Brain somatic mutations as RNA therapeutic targets in neurological disorders

• Published in: Annals of the New York Academy of Sciences Vol. 1514; no. 1; pp. 11 - 20
• Main Authors: Lee, Sungyul, Lee, Jeong Ho
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01.08.2022
• Subjects: Aging; antisense oligonucleotide (ASO); Antisense oligonucleotides; Antisense RNA; Antisense therapy; Brain; brain disease; Drug development; Etiology; Genetic screening; Germ cells; Mental disorders; Mutation; neural stem cell (NSC); Neural stem cells; Neurodevelopmental disorders; Neurological diseases; Neurological disorders; Pathogenesis; Ribonucleic acid; RNA; RNA therapeutics; siRNA; somatic mutation; Stem cells; Therapeutic applications; Therapeutic targets; brain disease; RNA therapeutics; antisense oligonucleotide (ASO); somatic mutation; neural stem cell (NSC)
• ISSN: 0077-8923; 1749-6632
• DOI: 10.1111/nyas.14786

Research into the genetic etiology of a neurological disorder can provide directions for genetic diagnosis and targeted therapy. In the past, germline mutations, which are transmitted from parents or newly arise from parental germ cells, were considered as major genetic causes of neurological disorders. However, recent evidence has shown that somatic mutations in the brain, which can arise from neural stem cells during development or over aging, account for a significant number of brain disorders, ranging from neurodevelopmental, neurodegenerative, and neuropsychiatric to neoplastic disease. Moreover, the identification of disease‐causing somatic mutations or mutated genes has provided new insights into molecular pathogenesis and unveiled potential therapeutic targets for treating neurological disorders that have few, or no, therapeutic options. RNA therapeutics, including antisense oligonucleotide (ASO) and small interfering RNA (siRNA), are emerging as promising therapeutic tools for treating genetic neurological disorders. As the number of approved and investigational ASO and siRNA drugs for neurological disorders associated with germline mutations increases, they may also prove to be attractive modalities for treating neurologic disorders resulting from somatic mutations. In this perspective, we highlight several neurological diseases caused by brain somatic mutations and discuss the potential role of RNA therapeutics in these conditions. In this perspective, we highlight several neurological disorders associated with brain somatic mutations and discuss the potential of RNA therapeutics for treating such conditions.