The emerging role of gene therapy in autism spectrum disorder

Abstract Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by heterogeneity in its genetic, epigenetic, and environmental etiologies, posing significant challenges for therapeutic development. While currently lacking curative treatments, substantial progress in understanding the genetic underpinnings of ASD, particularly monogenic forms, offers promising avenues for intervention. This review aims to elucidate recent advancements in gene therapy approaches for monogenic ASDs and discuss their potential implications for the broader autism spectrum, highlighting the crucial role of animal models in preclinical development and the identification of shared pathogenic mechanisms. Current gene therapy strategies encompassing transient methods like antisense oligonucleotides and RNA editing, alongside permanent genome-altering techniques such as CRISPR/Cas9-based editing and gene replacement, are being actively explored for disorders like Angelman syndrome, Rett syndrome, fragile X syndrome, and tuberous sclerosis complex. Preclinical studies in animal models mimicking these monogenic conditions have demonstrated encouraging results, including reversing neurological deficits even in symptomatic adult animals. These successes underscore the potential for therapeutic intervention beyond early developmental stages. Notably, the increasing recognition of convergent molecular pathways between syndromic and nonsyndromic ASD suggests that therapies developed for specific monogenic forms might hold broader applicability across the autism spectrum. The integration of advanced research tools, such as iPSC-derived neural cells and organoids, further enhances the translational relevance of these findings. In this context, insights gained from monogenic ASD research and encouraging preclinical outcomes provide optimism for the future development of targeted gene therapies. Continued research focused on identifying shared pathogenic mechanisms and refining gene therapy technologies is crucial for realizing this potential across the diverse autism spectrum.