Journal name: Drug Design, Development and Therapy Article Designation: Commentary Year: 2015 Volume: 9 Drug Design, Development and Therapy Dovepress Running head verso: Squitieri and de Yebenes Running head recto: Pridopidine treatment of Huntington disease open access to scientific and medical research DOI: 65738 Open Access Full Text Article COMMENTARY Profile of pridopidine and its potential in the treatment of Huntington disease: the evidence to date Ferdinando Squitieri1 Abstract: Huntington disease (HD) is a chronic, genetic, neurodegenerative disease for Justo Garcia de Yebenes2 which there is no cure. The main symptoms of HD are abnormal involuntary movements (chorea and dystonia), impaired voluntary movements (ie, incoordination and gait balance), 1IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo and Mendel progressive cognitive decline, and psychiatric disturbances. HD is caused by a CAG-repeat Institute of Human Genetics, Rome, expanded mutation in the HTT gene, which encodes the huntingtin protein. The inherited Italy; 2Fundación para Investigaciones Neurológicas, Madrid, Spain mutation results in the production of an elongated polyQ mutant huntingtin protein (mHtt). The cellular functions of the Htt protein are not yet fully understood, but the functions of its mutant variant are thought to include alteration of gene transcription and energy production, and dysregulation of neurotransmitter metabolism, receptors, and growth factors. The phenylpi- For personal use only. peridines pridopidine (4-[3-methanesulfonyl-phenyl]-1-propyl-piperidine; formerly known as ACR16) and OSU6162 ([S]-[-]-3-[3-methane [sulfonyl-phenyl]-1-propyl-piperidine) are members of a new class of pharmacologic agents known as “dopamine stabilizers”. Recent clinical trials have highlighted the potential of pridopidine for symptomatic treatment of patients with HD. More recently, the analysis of HD models (ie, in vitro and in mice) high- lighted previously unknown effects of pridopidine (increase in brain-derived neurotrophic factor, reduction in mHtt levels, and σ-1 receptor binding and modulation). These additional functions of pridopidine suggest it might be a neuroprotective and disease-modifying drug. Data from ongoing clinical trials of pridopidine will help define its place in the treatment of HD. This commentary examines the available preclinical and clinical evidence regarding the use of pridopidine in HD. Keywords: Huntington disease, dopamine, neuroprotection, pridopidine Drug Design, Development and Therapy downloaded from https://www.dovepress.com/ by 54.70.40.11 on 07-Nov-2018 Introduction Huntington disease (HD) is a chronic, neurodegenerative, dominantly transmitted genetic disease. Although the onset of HD generally occurs at around 40 years of age, it can, in rare cases, affect people younger than 20 years old (juvenile HD) and, even more rarely, children under 10 years of age. Patients with HD rapidly develop sub- stantial mental and physical disability. No cure or treatment to prevent the progression of HD is available.1 From the time of its onset, HD is characterized by three main clinical patterns Correspondence: Ferdinando Squitieri with subtle differences: psychiatric disturbances, often associated with a high rate of IRCCS Casa Sollievo della Sofferenza, suicide; cognitive decline; and extrapyramidal signs and symptoms. All three progress San Giovanni Rotondo and Mendel Institute of Human Genetics, Viale Regina to dementia and cachexia in five stages.1 Other sites are affected in addition to the Margherita 261, 00198, Rome, Italy brain, including muscles, bones, and testes. Inflammation contributes to the pathology Tel +39 06 4416 0527 Email [email protected] in the central nervous and peripheral systems.2 submit your manuscript | www.dovepress.com Drug Design, Development and Therapy 2015:9 5827–5833 5827 Dovepress © 2015 Squitieri and de Yebenes. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License. The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further http://dx.doi.org/10.2147/DDDT.S65738 permission from Dove Medical Press Limited, provided the work is properly attributed. Permissions beyond the scope of the License are administered by Dove Medical Press Limited. Information on how to request permission may be found at: http://www.dovepress.com/permissions.php Powered by TCPDF (www.tcpdf.org) 1 / 1 Squitieri and de Yebenes Dovepress From HTT-CAG mutation to It evolves to other abnormal movements, such as dystonia complex biological mechanisms of and Parkinsonism, generally in the advanced stages of the HD disease. Although chorea represents one of the main and most HD is associated with an expanded CAG-repeat mutation frequent symptoms of HD, it only marginally contributes to in the HTT gene that encodes the huntingtin protein (Htt).3,4 patients’ disability and loss of independence compared with A CAG stretch expansion beyond 35 repeats is associated other features, such as cognitive decline, psychiatric distur- with the disease.4 Repeats in the range 36–39 are consid- bances, and other neurological symptoms (incoordination, ered as low penetrance mutations (ie, the disease may start oculomotor abnormalities, ie, slow and saccade eye move- late or never during life), while full penetrance mutations ment impairments, dysarthria, dysphagia, gait disturbance, 11 (ie, all clinical manifestations are expected to present during and imbalance). Patients are frequently unaware of the life) are associated with $40 CAG repeats.4 The mutation symptoms of chorea, and approximately 8% of HD cases is unstable during intergenerational transmission. In the manifest atypical HD variants in which other signs and offspring, the trinucleotide instability may cause further symptoms, such as parkinsonism and dystonia, predominate 12 elongation of the translated polyQ stretch in the Htt protein, over choreic movements from the onset of the disease. thus amplifying its toxic effects in neurons and other tissues In accordance with the original descriptions of HD, and in each new generation.3 The Htt protein has many cellular taking into account both the prominence of chorea and the functions, but these have not yet been fully characterized. selective degeneration of the brain striatum as a key feature Mutant Htt (mHtt) with elongated polyQ may, instead, of the disease, therapeutic approaches to HD have included cause dysregulation of neurotransmitters, receptors, and either the control of behavioral changes (eg, neuroleptics, 13,14 growth factors.5 mHtt translocates from the cytoplasm to benzodiazepines, and mood stabilizers) or attempts to the nucleus and perinuclear regions where it interferes with reduce choreic movements with tetrabenazine, the only gene transcription, energy production, and processing of approved drug that inhibits dopamine release with a specific 13–15 6 indication for chorea. However, knowledge of the natural For personal use only. abnormal proteins. The biology of HD is, therefore, very complex; mHtt has history of HD has increased in recent years. The develop- many, as yet unclear, functions and interacts with a large ment of experimental HD models and new psychiatric drugs number of factors both within and outside the nervous system, (eg, atypical neuroleptics and antidepressants), as well as 16 especially in the striatum.5 One important, yet unsolved, issue novel findings regarding the neuropathology of the disease, is what causes the prominent early damage to the striatum have influenced HD management guidelines. The American in patients with HD. In addition to existing hypotheses for Academy of Neurology’s most recent guidelines for the the potential toxic mechanisms of mHtt,5 recent studies have pharmacologic treatment of HD recommend symptomatic 17 focused on the binding of the striatal-specific Rhes (Ras approaches. Curative treatment for HD would need to homologue enriched in striatum) protein to mHtt as a spe- take the following into account: 1) HD is not only related cific pathogenic mechanism leading to mHtt toxicity in the to striatum degeneration, but also to more extensive brain 16 7,8 damage, including the cortex and white matter; 2) chorea brain striatum, and regulation of the dopamine-D2 receptor Drug Design, Development and Therapy downloaded from https://www.dovepress.com/ by 54.70.40.11 on 07-Nov-2018 18 activity by Rhes.9 Dopaminergic and glutamatergic signaling is not the only symptomatic target; 3) choreic movements pathways act synergistically to enhance the sensitivity of make a marginal contribution to HD disability, and patients striatal neurons to mHtt toxicity and may represent crucial indicate that other abnormal voluntary movements, distinct therapeutic targets for HD treatment. Therefore, understand- from chorea (eg, gait imbalance, incoordination, dystonia) ing dysfunction of dopamine and other (eg, cholinergic) are the most disabling motor features (Squitieri and Mondher, receptors in HD is critical in interpreting the effects of personal communication); and 4) classical neuroleptics 19 pharmacotherapy.9 worsen HD progression. From Huntington “chorea” to Dopidines: an example of a new Huntington “disease” class of drugs Historically, the description of HD typically referred to one Pridopidine (4-[3-methanesulfonyl-phenyl]-1-propyl- of the most visible symptoms,