遺傳性脊髓小腦萎縮症之新治療

Developing Treatment for Inherited Spinocerebellar Ataxia

脊髓小腦萎縮症(spinocerebellar ataxia, SCA)是一群自體顯性遺傳的神經退化性疾病，由各個獨特致病基因編碼區域CAG三核苷酸重複序列擴增引起，這些帶有重複序列的基因會轉譯為帶有聚谷氨醯胺(polyglutamine)的蛋白。常見的SCA包括六型：SCA1、SCA2、SCA3、SCA6、SCA7、SCA17。這些疾病的典型特徵包含進行性共濟失調(ataxia)、言語障礙、吞咽困難、肢體協調、步態和運動功能障礙。脊髓小腦萎縮症具有神經細胞內聚集的病理特徵，並有許多共通的致病機制，例如內質網壓力、粒腺體功能障礙與氧化壓力、蛋白酶體與細胞自噬功能障礙、伴護蛋白降低、鈣離子失調、神經炎症、轉錄錯誤與RNA毒性等。目前，尚無治療方法可以減緩或阻止疾病進展。本文將回顧脊髓小腦萎縮症的臨床和分子生物機轉，並探討正在開發的RNA干擾(RNA interference)與反義寡核苷酸(antisense oligonucleotide)療法，這些治療未來有可能會進入臨床試驗，成為脊髓小腦萎縮症的新治療方法。

Spinocerebellar ataxia (SCA) is a group of auto-dominant neurodegenerative diseases caused by the expansion of CAG trinucleotide repeats in the coding region of each unique pathogenic gene, which is further transplanted into a protein with a polyglutamine tract. There are six common types of SCA, including SCA1, SCA2, SCA3, SCA6, SCA7 and SCA17. Typical features of SCA include progressive ataxia, speech impairment, dysphagia, limb incoordination, gait and motor dysfunction. SCAs are pathologically characterized by intraneuronal aggregation and could share common pathogenic mechanisms, such as endoplasmic reticulum stress, mitochondrial dysfunction and oxidative stress, proteasome and autophagy dysfunction, reduced chaperones, calcium dysregulation, neuroinflammation, transcription dysregulation and RNA toxicity. Currently, there are no treatments to slow or stop disease progression. This article will review the clinical and molecular mechanisms of SCA, and discuss ongoing RNA interference and antisense oligonucleotide therapies that may enter clinical trials in the future as new treatments for SCA.