Clinical Trials in HD: Lessons Learned, Progress, and Perspectives

Although HD is categorized as a movement disorder, the wide range of non-motor symptoms including cognitive impairment and behavioral abnormalities are considered by patients and their caregivers to be just as disabling as the motor symptoms. Motor and nonmotor symptomatic treatment is an important consideration to improve both functionality and quality of life in HD. A variety of symptomatic treatments are currently available. Pharmacological options for the motor symptoms include tetrabenazine and deutetrabenazine – the only two FDA-approved drugs for HD related chorea, neuroleptics, gabaergic and antiglutaminergic medications are often used off label. Antidepressants and neuroleptics are also used to treat the neuropsychiatiric symptoms. Interdisciplinary, nonpharmacological options are available such as, psychotherapy, physical, occupational and speech therapy, genetic counseling, social work and nutritional services. However, there is currently no approved diseasemodifying therapy for HD. After the discovery of the genetic cause for HD 26 years ago, great efforts have been made to identify a treatment capable of modifying the disease course. Recent advances in therapeutic strategies promise an exciting era for clinical trials in HD. Increased recognition of the phenotypic variability in HD can also improve the symptomatic treatment goals. This endeavor will be coupled with advances in novel therapeutics, including strategies in lowering the mutant huntingtin protein and targeting the HTT gene. Future novel HD treatments are focused on positively impacting both quality of life and longevity in individuals with HD, in addition to contributing to research in other neurodegenerative disorders. This chapter will present the past, current and future clinical trials targeting both symptomatic and disease-modifying treatments for HD.