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).

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Multiple sclerosis is an autoimmune disease that causes demeylination and axonal loss in the central nervous system. Although immune-linkage between the central nervous system and the gut is not well understood, recent studies indicated that activation of myelin-specific T cells by commensal bacteria initiated the development of autoimmune diseases in the central nervous system, suggesting that there is an autoimmune linkage between the gut and the central nervous system. We found that golli-myelin basic protein is expressed in the gut epithelial cells and myelin basic protein-specific T cells develop in the gut of transgenic mice expressing the HLA-DR2a and myelin basic protein-TCR genes. We also found that commensal bacteria-derived peptides can serve as an agonist/antagonist of HLA-DR2a-restricted myelin basic protein-specific T cells. This data suggests that commensal bacteria may play an important role in the development of myelin-specific pathogenic T cells.