Pre-clinical Update: As reported in the Year 3 Progress Report, we successfully engineered mesenchymal stem cells harvested from the bone marrow of healthy qualified donors to produce brain–derived neurotrophic factor (BDNF). BDNF is a factor important for the survival of brain cells and has been found to prevent cell death and stimulate growth and migration of new neurons in HD mouse models. We implanted the engineered stem cells into the brains of control mice and two transgenic HD mouse models: the YAC128, which has late-onset behavioral and movement-related changes similar to those seen in adults with HD, and the R6/2 model, which has early-onset motor changes, weight loss, and shortened life span, similar to the clinical features of juvenile Huntington’s disease. The results of these blinded and controlled studies were published in 2016 in a key paper in the journal Molecular Therapy (http://www.ncbi.nlm.nih.gov/pubmed/26765769).
Following positive feedback from the National Institutes of Health Recombinant DNA Committee and the Food and Drug Administration (FDA) during a pre–Investigational New Drug (IND) meeting regarding the pre-clinical studies and the design of the future planned Phase 1 safety and tolerability trial, we planned to conduct definitive dose-finding, biosafety, biodistribution, and large animal neurotransplantation targeting studies in preparation for an IND application. We still seek funding for the completion of these studies. The IND application to the FDA has been delayed pending their completion.
Clinical Update: We completed the lead-in observational study, PRE-CELL (ClinicalTrials.gov identifier: NCT01937923) for early-stage Huntington’s disease patients and their care partners. The goal of PRE-CELL was to establish baseline characteristics and track disease progression as measured by changes in clinical features, MRI brain scan structural and morphologic analysis, and measurement of biomarkers in blood and cerebrospinal fluid. An additional aim was to study bioethical perspectives in participating subjects and care partners. Interim analysis of PRE-CELL data demonstrated successful determination of baseline characteristics and the rate of change in neurological, cognitive, functional, behavioral, quality of life, imaging and biomarker measures for each subject and for the cohort overall. We demonstrated novel findings of significant rates of change over 6 months in a number of clinical and imaging measures. Study team collaborators under the direction of Dr. Steven Hersch at Massachusetts General Hospital developed and validated an ultrasensitive assay to detect cerebrospinal fluid levels of BDNF, a first in this disease. They also developed a novel assay for measuring levels of various types of mutant huntingtin protein levels in blood and cerebrospinal fluid. In summary, the PRE-CELL study successfully established the baseline and rate of change in clinical, imaging and biomarker features in this group of subjects with early-stage HD that will be informative for the design of a future planned Phase 1 safety and tolerability study of MSC/BDNF. These findings may also be generalizable to other studies of potential disease-modifying treatments in early-stage HD patients. Final analyses of PRE-CELL data are underway and will be submitted for peer-review and publication.