Grant Award Details
Human iPSC modeling and therapeutics for degenerative peripheral nerve disease
To develop human iPSC lines from patients with inherited peripheral neuropathy (Charcot Marie Tooth type 1A, or CMT1A) due to duplication of the PMP22 gene. The PI proposes to genetically correct the defect in these cells, differentiate them into Schwann cell precursors (SCPs), and determine whether genetic correction recovers their ability to effectively myelinate axons in vitro and in vivo. Finally they will transplant genetically corrected SCPs into a rat model of CMT1A, to determine whether these cells protect peripheral axons and alter disease progression.
During this award period we have made significant progress. We have established induced pluripotent stem cell (iPSC) lines from four patients with Charcot-Marie-Tooth disease type 1A (CMT1A) due to the PMP22 duplication. We have validated our strategy to genetically engineer induced pluripotent stem cells from patients with inherited neuropathy, and have genetically engineered several patient lines. We further have begun to differentiate these iPSCs into Schwann cell precursors, to begin to investigate cell type specific defects that cause peripheral neurodegeneration in patients with CMT1A. Finally we have imported and characterized a transgenic rat model of CMT1A in order to begin to investigate the ability to inject iPSC derived Schwann cell precursors into rodent nerves as a possible neuroprotective strategy.
During this reporting period we developed genetically corrected induced pluripotent stem cell lines from patients with CMT1A. We improved and validated a novel method for differentiating Schwann cells from iPSCs, and used this to generate human Schwann cells from patients and controls. Finally we have initiated pilot studies injecting human iPSC derived Schwann cells into the peripheral nerves of rats with myelin diseases to determine whether cell replacement therapy is a viable strategy in these disorders.
Overall we have made excellent progress on this proposal. We have successfully generated iPSC lines from CMT1A patients and characterized them; validated our TALEN approach to genetically “correct” the mutation in CMT1A patient iPSC lines; established differentiation protocols for iPSC lines into neural crest stem cells and tested several methods to generated Schwann cell precursors; imported and validated a rat model of CMT1A to be used for intraneural stem cell injection experiments.
<p>Our project demonstrates that Schwann cells (cells that support and protect peripheral nerves) could be cultured, genetically manipulated and surgically delivered to models of peripheral nerve disease. We found they could engraft to form myelin in either acquired or inherited myelin injury models, analogous to Charcot-Marie-Tooth disease or inflammatory neuropathies in humans. This demonstrates for the first time proof of concept for pursuing cell therapy for diseases of peripheral nerve outside of simple nerve injury. Remaining hurdles include the lack existing technology for generating human iPSC-derived Schwann cell precursors for transplantation that are competent to generate myelin. </p>
Grant Application Details
- Human iPSC modeling and therapeutics for degenerative peripheral nerve disease
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.
Statement of Benefit to California:
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.
Source URL: https://www.cirm.ca.gov/our-progress/awards/human-ipsc-modeling-and-therapeutics-degenerative-peripheral-nerve-disease