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 SMA and ALS patients harboring SOD1 mutations, respectively. Gene addition/silencing approaches using AAV are also currently under clinical investigation in trials for SMA and ALS. Here, we provide a brief overview of these current efforts alongside with their advantages and challenges. We also review genome editing approaches aimed either at correcting the disease-causing mutations or at modulating the expression of genetic modifiers, e.g. by repairing SOD1 mutations or SMN2 splicing defect, or deleting C9orf72 expanded repeats. This recent and accumulating body of work has shown promising results to approach therapeutic trials that should significantly lower the progression of these deadly disorders.
Copyright © 2021. Published by Elsevier Inc.