A phase II, open‐label evaluation of cysteamine tolerability in patients with Huntington's disease

Prundean, Adriana; Youssov, Katia; Humbert, Sandrine; Bonneau, Dominique; Verny, Christophe

doi:10.1002/mds.26101

Cited by 17 publications

(9 citation statements)

References 7 publications

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“…Cysteamine is the reduced form of cystamine, and through its interaction with heat-shock protein chaperones, is believed to stimulate the release of BDNF in the brain [Borrell-Pages and others 2006]. A variety of preclinical trials in mice have established that cysteamine is neuroprotective in HD [Bailey and Johnson 2006; Dedeoglu and others 2002; Fox and others 2004; Van Raamsdonk and others 2005]; however, clinical trials in human HD patients have yielded mixed results, failing to improve outcome measures in one case [Prundean and others 2015], but yielding significantly slower progression of TMS in a sub-group of HD patients who were not concurrently on TBZ, and revealing a trend toward slower progression in the overall study group [Corp. 2015].…”

Section: Trophic Factor Supplementationmentioning

confidence: 99%

Therapy development in Huntington disease: From current strategies to emerging opportunities

Dickey

Spada

2017

American J of Med Genetics Pt A

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Huntington disease (HD) is a progressive autosomal dominant neurodegenerative disorder in which patients typically present with uncontrolled involuntary movements and subsequent cognitive decline. In 1993, a CAG trinucleotide repeat expansion in the coding region of the huntingtin (HTT) gene was identified as the cause of this disorder. This extended CAG repeat results in production of HTT protein with an expanded polyglutamine tract, leading to pathogenic HTT protein conformers that are resistant to protein turnover, culminating in cellular toxicity and neurodegeneration. Research into the mechanistic basis of HD has highlighted a role for bioenergetics abnormalities stemming from mitochondrial dysfunction, and for synaptic defects, including impaired neurotransmission and excitotoxicity. Interference with transcription regulation may underlie the mitochondrial dysfunction. Current therapies for HD are directed at treating symptoms, as there are no disease-modifying therapies. Commonly prescribed drugs for involuntary movement control include tetrabenazine, a potent and selective inhibitor of vesicular monoamine transporter 2 that depletes synaptic monoamines, and olanzapine, an atypical neuroleptic that blocks the dopamine D2 receptor. Various drugs are used to treat non-motor features. The HD therapeutic pipeline is robust, as numerous efforts are underway to identify disease-modifying treatments, with some small compounds and biological agents moving into clinical trials. Especially encouraging are dosage reduction strategies, including antisense oligonucleotides, and molecules directed at transcription dysregulation. Given the depth and breadth of current HD drug development efforts, there is reason to believe that disease-modifying therapies for HD will emerge, and this achievement will have profound implications for the entire neurotherapeutics field.

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Section: Trophic Factor Supplementationmentioning

confidence: 99%

Therapy development in Huntington disease: From current strategies to emerging opportunities

Dickey

Spada

2017

American J of Med Genetics Pt A

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“…Another strategy is increasing BDNF expression or release by blocking ionotropic glutamate N ‐methyl‐ D ‐aspartate (NMDA) receptors (riluzole, memantine), modulating α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA) receptors (ampakine), or using serotonergic drugs (paroxetine, sertraline), or through interaction of cysteamine with the heat shock protein HSF1b . Salutary effects in preclinical models have been reported, and the drug has been studied in an early clinical trial . Because the beneficial effects of BDNF are mediated primarily by the TrkB receptor, several TrkB agonists show preclinical efficacy and are under development for HD …”

Section: Future Directionsmentioning

confidence: 99%

Therapeutic advances in Huntington's Disease

Shannon¹,

Fraint²

2015

Movement Disorders

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Huntington's disease is a rare hereditary degenerative disease with a wide variety of symptoms that encompass movement, cognition, and behavior. The genetic mutation that causes the disease has been known for more than 20 y, and animal models have illuminated a host of intracellular derangements that occur downstream of protein translation. A number of clinical trials targeting these metabolic consequences have failed to produce a single effective therapy, although clinical trials continue. New strategies targeting the protein at the level of transcription, translation, and posttranslational modification and aggregation engender new hope that a successful strategy will emerge, but there is much work ahead. Some of the clinical manifestations of the illness, particularly chorea, affective symptoms, and irritability, are amenable to palliative strategies, but physicians have a poor evidence base on which to select the best agents. Clinical trials since 2013 have dashed hopes that coenzyme Q10 or creatine might have disease-modifying properties but suggested other agents were safe or hinted at efficacy (cysteamine, selisistat, hydroxyquinoline) and could proceed into later-stage disease modification trials. The hunt for effective symptom relief suggested that pridopidine might be shown effective given the right outcome measure. This review summarizes recent progress in HD and highlights promising new strategies for slowing disease progression and relieving suffering in HD.

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“…A large body of literature exists describing the proinflammatory properties of amyloid-forming proteins, particularly Aβ; yet, the pathology of AD shows little evidence of inflammation and no evidence of classic innate or adaptive immunity and inflammation in lesions (74, 89), a situation that is vastly different from that seen in MS. In MS, there is a These small molecules also catalyze sulfhydration (64,65,71). As described above, the interplay of sulfhydrates on KEAP1 has remarkable similarities to the mechanism of action of dimethylfumarate (Figure 2) in allowing the nuclear translocation of NRF2.…”

Section: Amyloid-forming Moleculesmentioning

confidence: 86%

“…This protective mechanism may also be applicable to other neurodegenerative processes including Huntington's disease (HD), spinocerebellar ataxia type 1, and dentatorubralpallidoluysian atrophy (13,(65)(66)(67)(68)(69). Recent reports show that there may be clinical benefit of cysteamine in treating HD (70,71). A defect in cystathionine γ-lyase (CSE) may in fact underlie neurodegeneration in HD and other disorders including Parkinson's and perhaps progressive MS, providing a rationale for why small molecules like cysteamine are effective (13,61).…”

Section: Neurotransmitters: Gabamentioning

confidence: 99%

No quiet surrender: molecular guardians in multiple sclerosis brain

Steinman¹

2015

J. Clin. Invest.

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A phase II, open‐label evaluation of cysteamine tolerability in patients with Huntington's disease

Cited by 17 publications

References 7 publications

Therapy development in Huntington disease: From current strategies to emerging opportunities

Therapy development in Huntington disease: From current strategies to emerging opportunities

Therapeutic advances in Huntington's Disease

No quiet surrender: molecular guardians in multiple sclerosis brain

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