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Review
. 2023 Aug;18(8):1679-1683.
doi: 10.4103/1673-5374.363185.

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

Bruno P Imbimbo  1 , Viviana Triaca  2 , Camillo Imbimbo  3 , Robert Nisticò  4
Affiliations
Review

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

Bruno P Imbimbo et al. Neural Regen Res. 2023 Aug.

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.

Keywords: Alzheimer’s disease; Huntington’s disease; Parkinson’s disease; amyloid precursor protein; amyotrophic lateral sclerosis; glucocerebrosidase; huntingtin; presenilin 1; presenilin 2; superoxide dismutase 1.

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Conflict of interest statement

None

Figures

Figure 1
Figure 1
The 3D structures of amyloid precursor protein (APP), presenilin 1 (PS1), huntingtin (Htt), superoxide dismutase (SOD1), and α-synuclein (α-SYN) proteins are shown. Examples of protein mutations underlying familial dominant forms of Alzheimer’s disease (A), Huntington’s disease (B), amyotrophic lateral sclerosis (C), and Parkinson’s disease (D) are shown (for structure rendering see Additional file 1). (A) In Alzheimer’s disease, there are hundreds of point missense mutations of APP, PS1 and PS2 proteins. As example, the Glu693Gly mutation of APP and the Glu280Ala mutation of PS1 are shown. APP is initially cleaved by the β-secretase at the β-cleavage site and then by the γ-secretase complex within the transmembrane domain (TMD). The γ-secretase complex is formed by the sequential assembly of Aph1, nicastrin, presenilin (PS1 and PS2) and Pen-2 and generates the Aβ peptide and the APP intracellular domain. Most of the AD pathogenic alterations are identified in the PSEN1 gene, while mutations in PSEN2 and APP are less frequently observed. (B) In Huntington’s disease, the genetic expansion of the CAG triplet repeat of the HTT gene leads to extra glutamines in the poly-Q region near the N-terminus of the Htt protein. (C) In amyotrophic lateral sclerosis, more than 180 SOD1 variants exist. As example, the Ala4Val and Asp90Ala mutations of SOD1 are shown. The Ala4Val mutation is the most common SOD1-ALS mutation and it is localized within the dimer interface region and is frequent in the North American population and it is associated with an early onset, and short duration of the disease. The Asp90Ala mutation is diffused in the Scandinavia and it has a longer post-presentation survival. (D) In Parkinson’s disease, there are several α-synuclein mutations. As example, the Ala53Thr mutation at the α-synuclein N-terminus is shown. This missense mutation is associated with an aggressive early onset familial Parkinson’s disease form.
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