As humans age, the ability to regenerate skeletal muscle tissue is impaired. Injuries to the musculoskeletal system that require extended periods of immobilization lead to muscle atrophy and are particularly devastating to the elderly population. Loss of skeletal muscle mass and function reduces mobility, which negatively affects quality of life, and increases the risk of mobility-related accidents. Currently, strategies to ameliorate injury-related or heritable muscle atrophy are limited and consist primarily of exercise-based regimens to increase strength. Here we propose to develop a human stem cell therapy to prevent and/or reverse localized skeletal muscle atrophy in muscles of the aged. Specifically, we aim to (1) refine a strategy we have developed that enables us to isolate muscle stem cells (MuSCs) from human muscle biopsies, (2) apply a strategy which we developed for murine MuSCs to human MuSCs that rejuvenates and expands the stem cells in culture to clinically useful numbers using a combined bioengineering and small molecule treatment, and (3) demonstrate that transplantation of human MuSCs results in increased in vivo force generation and strength in atrophied muscles of aged recipients. Together, these studies will culminate in the validation of a novel stem cell-based "development candidate" to the treat skeletal muscle atrophy afflicting the ever increasing aged community and will advance the use of stem cells for therapy in the clinic.
Skeletal muscle is critical to our day-to-day movement and loss of muscle mass and function impairs quality of life and increases the risk of mobility related accidents particularly in the elderly. Currently there are no clinical approaches to prevent or reverse the muscle atrophy that occurs following musculoskeletal injury and subsequent immobilization other than physical activity. Since California is projected to be the fastest growing state in the U.S. in terms of population, with an elderly population that is projected to grow twice as fast as the total population of the state, it is more important than ever to develop strategies that positively impact the health of this demographic. The research in this CIRM application aims to provide a muscle stem cell transplantation therapy to overcome muscle atrophy. Initially, the application of this strategy to the function of small muscles of the eye critical to vision, to the pharynx critical to swallowing, or to the muscles of the hand are envisioned. A major effort will also entail scaling up muscle stem cell production for the treatment muscle atrophy occurring in ~60% of the aged knee or hip revision rehabilitation patients. This work will not only advance the use of stem cells in the clinic, but will also provide a novel therapy to ameliorate the devastating effects of muscle atrophy in our ever growing aged community.
The long-term goal of this Development Candidate Feasibility proposal is to provide an autologous cell-based therapy to replenish functional muscle stem cells in elderly patients, thereby ameliorating muscle decline (atrophy). Skeletal muscles are able to regenerate from rare intrinsic muscle stem cells throughout life, but much less so in aged individuals. As a consequence muscles lose mass and strength with age, a decline further exacerbated following various injuries. This results in disability and decreased quality of life. Based on methods developed using muscle stem cells from aged mice, the objective of this project is to expand in vitro and rejuvenate muscle stem cells isolated from aged humans, and test their therapeutic efficacy in improving muscle strength after local delivery into atrophied muscle groups in aged mice.
Objective and Milestones
- The objective is clearly defined as providing pre-clinical proof of concept of a therapeutic candidate by extending previous work using mouse cells into the new proposed studies using human cells.
- The milestones are clearly focused to appropriately serve the research plan.
- The target product profile has been clearly described, although there is a lack of clarity around the clinical target.
- No dose range has been specified in the target product profile; some reviewers stated that this will be important to define as part of the project, whereas others pointed out that this would have more significance if this were a Development Candidate proposal.
Rationale and Significance
- The scientific rationale is strong; it appears feasible that this research will result in a therapeutic human stem cell product for muscle atrophy and possibly for other applications such as muscular dystrophies.
- The ability to expand muscle stem cells in vitro would overcome a major bottleneck in obtaining a sufficient number of these cells to restore muscle function in humans.
- Muscle atrophy causes significant morbidity and poor quality of life in the aging population; there is no doubt that a treatment for muscle atrophy would address an unmet medical need.
- Reviewers questioned whether all the patient groups mentioned would be obvious targets. Treatment of permanent, chronic muscle atrophy from a variety of causes, e.g. following denervation injury, makes much sense. However, targeting increased muscle recovery after orthopedic surgery is questionable as a commercially realistic target and would require further, careful justification.
Research Project Feasibility and Design
- The research plan is clearly presented; the proposed studies are well designed and will rigorously demonstrate whether human muscle stem cells persist and self-renew in mouse muscle.
- The preliminary data is very strong. Published data appeared in excellent high impact journals and some new preliminary data are presented. This represents cutting edge work.
- All the tools required to complete the proposed studies are available to the applicant.
- The plan is achievable within the proposed timeline.
- There is a risk that human cells will behave differently from mouse cells. However, preliminary data, including the isolation of human muscle stem cells, alleviate some of the risk.
- While the approach for in vivo tracking of transplanted muscle stem cells is very valuable in preclinical studies, a similar system cannot be used in human clinical applications. The project should provide an alternative strategy that is useful in future human treatments.
- Some reviewers stated that potential toxic effects of the compound used for in vitro rejuvenation of muscle stem cells should have been more fully explored, while others pointed out that such studies are not necessarily needed at the proof-of-concept stage of research.
Qualifications of the Principal Investigator (PI) and Research Team
- The PI is a world-renowned muscle biologist with an excellent academic track record, and has pioneered much of the research in the area of muscle stem cells.
- The PI has been directly involved in translational work in the past, and is therefore ideally placed to lead this project.
- The co-investigators will bring additional laboratory expertise; appropriate clinical collaborators have been brought into the team to ensure an effective supply of human muscle biopsies.
- The PI and co-investigators all have a long-term commitment to the muscle regeneration field and are well committed to the project.
- The total budget is reasonable for the proposed research.
Collaborations, Assets, Resources and Environment
- Collaborations with clinical colleagues have already been established, and all collaborators have written strong letters of support.
- There is an equally enthusiastic letter of support from the institution.
- The environment will clearly be excellent for this project.
Responsiveness to the RFA
- The project meets the RFA objectives. It exploits the potential of human stem cells and is properly focused on proof of concept. The proposed approach is absolutely novel and is not adequately covered by the CIRM portfolio.