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 approach for targeting the molecular mechanisms underlying ASD, particularly in monogenic or syndromic forms in which single-gene mutations play a central role.

A scoping review was conducted following the PRISMA-ScR framework. PubMed, Scopus, Web of Science, PsycINFO, and the Cochrane Library were searched for studies published from 2000 to July 2025. Eligible studies included preclinical or translational investigations of gene-therapy modalities, such as adeno-associated viral vectors, antisense oligonucleotides, and CRISPR-based editing, targeting high-confidence ASD-linked genes. Non-gene-therapy studies, unrelated conditions, reviews, and non-English publications were excluded. Data were extracted using a standardized form and synthesized descriptively across two evidence streams. Stream 1 examined preclinical studies of gene therapy, and Stream 2 addressed translational advances and ethical issues. Twenty-one preclinical studies were identified in Stream 1, focusing on genes including UBE3A, MECP2, FMR1, SHANK3/2, SCN2A, and SYNGAP1. Most studies reported molecular correction and improvements in synaptic, electrophysiological, and behavioral outcomes, with therapeutic effects observed from early developmental to adult stages. Stream 2 included 12 studies highlighting translational barriers such as delivery challenges, safety concerns, and ethical issues related to pediatric consent, neurodiversity, and equity of access. Important limitations included heterogeneity across models, reliance on rodent studies, and the lack of completed human clinical trials.

Gene therapy for ASD shows substantial promise, especially for genetically defined forms of the condition, but major translational and ethical challenges remain. Future progress will depend on more standardized preclinical designs, stronger safety evaluation, and transparent engagement with stakeholders to support responsible clinical translation.