Two recent studies have shown that personalized therapy for neurodegenerative diseases associated with single-gene mutations could be within reach.
Up to 15% of ALS (at times referred to as motor neuronal disease or Lou Gehrig's disease) patients have a positive family history of ALS or frontotemporal dementia. A number of genes or gene loci play a role in familial ALS, including the SOD1 gene (copper-zinc superoxide dismutase-1 gene). Alterations in this gene are detectable in about 13-20% of Europeans with familial ALS and in about 3% of patients with sporadic ALS. Mutations in the SOD1 gene are inherited in an autosomal dominant pattern.1,2
There is even evidence that misfolded SOD1 could spread like a prion among motor neurons and contribute to the pathogenesis of sporadic ALS, even in patients in whom SOD1 is not mutated.
The editorial and two articles in the current issue of the New England Journal of Medicine focus on something that could mark the beginning of genomic therapies in ALS.1,3,4
An American team tested the intrathecal administration of different doses of tofersen (previously known as IONIS-SOD1Rx or BIIB067) in a phase I-II study on 48 ALS volunteers with SOD1 mutations.4 Tofersen is an antisense nucleotide that mediates the degradation of SOD1 messenger RNA and thus reduces SOD1 protein synthesis. The highest doses of tofersen led to a reduction in cerebrospinal fluid (CSF) SOD1 levels, which the authors consider a surrogate parameter for the target being hit. Under tofersen, neurofilament levels in CSF also decreased, which could be indirect evidence of reduced neurodegeneration.
A post hoc analysis divided the participants into two groups according to whether they had SOD1 alterations associated with rapid disease progression. In patients with such mutations, the neurofilament concentrations in the CSF seemed to decrease more strongly and the clinical worsening (measured by the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale, ALSFRS-R) seemed to be less steep than in treated patients without "fast progression" mutations.
Although the study was too small to assess efficacy, it could pave the way to potentially the first disease-modifying therapy for a portion of patients if efficacy can be demonstrated in phase-III studies with longer follow-up. In addition, reduced neurofilament levels could serve as a biomarker in future studies.
Another, small proof-of-concept study tested a virus-mediated microRNA therapy.3 Two participants received a one-time intrathecal microRNA embedded in a viral vector that targets SOD1.
In contrast to the study presented above, no significant changes in SOD1 protein levels in CSF were observed in these subjects, but post-mortem examination of samples from one of the patients indicated suppression of SOD1 concentrations in the spinal cord tissue. Whether this could be clinically useful is uncertain at this point. The viral vector caused meningoradiculitis in the first patient, which led to the administration of immunosuppressive drugs in the second patient.
The editorial also points out that over 200 gene variants of SOD1 are known, but pathogenicity has only been proven for a handful of them. Further therapies for other genetic forms of ALS are currently undergoing early clinical and preclinical studies. These beginnings in subgroups of patients with specific genetic characteristics represent hope for patients with genetic risk factors for this devastating disease.
References:
1. Hardiman, O. & van den Berg, L. H. The Beginning of Genomic Therapies for ALS. New England Journal of Medicine 383, 180-181 (2020).
2. Amyotrophic lateral sclerosis. http://www.klinikum.uni-muenchen.de/Friedrich-Baur-Institut/de/krankheitsbilder/amyotrophe_lateralsklerose/index.html.
3. Mueller, C. et al. SOD1 Suppression with Adeno-Associated Virus and MicroRNA in Familial ALS. New England Journal of Medicine 383, 151-158 (2020).
4. Miller, T. et al. Phase 1-2 Trial of Antisense Oligonucleotides Tofersen for SOD1 ALS. New England Journal of Medicine 383, 109-119 (2020).