HILTON HEAD—In their search for Huntington’s disease therapies, investigators are building a large database to help them identify biomarkers and study drugs that may treat chorea with improved tolerability. In addition, researchers have discovered an important protein—mutant huntingtin (mHTT)—that accumulates in the brains of patients with Huntington’s disease and may be a therapeutic target, according to a lecture at Vanderbilt University School of Medicine’s 38th Annual Contemporary Clinical Neurology Symposium. The discovery of mHTT follows similar findings of neurodegenerative proteins implicated in Parkinson’s disease (ie, alpha-synuclein) and Alzheimer’s disease (ie, amyloid and tau), said Daniel Claassen, MD, Assistant Professor of Neurology at Vanderbilt University in Nashville. “Now it’s Huntington’s turn to get involved in that story,” he said.
More Than a Movement Disorder
Approximately 35,000 people in the United States have Huntington’s disease, and about 600 patients with Huntington’s disease and their families live in Tennessee, Dr. Claassen said. “It’s an autosomal dominant disease and a complicated illness that essentially affects the entire nervous system.” Although chorea is a major symptom and the most common clinical presentation, Huntington’s disease “is probably the quintessential cognitive disorder, in my opinion,” he added.
Daniel Claassen, MD
Dr. Claassen is the director of the Huntington’s Disease Society of America Center of Excellence, which was established at Vanderbilt University in February. The center hosts a Huntington’s disease clinic each month that is run by specialists in neurology, neuropsychology, psychiatry, social work, and occupational, physical, and speech therapy. In addition to the characteristic twitching that often progresses to fluid choreiform movements, patients often exhibit executive dysfunction, impulsivity, apathy, delusions, and depression. “Unfortunately, a number of patients in our clinic have tried to commit suicide, and this is a serious clinical problem observed in Huntington’s disease,” Dr. Claassen said.
When the clinic first started, the researchers expected to see about 60 patients. “We now have over 150 patients and we receive six to eight new referrals each month,” he said. “The three main goals of the clinic are expert clinical care, research and clinical trials, and medical education. Residents, medical students, and medical fellows come through this clinic. It’s been a rewarding experience.”
The center is involved with Enroll-HD, an ongoing longitudinal, observational, multinational study. The goal of Enroll-HD is to build a large database of clinical information and biospecimens from Europe, North America, Latin America, and Asia. “Currently, there are over 2,000 patients signed up for this study,” Dr. Claassen explained. “Patients come in once a year to undergo a series of tasks, including the Unified Huntington’s Disease Rating Scale [UHDRS] and cognitive and behavioral inventories. They’ll also provide blood samples for international research efforts.”
The database will serve as a basis for future research efforts to develop tools and biomarkers for progression and prognosis, identify clinically relevant phenotypic characteristics, and establish clearly defined end points for interventional studies.
Potential Therapeutic Targets
Wild et al tested the effectiveness of an assay to detect mHTT in CSF in separate cohorts in Vancouver and London, Dr. Claassen said. The study included patients with premanifest Huntington’s disease (ie, those who had poorly differentiated, subclinical motor symptoms based on low UHDRS scores) and those with manifest Huntington’s disease. The assay was found to have high specificity, with mHTT undetectable in CSF in all controls but quantifiable in nearly all mutation carriers. “Therefore, mHTT has been shown to offer a potential diagnostic and therapeutic target,” Dr. Claassen said.
In a study of patients who had striatal fetal stem cell grafts to try to improve their symptoms, Cicchetti et al found that mHTT was present in this fetal tissue at autopsy. “It was suggested that mHTT is a toxic protein that may be transmissible from nerve cell to nerve cell,” he said. “If you have a therapy that can clear mHTT protein directly, it may significantly change the course of the disease.”
Another Huntington’s disease biomarker currently under investigation is [18F]MNI-659, a novel phosphodiesterase 10A PET ligand. In a 2014 study, eight patients with early-stage Huntington’s disease, three patients with premanifest disease, and nine age-matched healthy volunteers underwent clinical assessments, [18F]MNI-659 PET imaging, and brain MRI. The researchers found that the Huntington’s disease cohort had significantly lower striatal [18F]MNI-659 uptake than did healthy volunteers.
“The hope is that one could use the pathophysiologic information provided by this PET ligand to guide treatment that modulates the expression of phosphodiesterase 10A and improve symptoms,” said Dr. Claassen. Studies also are under way to determine the possible implications of phosphodiesterase inhibition in Huntington’s disease.