Therapeutic Development in Amyotrophic Lateral Sclerosis

Bucchia, Monica; Ramirez, Agnese; Parente, Valeria; Simone, Carla; Nizzardo, Monica; Magri, Francesca; Dametti, Sara; Corti, Stefania

doi:10.1016/j.clinthera.2014.12.020

Cited by 70 publications

(55 citation statements)

References 62 publications

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“…Amyotrophic lateral sclerosis (ALS) is an incurable and invariably fatal neurodegenerative condition characterized by the progressive loss of both upper and lower motor neurons in the cortex, brainstem, and spinal cord; it clinically results in progressive paralysis and death within 3-5 years of its onset, often due to respiratory failure [1]. No effective therapy is available for this disease.…”

Section: Introductionmentioning

confidence: 99%

Development of Therapeutics for C9ORF72 ALS/FTD-Related Disorders

et al. 2016

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The identification of the hexanucleotide repeat expansion (HRE) GGGGCC (G4C2) in the non-coding region of the C9ORF72 gene as the most frequent genetic cause of both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) has opened the path for advances in the knowledge and treatment of these disorders, which remain incurable. Recent evidence suggests that HRE RNA can cause gain-of-function neurotoxicity, but haploinsufficiency has also been hypothesized. In this review, we describe the recent developments in therapeutic targeting of the pathological expansion of C9ORF72 for ALS, FTD, and other neurodegenerative disorders. Three approaches are prominent: (1) an antisense oligonucleotides/RNA interference strategy; (2) using small compounds to counteract the toxic effects directly exerted by RNA derived from the repeat transcription (foci), by the translation of dipeptide repeat proteins (DPRs) from the repeated sequence, or by the sequestration of RNA-binding proteins from the C9ORF72 expansion; and (3) gene therapy, not only for silencing the toxic RNA/protein, but also for rescuing haploinsufficiency caused by the reduced transcription of the C9ORF72 coding sequence or by the diminished availability of RNA-binding proteins that are sequestered by RNA foci. Finally, with the perspective of clinical therapy, we Maria Sara Cipolat Mis and Simona Brajkovic contributed equally to this work.

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Section: Introductionmentioning

confidence: 99%

Development of Therapeutics for C9ORF72 ALS/FTD-Related Disorders

et al. 2016

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“…There is still no effective treatment for amyotrophic lateral sclerosis (ALS), a fatal, progressive neurodegenerative disease characterized by the selective loss of upper and lower motor neurons (MNs) (Bucchia et al, 2015). The degeneration of MNs clinically leads to progressive paralysis and early death due to respiratory failure.…”

Section: Introductionmentioning

confidence: 99%

“…Many pathways have been suggested to play a role in the disease pathogenesis including alteration of protein stability, conformation and degradation, disturbances of RNA metabolism, and axonal transport defects (Bucchia et al, 2015). In particular, mutated genes that cause ALS, such as superoxide dismutase 1 (SOD1), TAR DNA-binding protein 43 (TARDBP encoding for TDP-43), and RNA-binding protein FUS, encode proteins that can form aggregates (Al-Chalabi et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

Autophagy in motor neuron disease: Key pathogenetic mechanisms and therapeutic targets

Mis

Brajkovic

Frattini

et al. 2016

Molecular and Cellular Neuroscience

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a b s t r a c tAutophagy is a lysosome-dependant intracellular degradation process that eliminates long-lived proteins as well as damaged organelles from the cytoplasm. An increasing body of evidence suggests that dysregulation of this system plays a pivotal role in the etiology and/or progression of neurodegenerative diseases including motor neuron disorders. Herein, we review the latest findings that highlight the involvement of autophagy in the pathogenesis of amyotrophic lateral sclerosis (ALS) and the potential role of this pathway as a target of therapeutic purposes. Autophagy promotes the removal of toxic, cytoplasmic aggregate-prone pathogenetic proteins, enhances cell survival, and modulates inflammation. The existence of several drugs targeting this pathway can facilitate the translation of basic research to clinical trials for ALS and other motor neuron diseases..

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“…[53] About 90% of cases are sporadic while about 10% are hereditary and are Caused by mutations in the Super Oxide Dismutase 1 (SOD1), TARDBP and FUS genes. [2,8] The gene therapy attempts to ALS have had as major target the defective activity of superoxide dismutase correction. These experiments were made possible after the animal models development.…”

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confidence: 99%

“…Amyotrophic lateral sclerosis (ALS) is the most common form of MND, in which affected individuals generally die from respiratory failure within 2-5 years of diagnosis. [1,2] Also known as Charcot's disease (France) or Lou Gehrig's disease (USA) is a acquired disease and neurodegenerative of unknown cause that affects mainly the motor neurons of the spinal cord, brain stem and brain. [3] ALS is a devastating neurodegenerative disease, and luckily, very rare: only one to two people out of 100,000 develop ALS yearly.…”

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Amyotrophic Lateral Sclerosis: The Current World Situation

Júnior¹,

Silva²,

Oliveira³

et al. 2016

Int Arch Med

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Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of unknown cause that affects mainly the motor neurons of the spinal cord, brain stem and brain. The pathogenesis is still obscure and the diagnosis is based on patient history and clinical examination. A handful of factors have been proposed to be associated with ALS; however, the only established risk factors to date are older age, male sex, and a family history of ALS. The familial cases have their historical importance in causative gene identification since through these discoveries much has been uncovered about ALS pathogenesis. The understanding of clinical and epidemiological factors associated with functional impairment is of fundamental for early adoption of measures to promote a better survival and a better quality of life. Rapid diagnosis of amyotrophic lateral sclerosis (ALS) and other neurological disorders is vital if future treatments are to be applied at an early disease stage. The current pace of discovery and identification of novel disease mechanisms in ALS is unprecedented. Advances in this area, however, have also introduced challenges in the heterogeneity of diagnostic definitions affecting this patient population.

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Therapeutic Development in Amyotrophic Lateral Sclerosis

Cited by 70 publications

References 62 publications

Development of Therapeutics for C9ORF72 ALS/FTD-Related Disorders

Development of Therapeutics for C9ORF72 ALS/FTD-Related Disorders

Autophagy in motor neuron disease: Key pathogenetic mechanisms and therapeutic targets

Amyotrophic Lateral Sclerosis: The Current World Situation

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