Year 1

A) Pre-clinical: The remainder of the IND-enabling studies were designed in consultation with Biologics Consulting Group (BCG). The project will begin with the IND-enabling phase and transition through regulatory approvals and through an observational trial and the Phase I clinical trial of stem cell therapy. The project has a Preclinical unit, under the leadership of co-PI Dr. Jan Nolta, and a Clinical unit, under the leadership of PI Dr. Vicki Wheelock. The two units are well integrated, since the team has been meeting weekly since 2009 to plan the testing of MSC trials for HD. During the planning phase we had a minimum of 4 hours of HD meetings per week, and worked continually on the project. This team is truly translational, with both PIs highly dedicated to this trial and motivated by the HD community.

Co-PI Jan Nolta, Ph.D. is Scientific Director of the UC Davis/CIRM GMP Facility, and will continue to direct ongoing IND-enabling studies for MSC/BDNF. The Pre-Clinical team will perform all IND-enabling studies at the level of GLP, and will manufacture and qualify the MSC and MSC/BDNF products in the GMP facility at UC Davis that is directed by Dr. Bauer (CMC lead). These studies are ongoing and we have been advised by BCG consulting lead Andra Miller, who was formerly Gene Therapy Group Leader at the FDA, CBER, Division of Cell and Gene Therapies, for almost a decade. BCG is assisting us with IND preparation.
Ms. Geralyn Annett is the experienced Project Manager. She is the UCD Stem Cell Program Manager and has worked in the field of academic and industry stem cell trials for 20+ years. She will oversee the regulatory team and keep the IND-enabling studies on task to meet the milestones. GMP Facility Director Gerhard Bauer will be responsible for regulatory filings with assistance from Dr. Nolta, the CMC team, and Dr. Miller. Dr. Nolta has worked on clinical trials of stem cell gene therapy, and associated translational studies with Ms. Annett and Director Bauer for over 20 years.
B) Clinical. The Clinical team is led by PI Dr. Vicki Wheelock, who is Director of the HDSA Center of Excellence at UC Davis and, with nurse practitioner Terry Tempkin, follows over 250 patients with HD in the UC Davis Movement Disorders clinic. The PI has extensive experience in conducting clinical trials and has already accrued HD patients to 14 clinical trials to date. The planning grant allowed us to conduct longer weekly meetings with different team members to complete planning of the proposed clinical trial.

Weekly HD meetings during the planning phase included PI Dr. Wheelock, Co-PI Dr. Nolta, Nurse practitioner Terry Tempkin, Program Manager Geralyn Annett, Psychiatrist Dr. Lorin Scher, Neuropsychologist Dr. Sarah Farias, Social Worker Lisa Kjer, and members of the Imaging Unit led by Dr. Charles DeCarli. This team has worked together on multiple clinical trials for HD patients. Some meetings additionally included Dr. Kiarash Shahlaie, the UCD functional neurosurgeon who will perform the targeting and surgical implantation of the cells, Dr. Bauer who directs the GMP facility (and his team members), the translational team who is performing the IND-enabling studies in Rodents (they usually meet separately for 2 hours/week with Dr. Nolta), and Dr. Tarantal who is leading the IND-enabling studies in non-human primates.
We met with our CRO, Paragon, who will be responsible for regulatory and safety filings including outcomes reports, medical and safety monitoring and management including DSMB, medical writing and quality assurance, clinical events committee- adjudicate AEs, and generate clinical study reports. Paragon will also oversee the development of the electronic case report forms, site management and monitoring, biostatistical analysis, and management of the database. We had on-site meetings and conference calls with Paragon during the planning Phase.
Additional meetings were conducted with collaborators and consultants:
A) Dunbar lab and Hersch lab in the US, both leaders in the HD field – for HD trial IND-enabling study research and HD mouse and patient biomarkers, respectively.
B) Aylward lab in the US for detailed brain imaging analyses in HD.
C) Paulsen lab for interpretation of cognitive assays in HD.
D) Phil Starr and Dan Lim at UCSF for ClearPoint cell injection system.
E) Bachoud-Levi lab in France for cell implantation in HD.
F) Dr. Robert (Willie) Mays and Bob Deans, Athersys – for IND-enabling studies/regulatory
In conclusion, the planning grant helped us to finalize plans for the proposed clinical trial and to complete our detailed plans for the remainder of the IND-enabling studies required to obtain FDA approval. These goals were accomplished through frequent meetings with key consultants and collaborators during the intense planning phase, where we completed the Disease Team application to CIRM that could potentially fund our proposed Phase I clinical trial of MSC/BDNF therapy for Huntington’s disease.