Treatment of hereditary amyotrophic lateral sclerosis

Available online 3 November 2022

Abstract

Currently, only four molecules can be prescribed for amyotrophic lateral sclerosis (ALS), of which only one is approved worldwide for this indication, riluzole. Although progress in the therapeutic field remains unsatisfactory, we have to notice that genetics have undergone impressive improvements over the last three decades and, by extension, our knowledge of ALS cases linked to a pathogenic mutation that accounts for 10% of all cases (either sporadic or familiar) and is currently called hereditary ALS (hALS). In many neurological diseases treatment targeting pathogenic genes have significatively improved the natural profile of the disease: this is perfectly illustrated for familial amyloid neuropathy and spinal muscular atrophy. Because of these findings and the urgent need to find a cure for ALS, many trials have focused on familial ALS targeting the four most important genes linked to the disease: C9orf72, SOD1, TARDBP and FUS. We propose in this review an update on the perspectives of treatment that may be available in mid-term in hALS and will discuss in the last part the potential consequences for asymptomatic relatives of patients with a hALS and for ALS patients.

Section snippetsGene therapy

The gold standard of care for hALS does not differ from that of classical ALS: this relies in both situations on riluzole worldwide, and edaravone delivered intravenously in some countries such as the United States, Japan, Switzerland and Canada [13], [14]. Last June, a combination of sodium phenyl butyrate and ursodoxicoltaurine (Albrioza™) became available under stringent conditions for some patients with ALS in Canada. Recently a new drug has been approved for certain ALS patients, tofersen,

Viral-mediated gene delivery

Viral-mediated gene delivery has also been developed in patients with ALS linked to SOD1 mutation [31]. This research in patients has resulted from several trials in animal models showing that this approach could be promising in ALS; as shown in G93A SOD1 mice models, intravenous injection at birth of shRNA targeting SOD1 would improve the natural history of MND in these animals since the onset was delayed, progression slowed and median duration of the disease increased by 39% [32].

So far, two

New indications for licensed drugs

Some compounds already marketed in other diseases have been tested in ALS.

The most illustrative include arimoclomol, a co-inducer of heat shock protein, which was tested at the dosage of 200 mg t.i.d. in ALS linked to a SOD1 mutation [34]. Thirty-six patients were included in this double-blinded, placebo controlled, randomized 1:1 trial that showed a trend towards a positive effect of arimoclomol on ALSFRs-r slope and some respiratory functional tests. A phase III was conducted (NCT03491462) in

Potential therapeutic approaches that need to be confirmed

The last decade has been marked by a growing interest in the development of immunotherapy in neurological diseases such as Alzheimer's disease, Parkinson's disease and also ALS [36]. Immunotherapy could also become a promising therapeutic approach in hALS and probably in long term in ALS.

The mutated SOD1 gene has long been the target of monoclonal antibodies (Mab) and more precisely the d-binding region (DBR) epitope located in the N-terminal part of the mutated SOD1 protein but not

Monitoring of presymptomatic individuals

In the last five years, monitoring relatives of patients with ALS linked to a pathogenic genetic mutation has become a major topic of research. This may be explained by two outstanding improvements in ALS management: (i) easy access to genetic testing for all patients with both sALS and fALS due to recommendations for systematic screening, at least currently, for SOD1 and C9orf72 in sALS, and for C9orf72 and next generation sequencing screening in fALS [11], [41], [42]. (ii) as mentioned above

Conclusion

Despite numerous failures of clinical trials in ALS, optimism is currently growing because there is a body of evidence suggesting that we have the resources to improve the course of the disease: we have a better understanding of the ins and the outs that lead to motor neuron death. Therapeutic possibilities are increasing in ALS, mainly due to development of gene therapy, which strengthens the need to promote a personalized therapeutic approach in ALS rather than generalist care as proposed

Contributions

All authors PC, HB, SB, ASP, PV contributed equally to the inception and drafting of this review paper.

Disclosure of Interest

PV, SB, ASP, HB have nothing to disclose.

PC serve on scientific advisory boards for Biogen, Amylyx, Cytokinetics, VectorY.

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