Novel genome-editing-based approaches to treat motor neuron diseases: Promises and challenges

Abstract

Motor neuron diseases are untreatable with common pharmacological approaches. Spinal muscular atrophy (SMA) is caused by SMN1 gene mutations leading to lowered SMN expression. Symptoms are alleviated in infants with a higher copy number of the SMN2 gene, which, however, displays a splicing defect resulting in low SMN levels. Amyotrophic lateral sclerosis (ALS) is caused by a number of mutations, with C9orf72 repeat expansions the most common genetic cause and SOD1 gain-of-function mutations the first genetic cause identified for this disease. Genetic therapies based on oligonucleotides that enhance SMN2 splicing and SMN production or lower SOD1 expression have shown promise in initial clinical trials for individuals with SMA and ALS harboring SOD1 mutations, respectively. Gene addition/silencing approaches using adeno-associated viruses (AAVs) are also currently under clinical investigation in trials for SMA and ALS. Here we provide a brief overview of these efforts and their advantages and challenges. We also review genome editing approaches aimed at correcting the diseasecausing mutations or modulating the expression of genetic modifiers, e.g., by repairing SOD1 mutations or the SMN2 splicing defect or deleting C9orf72 expanded repeats. These studies have shown promising results to approach therapeutic trials that should significantly lower the progression of these deadly disorders.Both of these major neurological diseases lead to a severe handicap and cause early mortality in the majority of affected people. These disorders are currently untreatable with common pharmacological approaches. On the other hand, genetic therapy has been quite promising in early clinical trials, particularly for SMA. 16,17 Here we provide a brief overview of these initial therapeutic strategies and cover the pre-clinical studies exploiting genome editing approaches and their challenges and advantages.

Biomarkers for C9orf7-ALS in Symptomatic and Pre-symptomatic Patients: State-of-the-art in the New Era of Clinical Trials

“…In recent years, advances in the understanding of the molecular basis of C9orf72-related clinical phenotypes and the development of disease models have led to the identification of innovant disease modifying drugs [11,15,16]. Although currently available C9orf72 animal models lack some of the key features of the disease, such as reduced survival and neuromuscular decline [17,18], they can recapitulate the molecular signature of the disease and were used for therapeutic pre-clinical development [19,20].…”

Exon7 Targeted CRISPR-Prime Editing Approaches for SMN2 Gene Editing in Spinal Muscular Atrophy (SMA) Disease Can Increase In Vitro SMN Expression

“…Previous studies have shown that single point mutations on the SMN2 gene can lead to an increase in SMN expression. However, until now, it has not been shown with the CRISPR system whether these mutations can be created synthetically in the laboratory and have the capacity to increase the production of SMN protein (Miccio et al, 2022). We designed a proof-of-concept experiment for the first time with this study by performing pegRNA designs that can create these point mutations, and we used the Jurkat cell line with low SMN expression for this.…”

Promise of Nucleic Acid Therapeutics for Amyotrophic Lateral Sclerosis

“…Genome editing techniques enable direct, simple, and efficient repair and correction of abnormal genes, and are expected to enable treatments that were not possible with conventional gene therapy. Although many barriers, such as off‐target activity, delivery systems, and immunogenicity, must be overcome, the therapeutic application to single‐gene diseases, such as familial ALS, is promising 73 . A phase I study in patients with hereditary TTR amyloidosis has already started (http://clinicaltrials.gov Identifier: NCT04601051).…”