Disease-modifying therapies in amyotrophic lateral sclerosis

Abstract

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder of adult life, causing weakness and wasting of voluntary muscles, associated in about 50% of cases with a cognitive impairment.Pathologically, the disease is characterized by a degeneration of upper and lower motor neurons. A hallmark of the pathological process is the aggregation of the protein TDP43 in the cytoplasm of affected neurons detected in almost 97% of cases. About 15% of cases has a family history.Currently, only two drugs have been demonstrated to be effective in ALS, riluzole and edaravone, which show only modest effects on disease progression. The quest for disease-modifying therapies in ALS has several obstacles, the most important being the sub-optimal quality of the design of clinical trials, and the clinical and pathological heterogeneity of the disease.In this paper the pathological mechanisms relevant to ALS and current and future pharmacological and non-pharmacological trials, including gene and stem cells therapies, will be presented.

11C‐PK11195 PET–based molecular study of microglia activation in SOD1 amyotrophic lateral sclerosis

“…Cognitive and behavioral disturbances due to frontal dysfunction, involving about 50% of ALS patients 3,4 can be associated with motor impairment. Currently, no treatment is available to stop or reverse ALS, and the identification of reliable biomarkers for presymptomatic diagnosis as well as for monitoring disease progression is of utmost importance, favoring the understanding of pathophysiology and the development and evaluation of potential disease‐modifying drugs 5 …”

Duality of P2X7 Receptor in Amyotrophic Lateral Sclerosis

“…ALS is at least two centuries old and is a rare, relentless, multi-layered and heterogeneous familial/sporadic disease targeting motor neurons and additional cell phenotypes as muscles, glia and immune cells (Casterton et al, 2020;Yerbury et al, 2020). It typically causes death within 3-5 years from onset, but it still has no cure because all efforts in the search for treatments have failed so far (Mejzini et al, 2019;Chiò et al, 2020). Current therapies can only reduce morbidity.…”

TDP-43 proteinopathies: a new wave of neurodegenerative diseases

“…Pathogenic missense mutations in the TARDBP gene (>50 mutations) have been reported in both sporadic and familial cases of ALS and FTLD, 20 with the majority of mutations clustering in the C-terminal glycine-rich region which enhance the aggregation propensity and cytotoxicity of the TDP-43 protein, thereby leading to a toxic gain-of-function. The C-terminal region also interacts with the other hnRNPs to mediate RNA splicing, thereby providing an additional avenue for pathogenesis.…”

“…Several genetic therapeutic approaches could be used in TDP-43 proteinopathies, including antisense oligonucleotides, interference of RNA pathways through siRNAs, gene delivery techniques and antibody-mediated reduction of protein aggregation. 20 While a detailed discussion of the methodologies is beyond the scope of this review (see Chio and colleagues for a more detailed discussion), 20 these approaches could provide viable therapeutic options, although are still in the early stages of development.…”

“…100 The clinical efficacy of autophagy-enhancing agents is currently being assessed in both ALS and Guam ALS/PDC. 20…”