Investigational treatments for neurodegenerative diseases caused by inheritance of gene mutations: lessons from recent clinical trials

Abstract

We reviewed recent major clinical trials with investigational drugs for the treatment of subjects with neurodegenerative diseases caused by inheritance of gene mutations or associated with genetic risk factors. Specifically, we discussed randomized clinical trials in subjects with Alzheimer’s disease, Huntington’s disease and amyotrophic lateral sclerosis bearing pathogenic gene mutations, and glucocerebrosidase-associated Parkinson’s disease. Learning potential lessons to improve future therapeutic approaches is the aim of this review. Two long-term, controlled trials on three anti-β-amyloid monoclonal antibodies (solanezumab, gantenerumab and crenezumab) in subjects carrying Alzheimer’s disease-linked mutated genes encoding for amyloid precursor protein or presenilin 1 or presenilin 2 failed to show cognitive or functional benefits. A major trial on tominersen, an antisense oligonucleotide designed to reduce the production of the huntingtin protein in subjects with Huntington’s disease, was prematurely interrupted because the drug failed to show higher efficacy than placebo and, at highest doses, led to worsened outcomes. A 28-week trial of tofersen, an antisense oligonucleotide for superoxide dismutase 1 in patients with amyotrophic lateral sclerosis with superoxide dismutase 1 gene mutations failed to show significant beneficial effects but the 1-year open label extension of this study indicated better clinical and functional outcomes in the group with early tofersen therapy. A trial of venglustat, a potent and brain-penetrant glucosylceramide synthase inhibitor, in Parkinson’s disease subjects with heterozygous glucocerebrosidase gene mutations revealed worsened clinical and cognitive performance of patients on the enzyme inhibitor compared to placebo. We concluded that clinical trials in neurodegenerative diseases with a genetic basis should test monoclonal antibodies, antisense oligonucleotides or gene editing directed against the mutated enzyme or the mutated substrate without dramatically affecting physiological wild-type variants.

Mechanism Exploration of Amyloid-β-42 Disaggregation by Single-Chain Variable Fragments of Alzheimer’s Disease Therapeutic Antibodies

“…Solanezumab, which only binds soluble monomers, recognizes residues 13 to 24 of Aβ42 [26]. Crenezumab recognizes residues 13 to 24 of Aβ42 and has a high affinity for the oligomeric form [26][27][28]. Because of the distinct abilities of these mAbs, corresponding scFvs, scFv-C, scFv-S, and scFv-12B4 were designed and constructed.…”

Presenilin: A Multi-Functional Molecule in the Pathogenesis of Alzheimer’s Disease and Other Neurodegenerative Diseases

“…Gene editing technologies have been explored to correct certain presenilin mutations [115]. Recent studies have shown that CRISPR-Cas9 gene editing technology is able to selectively disrupt PSEN1 mutations leading to an autosomal dominant form of early-onset AD and counteract the AD-associated phenotype [116,117]. Despite challenges, targeting the γ-secretase complex, especially presenilin, remains a therapeutic focus in AD research.…”

Nucleic acid therapeutics as differentiation agents for myeloid leukemias

“…Lack of efficacy is one of the main reasons NATs fail in clinical trials [ 21 ]. Two recent examples of failed NATs include drisapersen (an exon skipping ASO developed for Duchenne muscular dystrophy) [ 23 ] and tominersen (an ASO targeting the mutated transcript in Huntington’s Disease) [ 24 ]. Despite demonstrating promising efficacy in two independent phase II trials, drisapersen development was terminated following its phase III trial as the treatment failed to significantly slow disease progression.…”