Department of Psychiatry, University of California San Diego, La Jolla, CA, USA.
Division of Biological Sciences, University of California San Diego, La Jolla, CA, USA.
Transl Psychiatry. 2023 Feb 16;13(1):58. doi: 10.1038/s41398-023-02356-y.
The past decade has yielded much success in the identification of risk genes for Autism Spectrum Disorder (ASD), with many studies implicating loss-of-function (LoF) mutations within these genes. Despite this, no significant clinical advances have been made so far in the development of therapeutics for ASD. Given the role of LoF mutations in ASD etiology, many of the therapeutics in development are designed to rescue the haploinsufficient effect of genes at the transcriptional, translational, and protein levels. This review will discuss the various therapeutic techniques being developed from each level of the central dogma with examples including: CRISPR activation (CRISPRa) and gene replacement at the DNA level, antisense oligonucleotides (ASOs) at the mRNA level, and small-molecule drugs at the protein level, followed by a review of current delivery methods for these therapeutics. Since central nervous system (CNS) penetrance is of utmost importance for ASD therapeutics, it is especially necessary to evaluate delivery methods that have higher efficiency in crossing the blood-brain barrier (BBB).
在过去的十年中，人们在鉴定自闭症谱系障碍（ASD）的风险基因方面取得了很大的成功，许多研究表明这些基因中的功能丧失（LoF）突变与 ASD 有关。尽管如此，到目前为止，在开发 ASD 治疗方法方面还没有取得重大的临床进展。鉴于 LoF 突变在 ASD 发病机制中的作用，许多正在开发的治疗方法旨在从转录、翻译和蛋白质水平上挽救基因的杂合不足效应。本综述将讨论从中心法则的各个层面开发的各种治疗技术，并举例说明：在 DNA 水平上的 CRISPR 激活（CRISPRa）和基因替换，在 mRNA 水平上的反义寡核苷酸（ASO），以及在蛋白质水平上的小分子药物，然后回顾这些治疗方法的当前递送方法。由于中枢神经系统（CNS）的通透性对 ASD 治疗至关重要，因此特别有必要评估那些能够更有效地穿过血脑屏障（BBB）的递送方法。
Zotero 插件
