Analysis of the impact of Tominersen (IONIS-HTTRX/RG6042) in the treatment of Huntington’s disease: A systematic review

Introduction: Huntington’s disease (HD) is a congenital pathology of a hereditary, neurodegenerative and progressive character, with a high mortality rate. This pathology is caused by repeated expansions of a single CAG codon in the gene encoding huntingtin. To date, several attempts to prevent and delay such a mutation have been carried out in patients. However, a promising drug, Tominersen, formerly called IONIS HTTRx/ RG6042, is in the testing phase and has shown a favorable therapeutic response, which acts directly on the messenger RNA of the gene encoding huntingtin (HTT). The drug, whose route of administration is intrathecal in bolus, intercepts and destroys the messenger before the corrupted protein can work. The present study aims to analyze the impact of Tominersen in the treatment of patients with HD and to evaluate its prognosis. Methods: The present study is a systematic literature review, in which an electronic search was performed in the PubMed, SciELO, Web of Science and Google Scholar databases. Results: In one of the double-blind randomized clinical trials (n = 46), 34 were assigned to receive the drug. The group that received Tominersen showed a decrease in the concentration of mutant HTT in cerebrospinal fluid after 28 days. In another study (n = 791), the GENERATION HD1 clinical trial is currently taking place and will last for 25 months. Conclusion: Tominersen decreases the concentration of HTT, that is, it suppressed the protein responsible for HD. Studies related to the drug are still very recent and require extra attention.

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A randomized, placebo-controlled trial of coenzyme Q10 and remacemide in Huntington’s disease

Neurology ◽

10.1212/wnl.57.3.397 ◽

2001 ◽

Vol 57 (3) ◽

pp. 397.1-404 ◽

Cited By ~ 214

Author(s):

Keyword(s):

Huntington's Disease ◽

Huntington’S Disease ◽

Controlled Trial ◽

Coenzyme Q ◽

Functional Decline ◽

Double Blind ◽

Clinical Trial Research ◽

Parallel Group ◽

To Receive ◽

Primary Measure

Objectives: To determine whether chronic treatment with coenzyme Q10 or remacemide hydrochloride slows the functional decline of early Huntington’s disease (HD).Methods: The authors conducted a multicenter, parallel group, double-blind, 2 × 2 factorial, randomized clinical trial. Research participants with early HD (n = 347) were randomized to receive coenzyme Q10 300 mg twice daily, remacemide hydrochloride 200 mg three times daily, both, or neither treatment, and were evaluated every 4 to 5 months for a total of 30 months on assigned treatment. The prespecified primary measure of efficacy was the change in total functional capacity (TFC) between baseline and 30 months. Safety measures included the frequency of clinical adverse events.Results: Neither intervention significantly altered the decline in TFC. Patients treated with coenzyme Q10 showed a trend toward slowing in TFC decline (13%) over 30 months (2.40- versus 2.74-point decline, p = 0.15), as well as beneficial trends in some secondary measures. There was increased frequency of nausea, vomiting, and dizziness with remacemide and increased frequency of stomach upset with coenzyme Q10.Conclusions: Neither remacemide nor coenzyme Q10, at the dosages studied, produced significant slowing in functional decline in early HD.

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The Impact of Upcoming Treatments in Huntington’s Disease: Resource Capacity Limitations and Access to Care Implications

Journal of Huntington s Disease ◽

10.3233/jhd-200462 ◽

2021 ◽

pp. 1-9

Author(s):

Mark Guttman ◽

Marco Pedrazzoli ◽

Marina Ponomareva ◽

Marsha Pelletier ◽

Louisa Townson ◽

...

Keyword(s):

Huntington's Disease ◽

Huntington’S Disease ◽

Healthcare Delivery ◽

Access To Treatment ◽

Capacity Limitations ◽

Second Year ◽

Capacity Gap ◽

The Impact ◽

To Receive ◽

Resource Capacity

Background: The most advanced disease-modifying therapies (DMTs) in development for Huntington’s disease (HD) require intrathecal (IT) administration, which may create or exacerbate bottlenecks in resource capacity. Objective: To understand the readiness of healthcare systems for intrathecally administered HD DMTs in terms of resource capacity dynamics and implications for patients’ access to treatment. Methods: Forty HD centres across 12 countries were included. Qualitative and quantitative data on current capacity in HD centres and anticipated capacity needs following availability of a DMT were gathered via interviews with healthcare professionals (HCPs). Data modelling was used to estimate the current capacity gap in HD centres. Results: From interviews with 218 HCPs, 25% of HD centres are estimated to have the three components required for IT administration (proceduralists, nurses and facilities). On average, 114 patients per centre per year are anticipated to receive intrathecally administered DMTs in the future. At current capacity, six of the sampled centres are estimated to be able to deliver DMTs to all the anticipated patients based on current resources. The estimated waiting list for IT administration at current capacity will average 60 months (5 years) by the second year after DMT availability. Conclusion: Additional resources are needed in HD centres for future DMTs to be accessible to all anticipated patients. Timely collaboration by the HD community will be needed to address capacity gaps. Healthcare policymakers and payers will need to address costs and navigate challenges arising from country- or region-specific healthcare delivery schemes.

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Abnormal Spinal Cord Myelination due to Oligodendrocyte Dysfunction in a Model of Huntington’s Disease

Journal of Huntington s Disease ◽

10.3233/jhd-210495 ◽

2021 ◽

pp. 1-8

Author(s):

Costanza Ferrari Bardile ◽

Harwin Sidik ◽

Reynard Quek ◽

Nur Amirah Binte Mohammad Yusof ◽

Marta Garcia-Miralles ◽

...

Keyword(s):

Spinal Cord ◽

Huntington's Disease ◽

Huntington’S Disease ◽

Oligodendrocyte Progenitor Cells ◽

Wild Type ◽

Specific Expression ◽

Relative Contribution ◽

Related Proteins ◽

The Impact ◽

Cervical Area

Background: The relative contribution of grey matter (GM) and white matter (WM) degeneration to the progressive brain atrophy in Huntington’s disease (HD) has been well studied. The pathology of the spinal cord in HD is comparatively less well documented. Objective: We aim to characterize spinal cord WM abnormalities in a mouse model of HD and evaluate whether selective removal of mutant huntingtin (mHTT) from oligodendroglia rescues these deficits. Methods: Histological assessments were used to determine the area of GM and WM in the spinal cord of 12-month-old BACHD mice, while electron microscopy was used to analyze myelin fibers in the cervical area of the spinal cord. To investigate the impact of inactivation of mHTT in oligodendroglia on these measures, we used the previously described BACHDxNG2Cre mouse line where mHTT is specifically reduced in oligodendrocyte progenitor cells. Results: We show that spinal GM and WM areas are significantly atrophied in HD mice compared to wild-type controls. We further demonstrate that specific reduction of mHTT in oligodendroglial cells rescues the atrophy of spinal cord WM, but not GM, observed in HD mice. Inactivation of mHTT in oligodendroglia had no effect on the density of oligodendroglial cells but enhanced the expression of myelin-related proteins in the spinal cord. Conclusion: Our findings demonstrate that the myelination abnormalities observed in brain WM structures in HD extend to the spinal cord and suggest that specific expression of mHTT in oligodendrocytes contributes to such abnormalities.

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Characterising Upper Limb Movements in Huntington's Disease and the Impact of Restricted Visual Cues

PLoS ONE ◽

10.1371/journal.pone.0133709 ◽

2015 ◽

Vol 10 (8) ◽

pp. e0133709 ◽

Cited By ~ 2

Author(s):

Jessica Despard ◽

Anne-Marie Ternes ◽

Bleydy Dimech-Betancourt ◽

Govinda Poudel ◽

Andrew Churchyard ◽

...

Keyword(s):

Huntington's Disease ◽

Huntington’S Disease ◽

Upper Limb ◽

Visual Cues ◽

Limb Movements ◽

Upper Limb Movements ◽

The Impact

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Pridopidine for the treatment of motor function in patients with Huntington's disease (MermaiHD): a phase 3, randomised, double-blind, placebo-controlled trial

The Lancet Neurology ◽

10.1016/s1474-4422(11)70233-2 ◽

2011 ◽

Vol 10 (12) ◽

pp. 1049-1057 ◽

Cited By ~ 105

Author(s):

Justo Garcia de Yebenes ◽

Bernhard Landwehrmeyer ◽

Ferdinando Squitieri ◽

Ralf Reilmann ◽

Anne Rosser ◽

...

Keyword(s):

Huntington's Disease ◽

Huntington’S Disease ◽

Motor Function ◽

Controlled Trial ◽

Phase 3 ◽

Double Blind ◽

Double Blind Placebo

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The impact of the gut microbiota on Huntington's disease mice

IBRO Reports ◽

10.1016/j.ibror.2019.07.1177 ◽

2019 ◽

Vol 6 ◽

pp. S370-S371

Author(s):

Carolina De Moura Gubert ◽

Geraldine Kong ◽

Jamie Liew ◽

Chloe Love ◽

Thibault Renoir ◽

...

Keyword(s):

Gut Microbiota ◽

Huntington's Disease ◽

Huntington’S Disease ◽

The Impact

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IKKβ slows Huntington’s disease progression in R6/1 mice

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1814246116 ◽

2019 ◽

Vol 116 (22) ◽

pp. 10952-10961 ◽

Cited By ~ 4

Author(s):

Joseph Ochaba ◽

Gianna Fote ◽

Marketta Kachemov ◽

Soe Thein ◽

Sylvia Y. Yeung ◽

...

Keyword(s):

Huntington's Disease ◽

Huntington’S Disease ◽

Neuronal Degeneration ◽

Neuronal Injury ◽

Therapeutic Interventions ◽

Striatal Neurons ◽

Microglial Response ◽

Relationship Of ◽

The Impact

Neuroinflammation is an important contributor to neuronal pathology and death in neurodegenerative diseases and neuronal injury. Therapeutic interventions blocking the activity of the inflammatory kinase IKKβ, a key regulator of neuroinflammatory pathways, is protective in several animal models of neurodegenerative disease and neuronal injury. In Huntington’s disease (HD), however, significant questions exist as to the impact of blocking or diminishing the activity of IKKβ on HD pathology given its potential role in Huntingtin (HTT) degradation. In cell culture, IKKβ phosphorylates HTT serine (S) 13 and activates HTT degradation, a process that becomes impaired with polyQ expansion. To investigate the in vivo relationship of IKKβ to HTT S13 phosphorylation and HD progression, we crossed conditional tamoxifen-inducible IKKβ knockout mice with R6/1 HD mice. Behavioral assays in these mice showed a significant worsening of HD pathological phenotypes. The increased behavioral pathology correlated with reduced levels of endogenous mouse full-length phospho-S13 HTT, supporting the importance of IKKβ in the phosphorylation of HTT S13 in vivo. Notably, many striatal autophagy genes were up-regulated in HD vs. control mice; however, IKKβ knockout partially reduced this up-regulation in HD, increased striatal neurodegeneration, and enhanced an activated microglial response. We propose that IKKβ is protective in striatal neurons early in HD progression via phosphorylation of HTT S13. As IKKβ is also required for up-regulation of some autophagy genes and HTT is a scaffold for selective autophagy, IKKβ may influence autophagy through multiple mechanisms to maintain healthy striatal function, thereby reducing neuronal degeneration to slow HD onset.

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Antidopaminergic treatment is associated with reduced chorea and irritability but impaired cognition in Huntington’s disease (Enroll-HD)

Journal of Neurology Neurosurgery & Psychiatry ◽

10.1136/jnnp-2019-322038 ◽

2020 ◽

Vol 91 (6) ◽

pp. 622-630

Author(s):

Kate L Harris ◽

Wei-Li Kuan ◽

Sarah L Mason ◽

Roger A Barker

Keyword(s):

Huntington's Disease ◽

Huntington’S Disease ◽

Case Reports ◽

Controlled Trial ◽

Rate Of Change ◽

Control Group ◽

Open Label ◽

Double Blind ◽

Before And After ◽

Rate Of Decline

ObjectivesAlterations in dopamine neurotransmission underlie some of the clinical features of Huntington’s disease (HD) and as such are a target for therapeutic intervention, especially for the treatment of chorea and some behavioural problems. However, justification for such an intervention is mainly based on case reports and small open label studies and the effects these drugs have on cognition in HD remain unclear.MethodsIn this study, we used the Enroll-HD observational database to assess the effects of antidopaminergic medication on motor, psychiatric and cognitive decline, over a 3-year period. We first looked at the annual rate of decline of a group of HD patients taking antidopaminergic medication (n=466) compared with an untreated matched group (n=466). The groups were matched on specified clinical variables using propensity score matching. Next, we studied a separate group of HD patients who were prescribed such medications part way through the study (n=90) and compared their rate of change before and after the drugs were introduced and compared this to a matched control group.ResultsWe found that HD patients taking antidopaminergic medication had a slower progression in chorea and irritability compared with those not taking such medications. However, this same group of patients also displayed significantly greater rate of decline in a range of cognitive tasks.ConclusionIn conclusion we found that antidopaminergic treatment is associated with improvements in the choreic movements and irritability of HD but worsens cognition. However, further research is required to prospectively investigate this and whether these are causally linked, ideally in a double-blind placebo-controlled trial.

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