New Faculty Physician Scientist
$2 772 000
Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurologic disease in which the nerves that connect to and control skeletal muscle prematurely die, resulting in muscle atrophy and weakness that steals away the ability to walk, stand, sit without support, speak, swallow, and breathe independently. ALS is inevitably fatal with no curative and only one disease-slowing treatment. Although the exact cause of ALS is unknown, the earliest abnormalities have been observed where the motor nerve attaches to and communicates with muscle, also known as the neuromuscular junction (NMJ). An intact NMJ is essential for normal muscle function and movement. Early in ALS, the NMJ begins to pull away and disconnect from muscle leading to paralysis. Currently, there are no medications known to prevent these changes. We are developing a therapy for ALS targeted to treat the NMJ, using mesenchymal stem cells (MSC) that over-secrete insulin-like growth factor I (IGF). IGF is a potent growth hormone with properties known to stabilize the NMJ and protect the motor nerve from death. MSC are adult stem cells found within bone marrow. These cells can be expanded, engineered to over-secrete IGF, and injected into skeletal muscle where increased levels of IGF can improve the health and promote retention of the NMJ. If effective, this therapy has the potential to slow disease progression, maintain muscle strength and function, and improve the quality-of-life for those living with ALS.
Statement of Benefit to California:
Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disease that causes severe disability, as those diagnosed with ALS inevitably lose muscle function and will transition from independent to dependent living. In California, approximately 2000 people live with ALS at any one time; however, ALS does not just affect patients. Due to the relentless course of ALS, family, friends and the greater community will necessarily provide essential basic daily care for their loved ones, making it a costly disease both in terms of patient life-years lost and caregiver burden. In addition, there are no effective treatments available to slow the functional losses suffered from ALS and many dollars are spent annually on unproven therapies by those hoping and searching for a cure. Our proposed therapy, aimed at maintaining the connection between muscle and motor neurons, has the potential to slow the functional decline of ALS. It is a novel therapy combining the healing properties of mesenchymal stem cells with insulin-like growth factor 1, a potent neurotrophic agent that has been shown to slow disease in animal models of ALS. California will benefit directly from the research and development of this stem cell therapy not only by providing a treatment for ALS where one does not exist, but socioeconomically by creating valuable jobs and training for scientists and students, and by becoming a treatment destination for those around the world fighting ALS.
Executive Summary A key feature of Amyotrophic Lateral Sclerosis (ALS) is disruption of the neuromuscular junctions (NMJ), the subcellular structures where motor neurons attach to and communicate with skeletal muscles. The research proposal focuses on developing a therapy for ALS that will protect the NMJ and prevent motor neuron death. The approach will involve the use of mesenchymal stem cells (MSC) that secrete insulin-like growth factor I (IGF); injection of these cells into skeletal muscle is proposed to stabilize NMJs and prevent disease progression. Proposed experiments will test the efficacy and safety of the approach in model systems and support preclinical and IND-enabling studies. Research Plan - The proposal is focused on a serious medical need, the development of an effective treatment for ALS. - Reviewers differed on their assessment of the project’s rationale; while one reviewer considered it logical and compelling, others found the rationale unconvincing and seriously questioned the feasibility of the approach. - The approach was poorly justified by either published or preliminary data. - There is little evidence that injected cells would migrate to and persist or survive at the NMJs. - Reviewers viewed the preclinical experiments as premature, poorly designed and insufficiently justified. - The proposal did not address potential difficulties or alternative strategies. Principal Investigator - The PI is a specialist in Physical Medicine and Rehabilitation with expertise in neuromuscular medicine. - The applicant has very limited experience with basic research and has produced very few research publications. - The PI’s career development plan is particularly clear, detailed and well designed. - Proposed mentors have substantial experience in translational medicine and neuromuscular disease. Institutional Commitment - Reviewers noted a substantial institutional commitment to the PI’s career development but expressed concern that the candidate was not assured a tenure-track appointment. - The institution appears to be strongly committed to promoting and supporting translational stem cell research programs; much infrastructure and appropriate collaborators are available at the applicant institution. Responsiveness - Reviewers found the proposal to be responsive to the RFA.