Gene Therapies for Monogenic Autism Spectrum Disorders.

Wout Weuring,Bobby P C Koeleman,Jeroen Geerligs

doi:10.3390/genes12111667

Wout Weuring, Bobby P C Koeleman + Show 1 more

Open Access

https://doi.org/10.3390/genes12111667

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Journal: Genes	Publication Date: Oct 22, 2021
Citations: 18	License type: CC BY 4.0

Affiliation: University Medical Center Utrecht

Abstract

Novel genome editing and transient gene therapies have been developed the past ten years, resulting in the first in-human clinical trials for monogenic disorders. Syndromic autism spectrum disorders can be caused by mutations in a single gene. Given the monogenic aspect and severity of syndromic ASD, it is an ideal candidate for gene therapies. Here, we selected 11 monogenic ASD syndromes, validated by animal models, and reviewed current gene therapies for each syndrome. Given the wide variety and novelty of some forms of gene therapy, the best possible option must be decided based on the gene and mutation.

Highlights

At present, gene therapies are on the rise (Figure 1)
Most current gene therapies are focused on monogenic diseases with a strong penetrant single genetic cause that is well understood in terms of disease mechanism
Intensive genetic studies have confirmed that autism spectrum disorder (ASD) has a strong genetic basis that shows a high degree of genetic heterogeneity [3]

Summary

Introduction

Gene therapies are on the rise (Figure 1). The first approved gene therapies for human diseases are being used in the clinic, and we are experiencing an exponential rise in putative gene therapies in development [1,2]. It is expected that gene therapies will become a possibility for a large range of diseases, including autism. Most current gene therapies are focused on monogenic diseases with a strong penetrant single genetic cause that is well understood in terms of disease mechanism. Syndromic ASD is typically more severe, and an underlying single genetic cause is known in most cases. It is for this category of ASD that gene therapy is most promising, and for which the first gene therapies are in an advanced stage of development (Table 1). We provide an overview of current gene therapies in development for 11 monogenic autism syndromes, which were chosen based on previous clinical publications and validation by animal models. SV: Structural variants ASO: Antisense oligonucleotide, GD: Gene delivery, RE: RNA editing, GR: Gene replacement, KO: CRISPR-KO, GE: Gene editing

Transient Gene Therapies That Do Not Edit the Genome

Permanent Gene Therapies That Alter the Genome

Discussion