals. Based on this simple idea, we have looked for chemical compounds that can be applicable for human diseases targeting kinase families of CDKs, CLKs, and DYRKs, which are involved in the regulation of gene expression, and eventually succeeded by finding FIT0391), TG0032), and ALGERNON3) as potential therapeutic drugs to cure diseases such as viral infections, Duchenne muscular dystrophy, and Down syndrome, respectively. In addition, we established splicing reporter assay with dual color (SPREADD) using a segment of pathogenic genes, and found a splicing modulator, RECTAS4), which can rectify the aberrant IKBKAP splicing in Familial Dysautonomia patient fibroblasts with SPREADD screening. Recently we found that our chemical therapeutics are applicable for other congenital diseases, such as Fabry disease and cystic fibrosis.
1) Yamamoto, Makoto, et al. CDK9 Inhibitor FIT-039 Prevents Replication of Multiple DNA Viruses.; Journal of Clinical Investigation 124,8:3479-88, 2014.
2) Nishida, Atsushi, et al.Chemical Treatment Enhances Skipping of a Mutated Exon in the Dystrophin Gene.Nature Communications 2,308.doi.org/10.1038/ncomms1306, 2011.
3) Nakano-Kobayashi, Akiko, et al. Prenatal Neurogenesis Induction Therapy Normalizes Brain Structure and Function in Down Syndrome Mice.Proceedings of the National Academy of Sciences of the United States of America 114,38: 10268-73. doi.org/10.1073/pnas.1704143114, 2017.
4) Yoshida, Mayumi, et al.Rectifier of Aberrant mRNA Splicing Recovers tRNA Modification in Familial Dysautonomia."" Proceedings of the National Academy of Sciences of the United States of America 112,9: 2764-69. doi.org/10.1073/pnas.1415525112 2015. | | 7月28日（日）11:20～11:50 第5会場（朱鷺メッセ 3F 302）
4S05a-2
脊髄性筋萎縮症に対するスプライシング制御治療
Kentaro Sahashi（佐橋 健太郎）
名古屋大院医神経内科
Loss-of-function mutations in the SMN1 gene cause spinal muscular atrophy (SMA), a leading genetic cause of infant mortality. Degeneration of alpha-motor neurons in the brain stem and spinal cord that results in progressive paralysis, is a pathological hallmark of SMA. Currently, peripheral-tissue involvement has been also implicated in the pathogenesis. Only humans have a closely related SMN2 gene, but it only expresses low levels of functional, full-length SMN protein, due to an alternative splicing event of exon 7 skipping. A decrease in ubiquitously expressed SMN, one of whose functions is to promote snRNP assembly that is required for splicing reactions, is responsible for SMA, although how this deficiency specifically affects alpha-motor neurons remains unclear. So far, no effective therapy had been available for SMA, but SMN restoration is thought to be necessary and sufficient for cure. Synthetic antisense oligonucleotides (ASOs) can be designed to specifically alter splicing patterns of target pre-mRNAs and are being developed as RNA-targeted therapeutics to correct disease-associated splicing defects. Based on an extensive screen of overlapping ASOs tiled along SMN2 exon 7 and its flanking introns, we identified and characterized an ASO complementary to positions +10 to +27 in SMN2 intron 7 that masks the splicing cis-element dubbed ISS-N1, and gives a robust increase in SMN2 exon 7 inclusion and resulting full-length SMN levels. The disease-modifying effects and safety have been proven in preclinical studies using mouse models of SMA and nonhuman primates, and further in clinical trials in infants and children with SMA. Exploring of the relationship between spatial and temporal effects of therapeutic ASOs yields relevant insights into the roles of SMN in SMA pathogenesis, as well as its normal physiological functions, which in turn have contributed to the successful development of the targeted therapeutics. | | 7月28日（日）11:50～12:20 第5会場（朱鷺メッセ 3F 302）
4S05a-3
福山型筋ジストロフィーを含めた糖鎖合成異常症・パーキンソン病の系統的な解明と治療をめざして
Tatsushi Toda（戸田 達史）
東京大学大学院医学系研究科神経内科学
福山型筋ジストロフィー(FCMD)は本邦の小児期筋ジストロフィーの中ではデュシェンヌ型に次いで多く、先天性筋ジストロフィーに多小脳回などの脳形成障害を伴う常染色体性劣性遺伝疾患であり、我々の90人に1人が保因者である。我々は原因遺伝子を同定し、遺伝子産物をフクチンと名付けた。フクチン遺伝子の変異によって発症し、ほとんどの患者は3'非翻訳領域にSVAレトロトランスポゾンの挿入変異を認める。福山型は、muscle-eye-brain病(MEB)などと類似疾患とされる。我々は糖転移酵素POMGnT1の遺伝子がMEB原因遺伝子であることを明らかにした。FCMDやMEB、Walker-Warburg(WWS)症候群、肢帯型2I型などに共通した病態として、αジストログリカン(αDG)の糖鎖修飾異常が発見され、同様な糖鎖異常を発症要因とする疾患群はジストログリカン異常症と呼ばれる。
我々は、さらにスプライス異常症という分子メカニズムと根本的治療法につながるアンチセンス核酸治療法を発見して、治験をめざしている。また近年、我々は、ジストログリカン異常症の原因遺伝子のうち、フクチン、fukutin-related protein (FKRP)、ISPDの機能を明らかにし、糖鎖構造には、哺乳類で初めて存在が確認されたリビトールリン酸が含まれていることを発見した。ジストログリカン異常症の多くは、この修飾異常によって引き起こされる「リビトールリン酸異常症」といえる。
一方パーキンソン病は、世界で最も多い運動症状を呈する脳の疾患であり、進行を抑制する根本的な治療法がまだ見つかっていない神経難病である。今回、我々の研究グループは、悪性黒色腫に対する薬として承認されているダブラフェニブが、パーキンソン病の進行を抑制する可能性を持つことを見出した。我々は、大阪大学の岡田教授が開発した薬剤データベースなどを利用した解析を用いて、パーキンソン病の治療薬候補を同定した。そのうちの1つであるダブラフェニブが、培養細胞やマウスのパーキンソン病モデルにおいて実際に神経保護効果を示すことを証明した。この薬剤スクリーニング手法は、アルツハイマー病や筋萎縮性側索硬化症などの他の神経難病のみならず、糖尿病や高血圧症といった様々な疾患で有用な可能性がある。本講演では、ベンチからベッドサイドへと展開する神経疾患の治療法開発について考察する 。
研究助成：Research funds : AMED 18km0405206h0003, 18ek0109249h0002 | | 7月28日（日）12:20～12:50 第5会場（朱鷺メッセ 3F 302）
4S05a-4
中枢神経疾患に対する神経回路の修復治療の開発
Toshihide Yamashita（山下 俊英）
大阪大院医分子神経科学
Initial behavioral deficits resulting from brain injury are frequently followed by spontaneous recovery of function, although this recovery is quite limited. It has been noted that synaptic plasticity in pre-existing pathways and the formation of new circuits through collateral sprouting of lesioned and unlesioned fibers are important aspects of the spontaneous recovery process. Although reorganization of the neural network is considered to contribute to this recovery, behavioral plasticity is not fully understood. Furthermore, the molecular mechanism of this phenomenon is poorly understood. We aim to elucidate the mechanisms underlying this plasticity, knowledge of which will contribute to enhancement of functional recovery after injury to the central nervous system. We have explored the mechanism of this behavioral plasticity, and more importantly, we have obtained evidence to show that immune modulation, inflammation-induced neovessels, and some types of microglia enhance plasticity and survival of neurons by secreting trophic factors. Disorders of the central nervous system, such as cerebrovascular diseases, cerebrospinal trauma, and encephalomyelitis, often cause spatiotemporal changes in the nervous system and in various biological systems, such as the immune system and vascular system. We analyzed the mechanism by which the spatiotemporal dynamics in those biological systems control a series of processes. Additionally, we aimed to elucidate the principles involved in the operation of living organisms with neural network disorders within the central nervous system by observing such disorders and their functional recovery process with respect to the dynamics of the entire biological system and by conducting a comprehensive analysis of the association between each system. These immune cells, neovessels, and microglia may prove to be drug targets for the treatment of CNS injuries, CNS inflammation, and neurodegenerative diseases. I will talk about our recent findings that uncover the molecular mechanism of formation and restoration of neuronal network in the CNS. | |
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