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Modern Gene Therapies Show Promise in Motor Neuron Disorders


A review of current research and drug development in motor neuron disorders such as amyotrophic lateral sclerosis and spinal muscular atrophy shows progress in the identification of treatment pathways and therapies.

Gene therapies are novel yet promising strategies for treating motor neuron disorders (MNDs) such as amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA). These diseases are characterized by progressive muscle weakness and atrophy, respiratory failure, and early death—but recent years have seen increased research and expanding treatment options for patients. A review of MND research overall and the gene therapies tested in clinical trials for MNDs highlights promising strategies to approach treatment.

SMA, the most common genetic cause of child mortality, was considered fatal and incurable until 2017. There are 5 types of SMA, and mortality is particularly high in type 1, which presents in infancy. Less than 8% of these patients survive for 20 months. ALS is the most common type of adult-onset MND in clinical practice. Onset is typically between ages 40 and 70 years, and most patients experience respiratory failure within 3 to 5 years.

The first novel drug approved for SMA was nusinersen, which modifies splicing of the SMN2 pre-mRNA resulting in the production of full‐length SMN protein. A second therapy, onasemnogene abeparvovec, originally known as AVXS‐101, was approved by FDA for intravenous therapy in patients with SMA under 2 years of age in 2019.

In ALS, just 2 noncurative drugs are approved, both of which slightly improve quality of life by slowing progression of the disease. Riluzole, a glutamate antagonist that prolongs the survival of patients by a few months, was approved in 1995 and delays the onset of ventilator dependence and tracheostomy. Edaravone, approved by the FDA in 2017, acts as a free radical scavenger. It slows disease progression by reducing oxidative stress and protecting neurons, specifically in patients who start treatment in the early stages of the disease.

These MNDs differ significantly when it comes to the number of causative genes. Research has identified more than 35 causative genes in ALS, the most common mutations occurring in C9orf72, SOD1, TARDP, and FUS. It is also multifactorial, with environmental factors also playing a role in its pathogenesis. Most cases are sporadic ALS (sALS), but some have familial history (fALS). SMA, on the other hand, is most commonly caused by a homozygous mutation of the SMN1 gene on chromosome 5q13.3.

In both MNDs overall, gene therapies hold promise for treatment. The review highlighted several types of vector-mediated gene therapies:

  • Retroviral/lentiviral vectors
  • Herpes simplex vectors
  • Adenoviral vectors
  • Adeno-associated vectors (AAVs)

“All drugs that contain an active substance that includes or consists of a recombinant nucleic acid (DNA or RNA), administered to a human being for the purpose to adjust, repair, replace, add, or remove a gene sequence, can be defined as gene therapy,” the author wrote. Viral vector technologies and RNA modulating therapy are gene therapies most relevant to MNDs.

In SOD1-linked fALS and C9orf72-linked ALS, clinical and preclinical research has found that antisense oligonucleotides (ASOs) might be effective in targeting the mutated genes. A patient with early-onset ALS, Jaci Hermstad, was treated with a personalized ASO to target an FUS mutation after the US House of Representatives passed a bill and the FDA approved Hermstad’s treatment.

ASOs are also being developed in preclinical settings to target mRNAs that encode the disease‐modifying proteins that play a part in motor neuron death in ALS. Given most ALS cases are sporadic, therapies targeting mutant genes are impossible in most cases, the review author notes. Therefore, targeting pathogenic pathways associated with ALS is of interest. Disturbances of RNA metabolism, stress granule (SG) response, and protein degradation pathways are key mechanisms. SGs are protein-RNA complexes that form due to genetic or environmental factors.

In sporadic and familial ALS, mutations of angiogenin gene (ANG), which is expressed in motor neurons and protects cultured motor neurons against injury, have been identified. This may be another therapeutic route in ALS.

Viral vector gene therapy for ALS has also been explored in preclinical studies, with vectors constructed using human therapeutic genes VEGF165 and ANG under the construction term “AdeVasc.” A phase 2 clinical trial showed efficacy in a high-dose cohort, slowing disease progression and motor and respiratory decline.

Overall, the review author highlights AAV-based viral vectors as the most promising strategy but cites cost as one major drawback. The most expensive drug in the world, the AAV9-based onasemnogene abeparvovec (sold as Zolgensma by Novartis), is priced at $2.1 million per treatment, she notes.

The review concludes on an optimistic tone that the future of MND treatment, particularly ALS, will brighten given the common molecular pathways of neurodegeneration in MNDs.

“Over the last 2 decades, gene therapy using ASOs or viral vectors has emerged as the most promising strategy for treating MNDs,” the author wrote. "Through developing ASO‐ and virus vector‐mediated drugs for SMA, much has been understood about opportunities of gene therapy in all MNDs, including ALS, one of the most fatal and progressive forms of the MNDs spectrum.”


Zakharova M. Modern approaches in gene therapy of motor neuron diseases. Med Res Rev. 2021;41(5):2634-2655. doi:10.1002/med.21705

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