New approaches to discovering drugs that treat dystonia

ABSTRACT

Introduction: Dystonia consists of involuntary movements, abnormal posturing, and pain. In adults, dystonia presents in a particular region of the body and causes significant disability due to pain as well as impairment in activities of daily living and employment. The current gold standard treatment, botulinum toxin (BoNT), has limitations – painful, frequent injections due to ‘wearing off’ of treatment effect; expense; and expected side effects like swallowing difficulty and weakness. There is a clear therapeutic gap in our current treatment options for dystonia and also a clear need for an effective novel treatment. Testing any novel treatment is complicated because most adults with focal dystonia are treated with BoNT.

Areas covered: This review focuses on establishing the need for novel therapeutics. It also suggests potential leads from preclinical studies; and, discusses the issue of clinical trial readiness in the dystonia field.

Expert opinion: Identifying a novel therapeutic intervention for dystonia patients faces two major challenges. The first is acknowledging the therapeutic gap that currently exists. Second, shifting some of our research aims in dystonia to clinical trial readiness is imperative if we are to be ready to test novel therapeutic agents.

KEYWORDS:

• Anticholinergic
• botulinum toxin
• dopamine
• dystonia
• therapeutics

Article highlights

• Dystonia is a lifelong disorder, requiring effective treatment often for decades.

• There is a current therapeutic gap in dystonia treatment as evidenced by reports on patient treatment satisfaction surveys indicating a large number of patients are not satisfied with current therapeutic strategies.

• Preclinical studies have identified a number of promising therapeutic options that have yet to be tested.

• Novel, selective muscarinic antagonists that are long-acting are a potential avenue for development.

• Drug re-purposing strategies looking at approved or investigational agents that address hyperkinetic movement disorders also will play a role in the development of new therapies for dystonia.

• Once a novel therapeutic is identified, there are several issues in clinical trial readiness in the dystonia field that remain as challenges: 1) the development of appropriate and sensitive patient-reported outcome measures and 2) how to handle the prevalence of BoNT treatment in assessing novel therapeutics.

This box summarizes the key points contained in the article.

Declaration of interest

S Pirio Richardson has received research grant support from the NIH (NCRR/NCATS, UNM CTSC KL2 1 TR001448-01 and ULITR001449) and Dystonia Coalition Projects (NIH/NINDS/ORDR) and has received publishing royalties from Springer. She has also served on the Scientific Advisory Board for the Benign Essential Blepharospasm Research Foundation. HA Jinnah has received active or recent grant support from the US government (National Institutes of Health), private philanthropic organizations (the Benign Essential Blepharospasm Research Foundation, Cure Dystonia Now), academically oriented institutions (the Dystonia Study Group), and industry (Cavion Therapeutics, Retrophin Inc., and Revance, Inc.). He has also served on advisory boards or as a consultant for COA Therapeutics and Retrophin Inc. Furthermore, he has received honoraria or stipends for lectures or administrative work from the American Academy of Neurology, the American Neurological Association, the Dystonia Medical Research Foundation, and the International Parkinson’s Disease and Movement Disorders Society. He also serves on the Scientific Advisory Boards for several private foundations including the Benign Essential Blepharospasm Research Foundation, Cure Dystonia Now, the Dystonia Medical Research Foundation, and Tyler’s Hope for a Dystonia Cure. He is also a principle investigator for the Dystonia Coalition, which receives the majority of its support through an NIH grant from the Office of Rare Diseases Research at the National Center for Advancing Translational Sciences, and previously from a grant from the National Institutes of Neurological Disorders and Stroke. The Dystonia Coalition has received additional material or administrative support from industry sponsors (Allergan Inc. and Merz Pharmaceuticals) as well as private foundations (The American Dystonia Society, Beat Dystonia, The Benign Essential Blepharospasm Foundation, Cure Dystonia Now, Dystonia Europe, Dystonia Inc., Dystonia Ireland, The Dystonia Medical Research Foundation, The Foundation for Dystonia Research, The National Spasmodic Dysphonia Association, and The National Spasmodic Torticollis Association). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer Disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This manuscript has not been funded.