Gene Therapy for Autism Spectrum Disorder: Preclinical Advances, Translational Barriers, and Ethical Dimensions - A...

Autism spectrum disorder (ASD) lacks disease-modifying therapies. Gene therapy offers a promising avenue to target the underlying molecular causes of ASD, particularly in monogenic or syndromic forms where single-gene mutations play a central role.

A scoping review was conducted following the PRISMA-ScR framework. We searched PubMed, Scopus, Web of Science, PsycINFO, and the Cochrane Library (2000-July 2025), with the last search completed in July 2025. Eligible studies included preclinical or translational investigations involving gene-therapy modalities (e.g., AAV vectors, ASOs, CRISPR-based editing) targeting high-confidence ASD-linked genes; non-gene-therapy studies, unrelated conditions, reviews, and non-English papers were excluded. Data were charted using a standardized extraction form and synthesized descriptively across two evidence streams. Stream 1 evaluated preclinical studies of gene therapy, while Stream 2 examined translational advances and ethical considerations.

Twenty-one preclinical studies were identified in Stream 1, focusing on genes such as UBE3A, MECP2, FMR1, SHANK3/2, SCN2A, and SYNGAP1. Most demonstrated molecular correction and improvements in synaptic, electrophysiological, and behavioral outcomes, with therapeutic effects observed from early developmental to adult timepoints. Stream 2 synthesized 12 studies highlighting translational challenges, including delivery innovations (e.g., engineered viral capsids, nanoparticles), safety concerns (immune responses, dose-dependent toxicities), and ethical considerations (pediatric consent, neurodiversity perspectives, equity in access). Limitations include heterogeneity across models, reliance on rodent studies, and absence of completed human clinical trials.

Gene therapy for ASD shows considerable promise but faces significant translational and ethical hurdles. Standardized study designs, comprehensive safety evaluation, and transparent stakeholder engagement will be critical for developing responsible and effective clinical applications.