Amyotrophic lateral sclerosis (ALS) is a devastating and incurable neurodegenerative disease characterized by the progressive loss of upper and lower motor neurons. ALS causes death, usually within 2–5 years of diagnosis. Riluzole, the only drug currently approved in Europe for the treatment of this condition, offers only a modest benefit, increasing survival by 3 months on average. Recent advances in our understanding of causative or disease-modifying genetic variants and in the development of genetic therapy strategies present exciting new therapeutic opportunities for ALS. In addition, the approval of adeno-associated virus-mediated delivery of functional copies of the SMN1 gene to treat spinal muscular atrophy represents an important therapeutic milestone and demonstrates the potential of gene replacement therapies for motor neuron disorders. In this Review, we describe the current landscape of genetic therapies in ALS, highlighting achievements and critical challenges. In particular, we discuss opportunities for gene replacement therapy in subgroups of people with ALS, and we describe loss-of-function mutations that are known to contribute to the pathophysiology of ALS and could represent novel targets for gene replacement therapies.
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease for which no effective disease-modifying therapy is currently available; emerging evidence suggests genetic therapy as an attractive new therapeutic strategy for this disease.
Genetic therapy can be classified into silencing, editing or replacement approaches, depending on whether the aim is to reduce the expression of toxic mutant proteins, introduce genomic modifications or provide functional copies of a dysfunctional gene.
Adeno-associated viruses (AAVs) are considered the vehicle of choice for the delivery of genetic materials. AAV9 is particularly attractive for neurological applications, as it can penetrate the blood–brain barrier and effectively deliver its cargo to both dividing and non-dividing cells.
Challenges that hinder the clinical application of genetic therapies in ALS include the multifactorial and oligogenic nature of the disease and the problem of efficiently and simultaneously targeting both motor neurons and glial cells. Nevertheless, some preclinical and clinical studies are currently testing gene therapy strategies for this disease, mostly focusing on silencing of toxic gene mutations.
Accumulating in vitro and in vivo evidence suggests loss of function as the mechanism underlying the effects of mutations in five ALS-associated genes (TBK1, OPTN, NEK1, FIG4 and ANG), and restoring the functions of these genes through replacement strategies could represent a promising therapeutic opportunity.
In the future, precision medicine approaches that target specific pathophysiological mechanisms in each affected individual can be envisaged.
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I.G. is supported by a SITraN postdoctoral fellowship. P.J.S. is supported as a National Institute for Health and Care Research (NIHR) Senior Investigator (NF-SI-0617-10077), by the NIHR Sheffield Biomedical Research Centre (IS-BRC-1215-20017). P.J.S. and M.A. are supported by the EU Innovative Medicines Initiative Accelerating Research and Development for Advanced Therapies (IMI ARDAT 945473) and a Medical Research Council (MRC) LifeArc award (MR/V030140/1). M.A. is further sponsored by the European Research Council (ERC Advanced Award 294745), an MRC Award (MR/G1001492), CureAP4, EU Joint Programme — Neurodegenerative Disease Research (MR/V000470/1) and Alzheimer’s Research UK. P.J.S. and J.K. are supported by the Motor Neurone Disease Association (AMBRoSIA 972-797 and NECTAR 974-797).
The authors declare no competing interests.
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Giovannelli, I., Higginbottom, A., Kirby, J. et al. Prospects for gene replacement therapies in amyotrophic lateral sclerosis. Nat Rev Neurol 19, 39–52 (2023). https://doi.org/10.1038/s41582-022-00751-5