Trial of Antisense Oligonucleotide Tofersen for
            <i>SOD1</i>
            ALS

Miller, Timothy M.; Cudkowicz, Merit; Genge, Angela; Shaw, Pamela J.; Sobue, Gen; Bucelli, Robert C.; Chiò, Adriano; Damme, Philip Van; Ludolph, Albert C.; Glass, Jonathan D.; Andrews, Jinsy; Babu, Suma; Benatar, Michael; McDermott, C. John; Cochrane, Thos; Chary, Sowmya; Chew, Sheena; Zhu, Han; Wu, Fan; Nestorov, Ivan; Graham, Danielle; Sun, Peng; McNeill, Manjit; Fanning, Laura; Ferguson, Toby A.; Fradette, Stephanie

doi:10.1056/nejmoa2204705

Cited by 435 publications

(267 citation statements)

References 26 publications

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“…A switch from the more resource demanding larger proteins, NfH and NfM, to a higher concentration of the smaller NfL in the heteropolymer comes at practically no risk to Nf heteropolymer stability (Kim et al, 2011), but helps the motor neuron to save time and energy (ADP) (Zucchi et al, 2018). Modulation of Nf stoichiometry should be of interest for gene silencing methods (McCampbell et al, 2018; Miller et al, 2020). The idea is to transiently and reversibly lower the expression of individual Nf isoforms.…”

Section: Stoichiometrymentioning

confidence: 99%

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The 2022 Lady Estelle Wolfson lectureship on neurofilaments

Petzold

2022

Journal of Neurochemistry

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Neurofilament proteins (Nf) have been validated and established as a reliable body fluid biomarker for neurodegenerative pathology. This review covers seven Nf isoforms, Nf light (NfL), two splicing variants of Nf medium (NfM), two splicing variants of Nf heavy (NfH), -internexin (INA) and peripherin (PRPH). The genetic and epigenetic aspects of Nf are discussed as relevant for neurodegenerative diseases and oncology. The comprehensive list of mutations for all Nf isoforms covers Amyotrophic Lateral Sclerosis, Charcot-Marie Tooth disease, Spinal muscular atrophy, Parkinson Disease and Lewy Body Dementia. Next, emphasis is given to the expanding field of post-translational modifications (PTM) of the Nf amino acid residues. Protein structural aspects are reviewed alongside PTMs causing neurodegenerative pathology and human autoimmunity. Molecular visualisations of NF PTMs, assembly and stoichiometry make use of Alphafold2 modelling. The implications for Nf function on the cellular level and axonal transport are discussed. Neurofilament aggregate formation and proteolytic breakdown are reviewed as relevant for biomarker tests and disease.Likewise, Nf stoichiometry is reviewed with regard to in vitro experiments and as a compensatory mechanism in neurodegeneration. The review of Nf across a spectrum of 87 diseases from all parts of medicine is followed by a critical appraisal of 33

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Section: Stoichiometrymentioning

confidence: 99%

“…CSF and blood Nf concentrations permit to identify individuals with rapid and slow disease progression (Brettschneider, Petzold, Suessmuth, et al, 2006; Gille et al, 2018; Lu et al, 2015). Consequently, Nf became a secondary endpoint for two clinical trials in ALS (Miller et al, 2020; Paganoni et al, 2020).…”

Section: Diseasesmentioning

confidence: 99%

The 2022 Lady Estelle Wolfson lectureship on neurofilaments

Petzold

2022

Journal of Neurochemistry

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“…ALS is such a heterogeneous disease that the FDA published guidelines in 2019 [ 4 ] encouraging drug developers to identify subsets of patients most responsive to their therapeutic approach. Among the many targets identified that have recently been tested clinically are those directed against ALS-associated genetic mutations [ 5 ], reactive oxygen species [ 6 ], misfolded proteins [ 7 ], dysfunctional mitochondria [ 8 ], growth factor deficiencies [ 9 ] and neuroinflammation [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

Macrophage-Targeted Sodium Chlorite (NP001) Slows Progression of Amyotrophic Lateral Sclerosis (ALS) through Regulation of Microbial Translocation

Zhang

Bracci

Azhir³

et al. 2022

Biomedicines

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Amyotrophic lateral sclerosis (ALS) is a heterogeneous, progressive, and universally fatal neurodegenerative disease. A subset of ALS patients has measurable plasma levels of lipopolysaccharide (LPS) and C-reactive protein (CRP) consistent with low-grade microbial translocation (MT). Unless interrupted, MT sets up a self-perpetuating loop of inflammation associated with systemic macrophage activation. To test whether MT contributed to ALS progression, blood specimens from a phase 2 study of NP001 in ALS patients were evaluated for changes in activity in treated patients as compared to controls over the 6-month study. In this post hoc analysis, plasma specimens from baseline and six-month timepoints were analyzed. Compared with baseline values, biomarkers related to MT were significantly decreased (LPS, LPS binding protein (LBP), IL-18, Hepatocyte growth factor (HGF), soluble CD163 (sCD163)) in NP001-treated patients as compared to controls, whereas wound healing and immunoregulatory factors were increased (IL-10, Epidermal growth factor (EGF), neopterin) by the end of study. These biomarker results linked to the positive clinical trial outcome confirm that regulation of macrophage activation may be an effective approach for the treatment of ALS and, potentially, other neuroinflammatory diseases related to MT.

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“…The recently reported therapeutic effect of the ASO Tofersen in some adult patients with SOD1 ALS, is a futher proof that ASOs can be successfully delivered and exert desired activity in the CNS [ 110 ]. However, better therapeutic options for patients with ALS are clearly needed [ 111 ].…”

Section: Discussion: Can Otis Combine the Powers Of Crispr/cas And As...mentioning

confidence: 99%

Oligonucleotide-Recognizing Topoisomerase Inhibitors (OTIs): Precision Gene Editors for Neurodegenerative Diseases?

Bax

Sutormin

McDonald

et al. 2022

IJMS

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Topoisomerases are essential enzymes that recognize and modify the topology of DNA to allow DNA replication and transcription to take place. Topoisomerases are divided into type I topoisomerases, that cleave one DNA strand to modify DNA topology, and type II, that cleave both DNA strands. Topoisomerases normally rapidly religate cleaved-DNA once the topology has been modified. Topoisomerases do not recognize specific DNA sequences, but actively cleave positively supercoiled DNA ahead of transcription bubbles or replication forks, and negative supercoils (or precatenanes) behind, thus allowing the unwinding of the DNA-helix to proceed (during both transcription and replication). Drugs that stabilize DNA-cleavage complexes with topoisomerases produce cytotoxic DNA damage and kill fast-dividing cells; they are widely used in cancer chemotherapy. Oligonucleotide-recognizing topoisomerase inhibitors (OTIs) have given drugs that stabilize DNA-cleavage complexes specificity by linking them to either: (i) DNA duplex recognizing triplex forming oligonucleotide (TFO-OTIs) or DNA duplex recognizing pyrrole-imidazole-polyamides (PIP-OTIs) (ii) or by conventional Watson–Crick base pairing (WC-OTIs). This converts compounds from indiscriminate DNA-damaging drugs to highly specific targeted DNA-cleaving OTIs. Herein we propose simple strategies to enable DNA-duplex strand invasion of WC-OTIs giving strand-invading SI-OTIs. This will make SI-OTIs similar to the guide RNAs of CRISPR/Cas9 nuclease bacterial immune systems. However, an important difference between OTIs and CRISPR/Cas9, is that OTIs do not require the introduction of foreign proteins into cells. Recent successful oligonucleotide therapeutics for neurodegenerative diseases suggest that OTIs can be developed to be highly specific gene editing agents for DNA lesions that cause neurodegenerative diseases.

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Trial of Antisense Oligonucleotide Tofersen for SOD1 ALS

Cited by 435 publications

References 26 publications

The 2022 Lady Estelle Wolfson lectureship on neurofilaments

The 2022 Lady Estelle Wolfson lectureship on neurofilaments

Macrophage-Targeted Sodium Chlorite (NP001) Slows Progression of Amyotrophic Lateral Sclerosis (ALS) through Regulation of Microbial Translocation

Oligonucleotide-Recognizing Topoisomerase Inhibitors (OTIs): Precision Gene Editors for Neurodegenerative Diseases?

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