Limb girdle muscular dystrophy type 2B (LGMD 2B) is a form of muscular dystrophy that leads to muscle degeneration and disability. In LGMD 2B, a vital muscle protein is mutated, and its absence leads to progressive degeneration of muscles in the body that are needed for mobility. To create a therapy, we will provide a new supply of stem cells that carry the missing protein that is lacking. These cells will be delivered to the body in such a way that they will engraft into the muscles and produce new, healthy muscle tissue on an ongoing basis.
We now possess methods to create stem cells that can become muscle cells out of adult skin cells by a process known as “reprogramming”. By reprogramming adult cells, together with addition to them of a correct copy of the gene that is mutated in LGMD 2B, we will create stem cells that have the ability to create new, healthy muscle cells in the body of a patient. This is the type of strategy that we are developing in this proposal. The corrected muscle stem cells will be transplanted into mice with LGMD 2B, and the ability of the cells to generate healthy new muscle tissue and increased muscle strength will be evaluated.
This project could lead to a new stem cell therapy that could improve the clinical condition of LGMD 2B patients. If we are successful with this disease, similar methods could be used to treat other degenerative disorders, and perhaps even some of the degeneration that occurs during muscle injury and normal aging.
The proposed research could lead to a stem cell therapy for limb girdle muscular dystrophy type 2B (LGMD 2B). This outcome would deliver a variety of benefits to the state of California. There would be a profound personal benefit to the Californians affected directly or indirectly by LGMD 2B.
Progress toward a cure for LGMD 2B is also likely to accelerate the development of treatments for other degenerative disorders. The most obvious targets would be other forms of muscular dystrophy and neuromuscular disorders. Muscle injury, and even some of the normal processes of muscle aging, may be treatable by a similar strategy.
An effective stem cell therapy for LGMD 2B would also bring economic benefits to the state by reducing the huge burden of costs associated with the care of patients with long-term degenerative disorders. Many of these patients would be more able to contribute to the workforce and pay taxes.
Another benefit is the effect of novel, cutting-edge technologies developed in California on the business economy of the state. Such technologies can have a profound effect on the competitiveness of California through the formation of new manufacturing and health care delivery facilities that would employ California citizens and bring new sources of revenue to the state.
Therefore, this project has the potential to bring health and economic benefits to California that are highly desirable for the state.
The goal of this development candidate feasibility (DCF) proposal is to correct and treat limb girdle muscular dystrophy type 2B (LGMD 2B). In this disease, patients suffer lifelong muscle degeneration and disability due to a mutation in a single gene, dysferlin. The goal of this proposal is to replace disease-induced degenerated muscles with new healthy muscle fibers. The applicant proposes to generate patient derived induced pluripotent stem cells (iPSCs), genetically correct the mutant copy of the dysferlin gene in vitro, differentiate the corrected iPSCs into muscle precursor cells, and finally transplant these cells into a relevant immunodeficient animal model of this disease, to test for the ability to restore muscle tissue.
Objective and Milestones
- The work proposed is appropriate for a DCF award and the milestones are clearly written.
- The target product profile (TPP) is well constructed, though reviewers commented that a more defined clinical efficacy endpoint is needed.
- Lack of sufficient product purity (at least 50% vs. reported 20%) at the early development stage is the key bottleneck and a risk factor for this project, which will face regulatory challenges in the future.
Rationale and Significance
- Reviewers felt that LGMD 2B is a good disease target since it is genetically homogeneous and only affects certain skeletal muscles and not the heart or diaphragm. Thus direct injection of corrected muscle progenitors into the affected tissue is a rational approach.
- There are no current treatments for this disease and, if successful, this therapy would significantly improve the lives of the patient population.
- Some reviewers cautioned that previous work on stem cell and myoblast transplantations in muscle degenerative diseases resulted in only modest reported improvements.
Feasibility and Design
- The research plan is clear, appropriate and feasible
Reviewers felt that the preliminary data showing successful engraftment and differentiation of muscle progenitors derived from gene-corrected patient iPSC were highly encouraging.
- Excellent readout for transplantation survival and clear demonstration that dysferlin positive fibers survive following transplantation into an animal model.
- Reviewers were concerned that it was not clearly defined what level of muscle repair is required for clinical benefit, and that it is not known whether transplanted muscle progenitor cells can continue to differentiate to enlarge the size of a graft over time.
- It was felt that the ~ 20% threshold for production of muscle precursor cells was too low for development of a useful product and that attaining better product purity and characterization should be an important goal.
Qualification of the PI (Co-PI, Partner PI) and Research Team
- The PI is an outstanding scientist, although it was noted that muscle biology is not the primary area of his/her expertise.
- Reviewers were confident that the assembled team is appropriate and can successfully execute the proposed work.
Collaborations, Assets, Resources and Environment
- There are no collaborations for this proposal.
- There are appropriate assets and institutional support, and an excellent environment for the proposed work.
Responsiveness to the RFA
- The proposal was judged to be highly responsive to the RFA