Year 3

Progress, Year 3 of the grant

Pre-clinical update: The pre-clinical team successfully engineered mesenchymal stem cells (MSCs) harvested from healthy qualified donors to overexpress BDNF (MSC/BDNF), using clinically relevant methods. MSC/BDNF were found to be stable with no change in their appearance, proliferation rate or differentiation when compared to non-engineered MSC. The efficacy studies of human MSC/BDNF were completed in two transgenic Huntington’s disease mouse models: the YAC 128 and R6/2. All animals underwent implantation of mini-osmotic pumps under the skin to provide immune suppression drugs to create a more favorable environment for the human cell product in the mouse brain prior to undergoing bilateral injection of MSC/BDNF into the target brain region, the striatum. All studies were conducted in randomized, controlled and blinded fashion. Implanted and control mice underwent weekly behavioral testing. The animals’ brains were sectioned and studied after death. Results demonstrated reduction in striatal atrophy and improvement in a key behavioral test measuring anxiety-like behaviors in YAC 128 mice, with evidence for the growth of new neurons in the area adjacent to the ventricle and a trend toward longer survival in R6/2 mice. For full description, please see the following publication in “Molecular Therapy:”

These data were submitted to the NIH Recombinant DNA Advisory Committee on June 6, 2015 (see The committee provided positive feedback about the pre-clinical studies and the design of the future planned Phase 1 safety and tolerability trial. The grant team also submitted a pre-Investigational New Drug (pre-IND) package to the Food and Drug Administration, and a successful teleconference was conducted on July 15, 2015. The FDA provided specific feedback about the development of MSC/BDNF, the results of pre-clinical efficacy studies, the design of the future planned Phase 1 safety and tolerability trial, with recommendations to conduct definitive dose-finding, biosafety, biodistribution, and large animal neurotransplantation targeting studies. The pre-clinical team is completing the additional recommended studies in transgenic HD mouse models and seeks funding to conduct the large animal neurotransplantation studies.

Clinical Update: The clinical team continues to conduct the PRE-CELL study ( identifier: NCT01937923), an observational study for early-stage Huntington’s disease patients and their care partners. The goal of PRE-CELL is 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 spinal fluid and serum. Subjects who complete at least one year of participation in PRE-CELL will be potential candidates for the future planned Phase 1 safety and tolerability trial, HD-CELL. PRE-CELL is fully enrolled and closed to new subjects in July 2015. Interim analysis 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. PRE-CELL has been extended to July 31, 2016.
The clinical team developed a draft protocol for the future planned Phase 1 safety and tolerability trial (HD-CELL) and revised the protocol based on feedback from the NIH RAC hearing and the FDA pre-IND meeting. We plan to submit an IND application by Quarter 4 of the current year pending successful completion of the additional IND-enabling studies described above.

Significance. There is still a critical unmet need for disease-modifying treatments for HD. Our progress to date supports the completion of the additional pre-clinical studies and our plan to submit an IND application to the FDA for the future planned Phase 1 safety and tolerability trial of MSC/BDNF in HD patients. This work also provides a platform for our future gene editing studies for HD, since we will use MSCs to deliver the needed molecules into the central nervous system.

There are potential applications of this research beyond HD. Our biological delivery system for BDNF sets the precedent for adult stem cell therapy in the brain and could potentially be modified for other neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS), spinocerebellar ataxia (SCA), Alzheimer’s disease, and Parkinson’s disease. The MSC/BDNF product could be considered for studies of regeneration in traumatic brain injury, spinal cord and peripheral nerve injury.