The applicant is an MD/PhD trained physician scientist, whose clinical expertise is neuromuscular disorders including peripheral nerve disease. The proposal is aimed at providing a research proposal and career development plan that will allow the applicant to develop an independent research program, which attempts to bring stem cell based therapies to patients with peripheral nerve diseases. The proposal will use “adult stem cells” derived from patients with an inherited nerve disease, correct the genetic abnormality in those cells, and determine the feasibility of transplanting the genetically engineered cells back into peripheral nerve to slow disease progression.
The proposed research will benefit the State of California as it will support the career development of a uniquely trained physician scientist to establish an innovative translational stem cell research program aimed toward direct clinical application to patients. The cutting edge technologies proposed are directly in line with the fundamental purpose of the California Initiative for Regenerative Medicine. If successful, both scientific and patient advocate organizations would recognize that these advances came directly from the unique efforts of CIRM and the State of California to lead the world in stem cell research. Finally, as a result of funding of this award, further financial investments from private and public funding organizations would directly benefit the State in the years to come.
Charcot-Marie-Tooth disease type 1A (CMT) is a peripheral nerve disease due to duplication of a specific gene that encodes a structural myelin protein in Schwann cells, leading to an increase in this gene and consequent abnormal myelin production, demyelination, and axonal degeneration that can result in muscle wasting and sensory loss. The proposal aims to develop Schwann cell precursors from genetically corrected CMT patient derived induced pluripotent stem cells (iPSCs), in order to restore functional remyelination. Genetically corrected iPSC-derived Schwann cell precursors will be then introduced into sciatic nerve in a rodent model of CMT to test for function.
- Reviewers agreed that the proposal is rational and the approach is exciting and innovative. The proposal utilizes cutting edge technologies in a focused set of aims that should yield meaningful results and provide guidance for further development as this work progresses towards translational therapy. If successful, the project could significantly advance treatment of CMT.
- The expertise of the research team and the preliminary data are generally supportive of the aims of the research plan.
- Some feasibility concerns were noted as the work progresses toward the translational goal. Some reviewers argued that the described protocol for generating iPSC-derived Schwann cell precursors appears to be quite long and additional time would be necessary for gene correction and safety testing prior to re-implantation into a CMT patient. Additionally, multiple site injections may be required to sufficiently target affected peripheral nerves.
- Inclusion of some functional assessments in the CMT1A model would be desirable in order to strengthen support for future development of this stem cell therapy.
- The PI has an established track record and interest in neuromuscular diseases including ALS and peripheral neuropathy, and has successfully managed a clinical career in parallel with independent laboratory research supported by NIH grants.
- A strong mentoring team is assigned to provide expertise and support in all areas of the proposed project where the PI has limited experience.
- The applicant has very strong institutional support with an excellent start-up package.
- The institution provides access to excellent core facilities covering all aspects of the proposal including an iPS/gene targeting core, animal facility, virus core and imaging flow cytometry.
- Reviewers agreed that the proposal is responsive to the RFA. The use of human iPSC is necessary to carry out the gene correction experiments and in vivo work as proposed in this proposal.