第751回 生医研セミナー(多階層生体防御システム研究拠点)


下記の通り、Stefan-Matthias Pulst 先生によるセミナーを開催致します。皆様方のご参加を心よりお待ちしております。

演題

ASO-based therapies of cerebellar neurodegeneration.

演者

Stefan-Matthias Pulst, M.D., Dr. med.
Professor and Chair, Department of Neurology, University of Utah

日時

2017年9月22日(金)  Sep. 22 (Fri), 2017
17:00~18:30

場所

生体防御医学研究所 本館1階 会議室
以下の地図の24番です。
(https://www.kyushu-u.ac.jp/f/28545/hospital_jp.pdf)

Seminar Room, Main Building 1F, Medical Institute of Bioregulation
No.24 on the following linked map.
(https://www.kyushu-u.ac.jp/f/28551/hospital_en.pdf)

要 旨

There are no disease-modifying treatments for adult human neurodegenerative diseases. Here we test RNA-targeted therapies in two mouse models of spinocerebellar ataxia type 2 (SCA2), an autosomal dominant polyglutamine disease. Both models recreate the progressive adult-onset dysfunction and degeneration of a neuronal network that are seen in patients, including decreased firing frequency of cerebellar Purkinje cells and a decline in motor function. We developed a potential therapy directed at the ATXN2 gene by screening 152 antisense oligonucleotides (ASOs). The most promising oligonucleotide, ASO7, downregulated ATXN2 mRNA and protein, which resulted in delayed onset of the SCA2 phenotype. After delivery by intracerebroventricular injection to ATXN2-Q127 mice, ASO7 localized to Purkinje cells, reduced cerebellar ATXN2 expression below 75% for more than 10 weeks without microglial activation, and reduced the levels of cerebellar ATXN2. Treatment of symptomatic mice with ASO7 improved motor function compared to saline-treated mice. ASO7 had a similar effect in the BAC-Q72 SCA2 mouse model, and in both mouse models it normalized protein levels of several SCA2-related proteins expressed in Purkinje cells, including Rgs8, Pcp2, Pcp4, Homer3, Cep76 and Fam107b. Notably, the firing frequency of Purkinje cells returned to normal even when treatment was initiated more than 12 weeks after the onset of the motor phenotype in BAC-Q72 mice. These findings support ASOs as a promising approach for treating some human neurodegenerative diseases.

関連論文

Scoles DR et al. Nature 544: 362–366 (2017).
Becker LA et al. Nature 544: 367–371 (2017).

連絡先

生体防御医学研究所 ゲノミクス分野
柴田 弘紀 092(642)6167