Experimental Therapeutics for Dystonia

Abstract

Summary: Dystonia is a neurological syndrome characterized by excessive involuntary muscle contractions leading to twisting movements and unnatural postures. It has many different clinical manifestations, and many different causes. More than 3 million people worldwide suffer from dystonia, yet there are few broadly effective treatments. In the past decade, progress in research has advanced our understanding of the pathogenesis of dystonia to a point where drug discovery efforts are now feasible. Several strategies can be used to develop novel therapeutics for dystonia. Existing therapies have only modest efficacy, but may be refined and improved to increase benefits while reducing side effects. Identifying rational targets for drug intervention based on the pathogenesis of dystonia is another strategy. The surge in both basic and clinical research discoveries has provided insights at all levels, including etiological, physiological and nosological, to enable such a targeted approach. The empirical approach to drug discovery, whereby compounds are identified using a nonmechanistic strategy, is complementary to the rational approach. With the recent development of multiple animal models of dystonia, it is now possible to develop assays and perform drug screens on vast numbers of compounds. This multifaceted approach to drug discovery in dystonia will likely provide lead compounds that can then be translated for clinical use.

Designing Clinical Trials for Dystonia

“…It has been suggested that several forms of dystonia may have shared etiologies [13][14][15] and therefore may respond to the same therapeutic intervention. Although the primary cause for the signs and symptoms of dystonia may differ, there are several reasons to suspect a common underlying process [6]. Thus, treatments aimed at downstream targets might prove effective across multiple etiologies and allow for broader subject inclusion based on phenotype rather than etiology.…”

“…A high-throughput screen conducted in a Caenorhabditis elegans model of DYT1 dystonia has revealed potential agents for further study, such as ampicillin [23]. Other promising agents have been identified through pharmacological studies of rodent models of dystonia, including the dystonic dt sz hamster and tottering mouse models [6,24]. Whether or not these agents are effective for patients with dystonia remains to be determined.…”

“…Novel treatments may arise from optimization of currently available compounds, identification of drugs through screening, or development of approaches targeted at the underlying pathophysiology [6]. Such agents may be new molecular entities not yet studied in humans or drugs developed for the treatment of other disorders.…”

Botulinum Neurotoxin: The Ugly Duckling

“…The main symptoms, which can be mild or severe, include involuntary muscle contraction and uncontrollable twisting of the affected body part (eyelids, neck, face, hand, foot). The exact causes of dystonia are still elusive, but it has been linked to communication problems with neurons located in the basal ganglia [31]. The first most frequent indication of botulinum toxin treatment among focal dystonias is cranial dystonia, notably blepharospasm, sometimes bruxism, trismus, oromandibular dystonia and rarely lingual dystonia.…”

Invertebrate Models of Dystonia

“…Mammalian models are invaluable tools for examining the DYT gene products, especially considering the wide range of clinical features associated with dystonia, such as muscle contraction, tremors, and/or myoclonus [3][4][5], that may illustrate under-explored aspects of neuronal misregulation. Nevertheless, these models may not recapitulate all pathological impairments of dystonia and are expensive.…”