Phase 1–2 Trial of Antisense Oligonucleotide Tofersen for <i>SOD1</i> ALS

Miller, Timothy M.; Cudkowicz, Merit; Shaw, Pamela J.; Benatar, Michael; Atassi, Nazem; Bucelli, Robert C.; Genge, Angela; Glass, Jonathan D.; Ladha, Shafeeq; Ludolph, Albert L.; Maragakis, Nicholas J.; McDermott, Christopher J.; Pestronk, Alan; Ravits, John; Salachas, François; Trudell, Randall; Damme, Philip Van; Zinman, Lorne; Bennett, C. Frank; Lane, Roger; Sandrock, Alfred; Runz, Heiko; Graham, Danielle; Houshyar, Hani; McCampbell, Alexander; Nestorov, Ivan; Chang, Ih; McNeill, Manjit; Fanning, Laura; Fradette, Stephanie; Ferguson, Toby A.

doi:10.1056/nejmoa2003715

Cited by 379 publications

(276 citation statements)

References 18 publications

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“…Furthermore, in humans, a phase 1-2 ascending dose trial evaluating the effect of Tofersen (an ASO that mediates SOD1 degradation) in SOD1 ALS, exploratory results on 50 SOD1 mutated patients showed a slowing in the decrease of ALSFRS-R, slow vital capacity and handheld dynamometry scores during time, a matched decrease of SOD1 protein in the CSF and of pNfH and NfL in plasma and CSF, especially in the group treated with the highest dose (100 mg) and in fast progressors, from baseline to day 85 and to a lesser extent also later on [103]. Notably, in the placebo group plasma and CSF NFs levels remained almost stable.…”

Section: Nfs As Disease-progression Biomarkersmentioning

confidence: 95%

Neurofilaments in motor neuron disorders: towards promising diagnostic and prognostic biomarkers

Zucchi

Bonetto

Sorarù

et al. 2020

Mol Neurodegeneration

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Motor neuron diseases (MNDs) are etiologically and biologically heterogeneous diseases. The pathobiology of motor neuron degeneration is still largely unknown, and no effective therapy is available. Heterogeneity and lack of specific disease biomarkers have been appointed as leading reasons for past clinical trial failure, and biomarker discovery is pivotal in today’s MND research agenda. In the last decade, neurofilaments (NFs) have emerged as promising biomarkers for the clinical assessment of neurodegeneration. NFs are scaffolding proteins with predominant structural functions contributing to the axonal cytoskeleton of myelinated axons. NFs are released in CSF and peripheral blood as a consequence of axonal degeneration, irrespective of the primary causal event. Due to the current availability of highly-sensitive automated technologies capable of precisely quantify proteins in biofluids in the femtomolar range, it is now possible to reliably measure NFs not only in CSF but also in blood. In this review, we will discuss how NFs are impacting research and clinical management in ALS and other MNDs. Besides contributing to the diagnosis at early stages by differentiating between MNDs with different clinical evolution and severity, NFs may provide a useful tool for the early enrolment of patients in clinical trials. Due to their stability across the disease, NFs convey prognostic information and, on a larger scale, help to stratify patients in homogenous groups. Shortcomings of NFs assessment in biofluids will also be discussed according to the available literature in the attempt to predict the most appropriate use of the biomarker in the MND clinic.

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Section: Nfs As Disease-progression Biomarkersmentioning

confidence: 95%

Neurofilaments in motor neuron disorders: towards promising diagnostic and prognostic biomarkers

Zucchi

Bonetto

Sorarù

et al. 2020

Mol Neurodegeneration

View full text Add to dashboard Cite

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“…We report that, upon stress, DRiPs diffuse into the nucleus and accumulate in nucleoli and PML bodies (5), which are biomolecular condensates similar to SGs. If not properly cleared by the PQC, DRiPs convert nucleoli and PML bodies from a dynamic into an amyloid-like state and compromise nuclear proteostasis.…”

Section: Serena Carramentioning

confidence: 90%

Platform Communications: Abstract Book - 31st International Symposium on ALS/MND (Complete printable file)

2020

Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration

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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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Phase 1–2 Trial of Antisense Oligonucleotide Tofersen for SOD1 ALS

Cited by 379 publications

References 18 publications

Neurofilaments in motor neuron disorders: towards promising diagnostic and prognostic biomarkers

Neurofilaments in motor neuron disorders: towards promising diagnostic and prognostic biomarkers

Platform Communications: Abstract Book - 31st International Symposium on ALS/MND (Complete printable file)

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

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