Safety and Tolerability of Triumeq in Amyotrophic Lateral Sclerosis: The Lighthouse Trial

Gold, Julian; Rowe, Dominic B.; Kiernan, Matthew C.; Vucic, Steve; Mathers, Susan; Eijk, Ruben P A van; Nath, Avindra; Montojo, Marta Garcia; Norato, Gina; Santamaria, Ulisses A.; Rogers, Mary‐Louise; Malaspina, Andrea; Lombardi, Vittoria; Mehta, Pritesh; Westeneng, Henk‐Jan; Berg, Leonard H van den; Al‐Chalabi, Ammar

doi:10.2139/ssrn.3347916

Cited by 18 publications

(25 citation statements)

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“…It would be interesting to test the therapeutic potential of strategies that block the expression or activity of TEs in NDs. Indeed, several ongoing clinical trials are currently testing the safety and tolerability of reverse transcriptase inhibitors in AD (https://clinicaltrials.gov/ct2/show/NCT04500847; https://clinicaltrials.gov/ct2/show/results/NCT04552795), ALS [213], and AGS (https://clinicaltrials.gov/ct2/show/NCT02363452). These approaches are based on the use of reverse transcriptase inhibitors either alone or in combination with anti‐HERV integrase inhibitors [143] to target different TEs.…”

Section: Tes As New Therapeutic Targetsmentioning

confidence: 99%

Transposable elements as new players in neurodegenerative diseases

et al. 2021

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Neurodegenerative diseases (NDs), including the most prevalent Alzheimer’s disease and Parkinson disease, share common pathological features. Despite decades of gene‐centric approaches, the molecular mechanisms underlying these diseases remain widely elusive. In recent years, transposable elements (TEs), long considered ‘junk’ DNA, have gained growing interest as pathogenic players in NDs. Age is the major risk factor for most NDs, and several repressive mechanisms of TEs, such as heterochromatinization, fail with age. Indeed, heterochromatin relaxation leading to TE derepression has been reported in various models of neurodegeneration and NDs. There is also evidence that certain pathogenic proteins involved in NDs (e.g., tau, TDP‐43) may control the expression of TEs. The deleterious consequences of TE activation are not well known but they could include DNA damage and genomic instability, altered host gene expression, and/or neuroinflammation, which are common hallmarks of neurodegeneration and aging. TEs might thus represent an overlooked pathogenic culprit for both brain aging and neurodegeneration. Certain pathological effects of TEs might be prevented by inhibiting their activity, pointing to TEs as novel targets for neuroprotection.

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Section: Tes As New Therapeutic Targetsmentioning

confidence: 99%

Transposable elements as new players in neurodegenerative diseases

et al. 2021

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“…In a recent phase 2 study HERV-K was targeted using the antiretroviral drug, Triumeq. In response to treatment with Triumeq a favorable response on HERV-K expression was seen, which was accompanied by a decline in ALSFRS-R progression rate of ±20% [116].…”

Section: Expert Opinionmentioning

confidence: 97%

Is it accurate to classify ALS as a neuromuscular disorder?

Goedee

Westeneng

et al. 2020

Expert Review of Neurotherapeutics

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Introduction: Amyotrophic lateral sclerosis (ALS) is a fatal disorder characterized by the progressive loss of upper and lower motor neurons. ALS has traditionally been classified within the domain of neuromuscular diseases, which are a unique spectrum of disorders that predominantly affect the peripheral nervous system. However, over the past decades compounding evidence has emerged that there is extensive involvement of the central nervous system. Therefore, one can question whether it remains accurate to classify ALS as a neuromuscular disorder. Areas covered: In this review, the authors sought to discuss current approaches toward disease classification and how we should classify ALS based on novel insights from clinical, imaging, pathophysiological, neuropathological and genetic studies. Expert opinion: ALS exhibits the cardinal features of a neurodegenerative disease. Therefore, classifying ALS as a neuromuscular disease in the strict sense has become untenable. Diagnosing ALS however does require significant neuromuscular expertise and therefore neuromuscular specialists remain best equipped to evaluate this category of patients. Designating motor neuron diseases as a separate category in the ICD-11 is justified and adequately deals with this issue. However, to drive effective therapy development the fields of motor neuron disease and neurodegenerative disorders must come together.

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“…In cell culture experiments, L1 retrotransposition is strongly inhibited by nucleoside reverse transcriptase inhibitors (NRTIs) and recent studies have identified NRTIs that limit L1s and/or HERVs, including drugs widely used against HIV-1 infection [123][124][125]. Of interest, pilot clinical trials using NRTI inhibitors to reduce retrotransposon activity have begun for amyotrophic lateral sclerosis (Clinical-Trials.gov Identifiers NCT02437110, NCT02868580, [181]) and AGS (NCT02363452, NCT03304717). One of the AGS trials, now completed, reported reduction in interferonstimulated gene expression in treated patients [182].…”

Section: Testing the Hypothesismentioning

confidence: 99%

A potential new mechanism for pregnancy loss: considering the role of LINE-1 retrotransposons in early spontaneous miscarriage

Lou

Goodier

Qiang

2020

Reprod Biol Endocrinol

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LINE1 retrotransposons are mobile DNA elements that copy and paste themselves into new sites in the genome. To ensure their evolutionary success, heritable new LINE-1 insertions accumulate in cells that can transmit genetic information to the next generation (i.e., germ cells and embryonic stem cells). It is our hypothesis that LINE1 retrotransposons, insertional mutagens that affect expression of genes, may be causal agents of early miscarriage in humans. The cell has evolved various defenses restricting retrotransposition-caused mutation, but these are occasionally relaxed in certain somatic cell types, including those of the early embryo. We predict that reduced suppression of L1s in germ cells or early-stage embryos may lead to excessive genome mutation by retrotransposon insertion, or to the induction of an inflammatory response or apoptosis due to increased expression of L1-derived nucleic acids and proteins, and so disrupt gene function important for embryogenesis. If correct, a novel threat to normal human development is revealed, and reverse transcriptase therapy could be one future strategy for controlling this cause of embryonic damage in patients with recurrent miscarriages.

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Safety and Tolerability of Triumeq in Amyotrophic Lateral Sclerosis: The Lighthouse Trial

Cited by 18 publications

References 0 publications

Transposable elements as new players in neurodegenerative diseases

Transposable elements as new players in neurodegenerative diseases

Is it accurate to classify ALS as a neuromuscular disorder?

A potential new mechanism for pregnancy loss: considering the role of LINE-1 retrotransposons in early spontaneous miscarriage

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