Efficacy and Safety of the Dopaminergic Stabilizer Pridopidine (ACR16) in Patients With Huntington's Disease

Lundin, Anders; Dietrichs, Espen; Haghighi, Sara; Göller, Marine-Louise; Heiberg, Arvid; Loutfi, Ghada; Widner, Håkan; Wiktorin, Klas; Wiklund, Leif; Svenningsson, Anders; Sonesson, Clas; Waters, Nicholas; Tedroff, Joakim

doi:10.1097/wnf.0b013e3181ebb285

Cited by 67 publications

(61 citation statements)

References 16 publications

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“…HD management is limited to supportive care and symptomatic treatment (Bates et al, 2015). Pridopidine (ACR16) is emerging in clinical trials as a potential therapeutic to mitigate motor symptoms ( e.g ., total motor score improvement was observed when tested as a secondary endpoint in two independent clinical trials) in HD patients (de Yebenes et al, 2011; Esmaeilzadeh et al, 2011; Huntington Study Group, 2013; Lundin et al, 2010). Pridopidine was initially identified as a stabilizer of the dopamine system, normalizing hyper- and hypodopaminergic behaviors, with the proposed mode of action of a D 2 receptor (D2R) antagonist, a partial weak agonist, or both a positive allosteric modulator and an orthosteric antagonist (Dyhring et al, 2010; Nilsson et al, 2004; Rung et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

The sigma-1 receptor mediates the beneficial effects of pridopidine in a mouse model of Huntington disease

Ryskamp

Geva

et al. 2017

Neurobiology of Disease

104

149

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The tri-nucleotide repeat expansion underlying Huntington disease (HD) results in corticostriatal synaptic dysfunction and subsequent neurodegeneration of striatal medium spiny neurons (MSNs). HD is a devastating autosomal dominant disease with no disease-modifying treatments. Pridopidine, a postulated “dopamine stabilizer”, has been shown to improve motor symptoms in clinical trials of HD. However, the target(s) and mechanism of action of pridopidine remain to be fully elucidated. As binding studies identified sigma-1 receptor (S1R) as a high-affinity receptor for pridopidine, we evaluated the relevance of S1R as a therapeutic target of pridopidine in HD. S1R is an endoplasmic reticulum - (ER) resident transmembrane protein and is regulated by ER calcium homeostasis, which is perturbed in HD. Consistent with ER calcium dysregulation, we observed striatal upregulation of S1R in aged YAC128 transgenic HD mice and HD patients. We previously demonstrated that dendritic MSN spines are lost in aged corticostriatal co-cultures from YAC128 mice. We report here that pridopidine and the chemically similar S1R agonist 3-PPP prevent MSN spine loss in aging YAC128 co-cultures. Spine protection was blocked by neuronal deletion of S1R. Pridopidine treatment suppressed supranormal ER Ca2+ release, restored ER calcium levels and reduced excessive store-operated calcium (SOC) entry in spines, which may account for its synaptoprotective effects. Normalization of ER Ca2+ levels by pridopidine was prevented by S1R deletion. To evaluate long-term effects of pridopidine, we analyzed expression profiles of calcium signaling genes. Pridopidine elevated striatal expression of calbindin and homer1a, whereas their striatal expression was reduced in aged Q175KI and YAC128 HD mouse models compared to WT. Pridopidine and 3-PPP are proposed to prevent calcium dysregulation and synaptic loss in a YAC128 corticostriatal co-culture model of HD. The actions of pridopidine were mediated by S1R and led to normalization of ER Ca2+ release, ER Ca2+ levels and spine SOC entry in YAC128 MSNs. This is a new potential mechanism of action for pridopidine, highlighting S1R as a potential target for HD therapy. Upregulation of striatal proteins that regulate calcium, including calbindin and homer1a, upon chronic therapy with pridopidine, may further contribute to long-term beneficial effects of pridopidine in HD.

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Section: Introductionmentioning

confidence: 99%

The sigma-1 receptor mediates the beneficial effects of pridopidine in a mouse model of Huntington disease

Ryskamp

Geva

et al. 2017

Neurobiology of Disease

104

149

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“…In clinical situations, these factors should be weighed up against its benefit in reducing chorea. Neuroleptics are used clinically to treat both chorea and psychoses, but the three studies on neuroleptics [25][26][27] showed no conclusive evidence for any beneficial effect on chorea. Also, none of these three studies looked into the ef-fect on psychoses.…”

Section: Discussionmentioning

confidence: 99%

“…However, the lower dose and difference in assessment and rating scales could have contributed to the different outcomes. A recent study by Lundin et al [27] found pridopidine, a dopaminergic stabiliser, to have a similar effectiveness to placebo.…”

Section: Neurolepticsmentioning

confidence: 98%

The Pathophysiology and Pharmacological Treatment of Huntington Disease

Pidgeon

Rickards

2013

Behavioural Neurology

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Abstract.Introduction: Huntington disease (HD) is a progressive neurodegenerative condition characterised by motor, cognitive and behavioural dysfunction, and has an autosomal dominant mode of inheritance. As there is currently no treatment to delay progression of the disease, pharmacological intervention is aimed at symptomatic relief. Methods: We set out to assess the current evidence on the pharmacological treatment of motor and non-motor symptoms in HD by carrying out a systematic literature review across five large scientific databases. Results: The search generated 23 original studies meeting our search criteria. Studies on the following drug classes were obtained: dopamine (DA) depleting agents, neuroleptics, anti-glutamatergic agents, acetylcholinesterase inhibitors, GABA agonists, cannabinoids, antidepressants and potential neuroprotective agents. Tetrabenazine (TBZ), a DA depleting agent, was the only pharmacotherapy shown to have a clinically meaningful, statistically significant effect on chorea. The majority of the reviewed studies focussed on the treatment of motor symptoms of HD. Discussion: Overall, the evidence base for the pharmacological management of HD is poor. There is a clear need for future high quality randomised controlled trials on the symptomatic treatment of HD, particularly on the pharmacotherapy of non-motor symptoms of HD.

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“…Three randomized, placebo-controlled clinical studies have investigated the efficacy and safety of pridopidine in HD [107–109]. The primary outcome measure for all studies was change in the modified motor score (mMS), comprising 13 items from the UHDRS (the items chorea, dystonia, and ocular movements were excluded to reduce potential noise in the motor results), with a maximum score of 52.…”

Section: Pharmacological Treatment Of Chorea In Hdmentioning

confidence: 99%

Current Pharmacological Approaches to Reduce Chorea in Huntington’s Disease

Coppen

Roos

2016

Drugs

108

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There are currently no effective pharmacological agents available to stop or prevent the progression of Huntington’s disease (HD), a rare hereditary neurodegenerative disorder. In addition to psychiatric symptoms and cognitive impairments, HD causes progressive motor disturbances, in particular choreiform movements, which are characterized by unwanted contractions of the facial muscles, trunk and extremities. Management of choreiform movements is usually advised if chorea interferes with daily functioning, causes social isolation, gait instability, falls, or physical injury. Although drugs to reduce chorea are available, only few randomized controlled studies have assessed the efficacy of these drugs, resulting in a high variety of prescribed drugs in clinical practice. The current pharmacological treatment options to reduce chorea in HD are outlined in this review, including the latest results on deutetrabenazine, a newly developed pharmacological agent similar to tetrabenazine, but with suggested less peak dose side effects. A review of the existing literature was conducted using the PubMed, Cochrane and Medline databases. In conclusion, mainly tetrabenazine, tiapride (in European countries), olanzapine, and risperidone are the preferred first choice drugs to reduce chorea among HD experts. In the existing literature, these drugs also show a beneficial effect on motor symptom severity and improvement of psychiatric symptoms. Generally, it is recommended to start with a low dose and increase the dose with close monitoring of any adverse effects. New interesting agents, such as deutetrabenazine and pridopidine, are currently under development and more randomized controlled trials are warranted to assess the efficacy on chorea severity in HD.

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Efficacy and Safety of the Dopaminergic Stabilizer Pridopidine (ACR16) in Patients With Huntington's Disease

Abstract: Pridopidine shows promise as a treatment for some of the symptoms of HD. In this small-scale study, the most notable effect was improvement in voluntary motor symptoms. Larger, longer-term trials are warranted.

Cited by 67 publications

References 16 publications

The sigma-1 receptor mediates the beneficial effects of pridopidine in a mouse model of Huntington disease

The sigma-1 receptor mediates the beneficial effects of pridopidine in a mouse model of Huntington disease

The Pathophysiology and Pharmacological Treatment of Huntington Disease

Current Pharmacological Approaches to Reduce Chorea in Huntington’s Disease

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