<i>SOD1</i>Suppression with Adeno-Associated Virus and MicroRNA in Familial ALS

Mueller, Christian; Berry, James; McKenna‐Yasek, Diane; Gernoux, Gwladys; Owegi, Margaret; Pothier, Lindsay; Douthwright, Catherine; Gelevski, Dario; Luppino, Sarah; Blackwood, Meghan; Wightman, Nicholas; Oakley, Derek H.; Frosch, Matthew P.; Flotte, TR; Cudkowicz, Merit; Brown, Robert H.

doi:10.1056/nejmoa2005056

Cited by 200 publications

(172 citation statements)

References 17 publications

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“…It is also possible that partial knockdown of human wild-type SOD1 through antisense oligonucleotides or RNA-based therapies might be tested in sporadic ALS, beyond the SOD1-mutant familial ALS for which these gene therapy modalities have recently demonstrated efficacy (62,63). trihydrochloride (#H3570, Thermo Fisher, Canada), Fluoromount-G (#00-4958-02, SouthernBiotech, USA).…”

Section: Discussionmentioning

confidence: 99%

Tryptophan residues in TDP-43 and SOD1 mediate the cross-seeding and toxicity of SOD1

Pokrishevsky

DuVal

McAlary

et al. 2020

Preprint

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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease of motor neurons. Neuronal superoxide dismutase-1 (SOD1) inclusion bodies are characteristic of familial ALS with SOD1 mutations, while a hallmark of sporadic ALS is inclusions containing aggregated wild-type TAR DNA-binding protein 43 (TDP-43). Co-expression of mutant or wild-type TDP-43 with SOD1 leads to misfolding of endogenous SOD1 and aggregation of SOD1 reporter protein G85R-GFP in HEK293FT cells, and promotes synergistic axonopathy in zebrafish. This pathological interaction is dependent upon natively solvent-exposed tryptophans in SOD1 (tryptophan-32) and TDP-43 RRM1 (tryptophan-172), in concert with natively sequestered TDP-43 N-terminal domain tryptophan-68. TDP-43 RRM1 intrabodies reduce wild-type SOD1 misfolding in HEK293FT cells, via blocking tryptophan-172. Tryptophan-68 becomes antibody-accessible in aggregated TDP-43 in sporadic ALS motor neurons and cell culture. 5-fluorouridine inhibits TDP-43-induced G85R-GFP SOD1 aggregation in HEK293FT cells, and ameliorates axonopathy in zebrafish, via its interaction with SOD1 tryptophan-32. Collectively, our results establish a novel and potentially druggable tryptophan-mediated mechanism whereby two principal ALS disease effector proteins might directly interact in disease.

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Section: Discussionmentioning

confidence: 99%

Tryptophan residues in TDP-43 and SOD1 mediate the cross-seeding and toxicity of SOD1

Pokrishevsky

DuVal

McAlary

et al. 2020

Preprint

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“…Patient 1 developed meningoradiculitis after viral infusion and only transient improvement in the strength of his right leg was observed, with no change in vital capacity. In contrast, Patient 2, who received immunosuppressive drugs, had stable scores on a composite measure of ALS function and a stable vital capacity during a 12-month period [52]. The follow-up of this patient should give further indications on the effects of this novel therapeutic approach.…”

Section: Aav-mediated Silencing Approaches For Fals (Sod1 and C9orf72mentioning

confidence: 91%

“…The vector lowered SOD1 expression in the entire spinal cord motor neurons and was found to be well tolerated with no negative effects [77]. Importantly, a similar AAV vector was recently tested in a compassionate-use study on two SOD1-ALS patients who were respectively 22-years (patient 1) and 56-years-old (patient 2) [52]. The results of this study showed post-mortem decreased levels of SOD1 in spinal cord tissue of patient 1 compared to untreated patients with SOD1-linked ALS and healthy controls.…”

Section: Aav-mediated Silencing Approaches For Fals (Sod1 and C9orf72mentioning

confidence: 99%

Beyond the Traditional Clinical Trials for Amyotrophic Lateral Sclerosis and The Future Impact of Gene Therapy

Cappella

Pradat

Querin

et al. 2020

Journal of Neuromuscular Diseases

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Amyotrophic lateral sclerosis (ALS) is a devastating and incurable motor neuron (MN) disorder affecting both upper and lower MNs. Despite impressive advances in the understanding of the disease’s pathological mechanism, classical pharmacological clinical trials failed to provide an efficient cure for ALS over the past twenty years. Two different gene therapy approaches were recently approved for the monogenic disease Spinal muscular atrophy, characterized by degeneration of lower MNs. This milestone suggests that gene therapy-based therapeutic solutions could be effective for the treatment of ALS. This review summarizes the possible reasons for the failure of traditional clinical trials for ALS. It provides then a focus on the advent of gene therapy approaches for hereditary forms of ALS. Specifically, it describes on-going clinical trials in which antisense oligonucleotides are used in three familial forms of ALS, caused by mutations in SOD1, C9orf72 and FUS genes, respectively. Clinical and pre-clinical studies based on AAV-mediated gene therapy approaches for both familial and sporadic ALS cases are presented as well. Overall, this overview highlights the potential of gene therapy as a transforming technology that will have a huge impact on treatment perspective for ALS patients and on the design of future clinical trials.

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“…The second study, led by Christian Mueller, PhD, Associate Professor of Pediatrics at the University of Massachusetts Medical School in Worcester, conducted a proof-of-concept study to assess the feasibility of a new method of gene silencing that could be used to halt the activity of mutated SOD1 in patients with familial ALS (Mueller et al, 2020). In this study, 2 male patients, aged 22 and 56 years, received a single intrathecal infusion of adeno-associated virus encoding a microRNA that targeted SOD1.…”

Section: Gene Silencingmentioning

confidence: 99%

SOD1 Targeted as Treatment for Amyotrophic Lateral Sclerosis

2020

American J of Med Genetics Pt A

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SOD1Suppression with Adeno-Associated Virus and MicroRNA in Familial ALS

Cited by 200 publications

References 17 publications

Tryptophan residues in TDP-43 and SOD1 mediate the cross-seeding and toxicity of SOD1

Tryptophan residues in TDP-43 and SOD1 mediate the cross-seeding and toxicity of SOD1

Beyond the Traditional Clinical Trials for Amyotrophic Lateral Sclerosis and The Future Impact of Gene Therapy

SOD1 Targeted as Treatment for Amyotrophic Lateral Sclerosis

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