Therapeutic strategies for autism: targeting three levels of the central dogma of molecular biology.

Researchers reviewed new treatment approaches for autism that work at different levels in cells. These include gene therapies, treatments that affect how genes make proteins, and traditional medications. While scientists have found many genes linked to autism in recent years, turning this knowledge into actual treatments has been challenging. Getting treatments into the brain remains a major hurdle that needs solving.

This review examines therapeutic strategies for autism spectrum disorder (ASD) targeting loss-of-function mutations at three molecular levels. The authors discuss gene-based approaches including CRISPR activation and gene replacement at the DNA level, antisense oligonucleotides at the mRNA level, and small-molecule drugs at the protein level. Despite significant progress in identifying ASD risk genes with loss-of-function mutations over the past decade, no major clinical advances in ASD therapeutics have emerged. The review emphasizes that central nervous system penetrance is crucial for ASD treatments, necessitating delivery methods that effectively cross the blood-brain barrier.

The therapeutic approaches aim to rescue haploinsufficient gene effects across different molecular pathways.

Clinicians should be aware that while genetic understanding of autism has advanced significantly, translation to clinical treatments remains challenging. Future autism therapies may require personalized approaches based on specific genetic profiles and innovative delivery methods to achieve brain penetrance.

As a narrative review, findings represent expert opinion rather than systematic analysis of evidence. No quantitative synthesis of therapeutic efficacy data is provided. The review does not assess the current clinical trial status or comparative effectiveness of discussed approaches.

The past decade has yielded much success in the identification of risk genes for Autism Spectrum Disorder (ASD), with many studies implicating loss-of-function (LoF) mutations within these genes. Despite this, no significant clinical advances have been made so far in the development of therapeutics for ASD. Given the role of LoF mutations in ASD etiology, many of the therapeutics in development are designed to rescue the haploinsufficient effect of genes at the transcriptional, translational, and protein levels. This review will discuss the various therapeutic techniques being developed from each level of the central dogma with examples including: CRISPR activation (CRISPRa) and gene replacement at the DNA level, antisense oligonucleotides (ASOs) at the mRNA level, and small-molecule drugs at the protein level, followed by a review of current delivery methods for these therapeutics.

Since central nervous system (CNS) penetrance is of utmost importance for ASD therapeutics, it is especially necessary to evaluate delivery methods that have higher efficiency in crossing the blood-brain barrier (BBB).