Aug 2026· Neuropsychobiology· pp.
1-22
· 0 citations
Medicine
TL;DR
Gene therapy for ASD shows considerable promise but faces significant translational and ethical hurdles and standardized study designs, comprehensive safety evaluation, and transparent stakeholder engagement will be critical for developing responsible and effective clinical applications.
Abstract
Background
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.
Methods
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.
Results
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.
Conclusions
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.
The study provides an integrated framework linking genetic variation to molecular dysfunction and clinical outcomes, offering valuable insights for future research and therapeutic development in pediatric neurology.
Varada Vidya Rani, Suryanarayana Reddy Kovvuri, D. Arya· Genetics and Molecular Resea...· 0 citations
The framework used to evaluate the relevance of animal models-construct, face, and predictive validity-is outlined and the behavioural paradigms used to assess core ASD-related domains in rodents are summarized, including social interaction and communication, restricted and repetitive behaviours, and cognitive flexibility.
Pilar Martinez Olondo, Alban de Kerchove d'Exaerde· Developmental Medicine & Chi...· 0 citations
Autism spectrum disorder is a heterogeneous condition marked by social communication difficulties and restricted/repetitive behaviors. Although major progress has been made over the past two decades in understanding its genetics and molecular mechanisms, effective treatments remain limited. Report from the 2021 Lancet Commission on autism recommends that research should focus on improving quality of life through personalized assessment and intervention. Due to its heterogeneity, multiple treatment strategies will likely be needed. For some individuals, especially those with severe syndromic autism, gene therapy may offer future therapeutic options. To match patient subgroups to treatments, both "mutation clustering to treatment" forward approach and "treatment to disease subgroup" reverse approach can be used. Building a broad treatment portfolio will take time, but even incremental advances would be meaningful. Principles of neural plasticity, such as early intervention and repeated practice, may also enhance outcomes alone or alongside other therapies.
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This review evaluates the potential of CRISPR-based editing as a therapeutic strategy for monogenic NDDs and evaluates the limitations that must be addressed before its widespread application in human patients.
Julia Mulles· American Journal of Student...· 0 citations
Genetic neurodevelopmental disorders (NDDs) encompass a heterogeneous group of conditions characterized by impaired cognitive, behavioral, and neurological development resulting from pathogenic variants affecting brain development and synaptic function. Advances in molecular genetics and next-generation sequencing have significantly expanded the understanding of the genetic architecture underlying disorders such as Rett syndrome (RTT), Fragile X syndrome (FXS), Angelman syndrome (AS), and autism spectrum disorders. Beyond these classical neurodevelopmental disorders, spinal muscular atrophy (SMA) is included as a paradigmatic example of successful RNA-based therapeutic translation. Concurrently, RNA-based therapeutics have emerged as promising precision medicine strategies capable of modulating gene expression at the transcriptional and post-transcriptional levels. These approaches include antisense oligonucleotides (ASOs), small interfering RNAs (siRNAs), messenger RNA (mRNA) therapies, RNA editing technologies, and splice-modulating agents. Recent clinical successes, particularly in spinal muscular atrophy, have demonstrated the transformative potential of RNA therapeutics in neurological disease. However, substantial challenges remain, including BBB penetration, long-term safety, immune activation, and genotype-specific variability in therapeutic response. This review summarizes current advances in RNA-based therapeutics for genetic NDDs, highlighting molecular mechanisms, disease-specific therapeutic strategies, translational progress, delivery challenges, and future directions. Overall, continued progress will depend on the integration of disease biology, rational RNA therapeutic design, and effective CNS-targeted delivery, supporting the broader implementation of precision RNA medicine for genetic neurodevelopmental disorders.
I. Focșa, C. Iliescu, C. Pomeran et al.· International Journal of Mol...· 0 citations
Autism spectrum disorder (ASD) exhibits pronounced heterogeneity across genetic, neurobiological, and clinical phenotypic levels, posing substantial challenges for mechanistic elucidation and clinical translation. This review synthesizes advances in data-driven approaches to parsing ASD heterogeneity and centers the discussion on three complementary strata: neural, behavioral, and transdiagnostic subtypes. At the neuroimaging level, studies leveraging features such as functional connectivity and brain structure have consistently identified two core neurosubtypes characterized by increased and decreased neural activity, respectively. These neurosubtypes differ in time-varying dynamics, spatial architecture, and network hierarchy, and they are closely associated with specific symptom dimensions and cognitive functions. At the behavioral level, data-driven methods delineate phenotypes along axes of severity and functional impairment, and further reveal their links to neural circuits. Transdiagnostic investigations indicate that ASD and frequently co-occurring disorders share neurobiological substrates and cognitive endophenotypes. Collectively, these findings argue against a simple one-to-one correspondence between behavioral and neural subtypes; instead, the evidence is more consistent with multi-to-one, one-to-many, or many-to-many mappings that converge on the overall functional impairment. Notwithstanding this progress, major challenges remain, including sample heterogeneity, methodological inconsistency, and the integration of categorical and dimensional models. Future research should prioritize large samples, multi-site collaboration, longitudinal designs, and transdiagnostic frameworks, coupled with reverse validation via intervention response, to build robust evidence for mechanism-informed individualized assessment and intervention in ASD.
Xingke Wang, Zhou Zhang, Shuang Li et al.· Translational Psychiatry· 0 citations
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