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

Abstract

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).

Treatability of the KMT2-Associated Neurodevelopmental Disorders Using Antisense Oligonucleotide-Based Treatments

“…The molecular pathomechanism and phenotypic presentation of the KMT2-associated NDDs make them attractive candidates to be considered for ASO strategies. In general, several reports support the notion that the KMT2-associated NDDs would benefit from ASO treatments [86,87].…”

“…ASO-based treatments are emerging as therapeutic options for an increasing number of rare genetic disorders, including NDDs [16,86,87]. The molecular pathomechanism and phenotypic presentation of the KMT2-associated NDDs make them attractive candidates to be considered for ASO strategies.…”

“…No disease-modifying, genetic treatments are yet available for any of the KMT2-associated disorders, and most therapeutic strategies focus on managing clinical manifestations and preventing secondary complications [32,34,40,85]. Yet, based on the clinical presentation, the KMT2-associated NDDs can potentially benefit from ASO approaches, which has already been suggested by others [86][87][88].…”

Suberoylanilide Hydroxamic Acid (SAHA) Is a Driver Molecule of Neuroplasticity: Implication for Neurological Diseases

“…Autism spectrum disorder (ASD) is a neurodevelopmental disorder affecting almost 1% of children, characterized by impairments in language and social interaction coupled with various degrees of intellectual disability (ID) [ 64 ]. Several studies have demonstrated a strong association between rare de novo and inherited copy number variants (CNV) with ASD.…”

Hydrogels in Gene Delivery Techniques for Regenerative Medicine and Tissue Engineering

“…Vector transport has considerable therapeutic potential, but limitations in its in vivo delivery have been reported, including immunogenicity leading to an immune response, difficulty in controlling the release rate, and high loss rate. [4] The use of cell proliferation to remodel diseased tissue is a promising approach in regenerative medicine, known as cell therapy. [5] The effectiveness of cell therapy is primarily influenced by the type and physicochemical properties of the cells.…”