HSG 2015 Round-Up: Innovation
Julie Stout presented the beta study for HD-CAB, a Standardized Cognitive Assessment Battery for Clinical Trials, which included 250 participants across 20 English-speaking sites in order to vet the HD-CAB assessment tool. HD-CAB was developed to produce cognitive assessment data that is accurate and high in quality. The study was run as though it were a clinical trial, including site monitoring and a double-blind study team. Goals for the HD-CAB included sensitivity, reliability, feasibility, tolerability, and practice effects. Tests in the HD-CAB include Symbol Digit Modalities, Paced Tapping, One Touch Stockings of Cambridge, Trail Marking A & B, Emotion Recognition, and the Hopkins Verbal Learning Test. The HD-CAB beta study demonstrated that reliability in cognitive assessment is best obtained under optimal conditions where the participant was well rested and the examiners were confident and efficient.
Chandler Swope from HDYO discussed the value of involving young people in the process of research during Novel Outreach Methods. Youth engagement can be achieved through simple, and easy to understand depictions. Peer networks among HD-affected youth are also a meaningful component of getting young people engaged in clinical research. Kevin Biglan from the University of Rochester discussed his telemedicine study which showed that telemedicine can increase access to care for individuals with HD. 83% of the study’s telemedicine visits were completed as scheduled. Motor assessments conducted via telemedicine were shown to be just as reliable as those conducted in person. Katie Jackson with Help4HD shared the impact of social media presence within the HD patient community. The Help4HD model utilizes integrated communications and deep connections with HD-patient, pharma, and regulatory agencies to improve the flow of information.
In a new study, William Yang showed that ataxia-telangiectasia mutated (ATM), a pivotal signaling molecule in the DNA damage response pathway, can modify the toxicity of the mutant protein that causes HD. ATM signaling activity was aberrantly increased in HD cells, animal models of HD, and postmortem brain tissue from HD patients. Reducing ATM signaling by genetic manipulation or using small-molecule inhibitors of ATM consistently reduced HD protein toxicities in cellular and animal models.
Implications for HD pathophysiology through study of blood-brain barrier impairments were presented by Janelle Drouin-Ouellet. Although it remains unclear exactly how structural or functional changes in cerebral vasculature affect or are affected by brain cell survival and disease progression, there is evidence that significant changes are happening in the HD brain’s circulatory system.
A highly sensitive mutant huntingtin (mHTT) detection assay was developed using micro-bead based immunoprecipitation and flow cytometry (IP-FCM). Research presented by Stephen Smith suggested that IP-FCM will help quantify the mHTT in the brain. This technique demonstrates that mHTT levels in cerebrospinal fluid (CSF) reflect brain levels, increasing with disease stage and decreasing following brain HTT suppression.
The measurement and quantification of mHTT in CSF was also discussed by Ed Wild. The research team developed an ultrasensitive single-molecule counting (SMC) mHTT immunoassay that was used to quantify mHTT levels in CSF. Analysis of the CSF samples showed that mHTT was undetectable in CSF from all controls but quantifiable in nearly all mutation carriers. The ability to quantify CSF mHTT will facilitate the study of HD, and mHTT quantification could potentially serve as a biomarker for the development and testing of experimental mHTT-lowering therapies for HD.
David Corey, Lisa Stanek, and Sarah Tabrizi expanded upon the therapeutic pipeline in the Huntingtin Lowering Therapies session. David Corey’s presentation focused on Antisense Oligonucleotides (ASOs) and gene silencing as a viable option to the “undruggable target” of HD. Gene silencing was presented as a possibility for being a major therapeutic opportunity. ASOs were proven to target HTT effectively in mouse and primate brain. ASOs were a hot topic at this year’s HSG, with an additional presentation on the ISIS-HttRx trial from Sarah Tabrizi. ISIS- HTT targets the HTT message molecule, telling the cell to dispose of it, thereby reducing production of the mHTT protein. Administered by injection into spinal fluid to improve its delivery to the brain, the drug is the first tested in patients that targets the mHTT, The trial is set to recruit patients with very early symptoms of Huntington’s from six centers in Europe and Canada. Lisa Stanek presented on AAV-RNAi for the Treatment of HD. Adeno-associated viral vectors (AAV) can be used to achieve RNAi-mediated gene silencing in the brain. AAV1 is a suitable serotype for the HD program due to its superior neuronal transduction properties and ability to transduce both neurons and astrocytes. Two issues remaining include delivery to ensure optimal coverage of HD devastated brain regions, as well as safety issues surrounding off-target silencing of non-HTT related genes and the silencing of both mutant and nonmutant HTT.
HD Clinical Trial Round Up:
Together with Auspex and Teva, Drs. Sam Frank and Claudia Testa and the First-HD and ARC-HD investigators and coordinators conducted a successful Phase 3 trial of SD-809 for the treatment of chorea. Teva filed a New Drug Application (NDA) with the FDA for SD-809 this summer. If approved, this would be the second drug for HD, a major step forward for the HSG and HD Community in seeking treatments that make a difference to those affected by HD. First-HD aims to study the effects of SD-809, while ARC-HD aims to study the effect of switching to SD-809 from Tetrabenazine.
Pride-HD, sponsored by Teva with PIs Drs. Karl Kieburtz, Andrew McGarry, and Ralf Reilmann aims to enroll approximately 400 patients at 30 sites across the globe and evaluate the safety and efficacy of pridopidine. Pridopidine is an investigational drug being developed for the symptomatic treatment of Huntington’s disease.
LEGATO-HD sponsored by TEVA with PIs Karen Anderson, Andrew Feigin, and Ralf Reilmann, is currently testing the effects of laquinimod after 12 months of administration. SIGNAL, sponsored by Vaccinex and led by PI Andrew Feigin, is designed to assess the safety, tolerability, and effectiveness of VX15, a novel monoclonal antibody, in people with late prodromal or early manifest HD.
Save the Date!
Join HSG in the Music City in 2016! The Tenth Annual HSG meeting will take place November 3-5, 2016 at Opryland USA in Nashville, Tennessee.