Antisense oligonucleotides as a potential treatment for brain deficits observed in myotonic dystrophy type 1.
Antisense oligonucleotides as a potential treatment for brain deficits observed in myotonic dystrophy type 1.
复制标题
DOI：
10.1038/s41434-022-00316-7
复制
发表时间：
2022-12
期刊：
影响因子：
5.1
通讯作者：
中科院分区：
文献类型：
--
作者：
肌强直性营养不良或肌强直性营养不良1型（DM1）是一种多系统疾病，是成人最常见的肌营养不良形式。它不仅影响肌肉，还影响许多器官，包括大脑。脑损伤包括认知缺陷、白天嗜睡、视觉空间和记忆功能丧失。携带CUG重复序列的突变转录本的表达导致毒性mRNA功能的增加。反义寡核苷酸（ASO）治疗DM1脑缺陷的策略受到全身给药后ASO不能穿过血脑屏障这一事实的限制，表明应考虑其他给药方法。ASO技术已成为开发多种人类疾病潜在新疗法的有力工具，其潜力已在最近的临床试验中得到证实。用IONIS 486178 ASO靶向从DM1患者身上获得的人诱导多能干细胞衍生的神经细胞中的DMPK mRNA，可消除cug扩大的病灶，使MBNL1/2的核重新分布，并纠正异常剪接。在DMSXL小鼠脑室内注射IONIS 486178 ASO可使不同脑区的突变DMPK mrna水平降低高达70%。它还逆转了新生儿服药后的行为异常。本研究表明，IONIS 486178 ASO靶向脑内突变的DMPK mrna，有力地支持了基于鞘内注射ASO治疗DM1患者的可行性。
Myotonic dystrophy, or dystrophia myotonica type 1 (DM1), is a multi-systemic disorder and is the most common adult form of muscular dystrophy. It affects not only muscles but also many organs, including the brain. Cerebral impairments include cognitive deficits, daytime sleepiness, and loss of visuospatial and memory functions. The expression of mutated transcripts with CUG repeats results in a gain of toxic mRNA function. The antisense oligonucleotide (ASO) strategy to treat DM1 brain deficits is limited by the fact that ASOs do not cross the blood–brain barrier after systemic administration, indicating that other methods of delivery should be considered. ASO technology has emerged as a powerful tool for developing potential new therapies for a wide variety of human diseases, and its potential has been proven in a recent clinical trial. Targeting DMPK mRNA in neural cells derived from human induced pluripotent stem cells obtained from a DM1 patient with the IONIS 486178 ASO abolished CUG-expanded foci, enabled nuclear redistribution of MBNL1/2, and corrected aberrant splicing. Intracerebroventricular injection of the IONIS 486178 ASO in DMSXL mice decreased the levels of mutant DMPK mRNAs by up to 70% throughout different brain regions. It also reversed behavioral abnormalities following neonatal administration. The present study indicated that the IONIS 486178 ASO targets mutant DMPK mRNAs in the brain and strongly supports the feasibility of a therapy for DM1 patients based on the intrathecal injection of an ASO.
登录
查看更多内容
影响因子：
9.9
作者：
Bassez, G;Lazarus, A;Duboc, D
通讯作者：
Duboc, D
影响因子：
158.5
作者：
Groh, William J.;Groh, Miriam R.;Pascuzzi, Robert M.
通讯作者：
Pascuzzi, Robert M.
影响因子：
4.3
作者：
Todd PK;Ackall FY;Hur J;Sharma K;Paulson HL;Dowling JJ
通讯作者：
Dowling JJ
影响因子：
12.4
作者：
Gao, Yuanzheng;Guo, Xiuming;Xia, Guangbin
通讯作者：
Xia, Guangbin
影响因子：
2.8
作者：
Di Costanzo, A;Di Salle, F;Tedeschi, G
通讯作者：
Tedeschi, G