Funding opportunities

Motor neuron diseases: Finding cures through basic, translational, and clinical collaboration

Funding Type: 
Disease Team Planning
Grant Number: 
DT1-00659
Principle Investigator: 
Funds requested: 
$54 798
Funding Recommendations: 
Recommended
Grant approved: 
Yes
Public Abstract: 
Spinal Muscular Atrophy (SMA) and Amyotrophic Lateral Sclerosis (ALS) are motor neuron diseases. Motor neurons control the voluntary muscles that are used for activities such as crawling, walking, head and neck control, and swallowing; and sadly there are no known cures for motor neuron diseases at this time. SMA is a genetically inherited disorder and about 1 in 40 people are carriers. SMA symptoms typically become are apparent soon after birth and is a devastating childhood disorder that is relatively common and affects approximately 1 in 6000 babies. A mutation in the SMN1 gene has been identified as being responsible for SMA and researchers have developed excellent animals models to investigate the cellular and molecular features of the disorder. Although ALS is distinct from SMA and does not typically begin to manifest itself until 30-40 years of age, it too is a motor neuron disorder which affects an estimated 100,000 Americans. 3% of ALS cases are due to mutations in the SOD1 gene, and like SMA excellent animal models have been created by researchers to study the disease and test ideas for treatment. The potential to use stem cells to help characterize drugs and test cell replacement strategies is extremely exciting for motor neuron diseases because of two recent findings: the ability to efficiently convert ES cells (both mouse and human) into cholinergic motor neurons and the promise of deriving ES cells from many different cellular sources. Although much work remains to be completed, science is well positioned to begin translating its findings into beneficial treatments. This grant will be used to hold a workshop among experts in the field of motor neuron diseases to identify the most promising approaches for treating a particular motor neuron disease. Several criteria will be used in this planning process, including: (1) evaluating where the state-of-the-art science is at that moment, (2) considering current approaches being tested and avoiding unnecessary overlap, (3) finding the “lowest hanging fruit” and focusing efforts primarily on those objectives, (4) taking optimal advantage of the immense human and physical resources available in the {REDACTED} community by combining the efforts of researchers and clinicians located at the {REDACTED}, {REDACTED}, {REDACTED}, and {REDACTED}. The deliverable from this grant will be to create a report that outlines recommendations for using stem cells as a tool or a treatment for curing a motor neuron disease. This plan will include recommendations for the scientific direction, as well as managment and administration suggestions to ensure the highest possibility of success.
Statement of Benefit to California: 
The primary goal of this collaborative endeavor is to develop highly efficacious treatments and cures for motor neuron diseases which affect the lives of thousands of Californians. This should not only markedly improve the longevity and quality of life for affected individuals, but will help to address the immense burden and expense of providing care to individuals with motor neuron diseases. We also anticipate several indirect benefits to the citizens of California, including the creation of intellectual property that can help to create new jobs in the technology sector. In addition, it is likely that the process identified for treating motor neuron diseases can likewise serve as a template for creating strategies that will ultimately yield treatments for more challenging neurological diseases and disorders including spinal cord injury, Parkinson’s, and Alzheimer’s disease, for example.
Review Summary: 
Executive Summary This applicant proposes to organize a team that will develop the most promising target for treating either amyotrophic lateral sclerosis (ALS) or spinal muscular atrophy (SMA). The goal of this proposal is to hold a workshop to collect experts from both the local community as well as national and international consultants associated with these diseases, including patient advocates, clinicians and basic scientists, to discuss the options in ALS and SMA. The products of these meetings will be a detailed report that summarizes the conclusions of the planning workshop, and a consortium of scientists and clinicians in the region able to collaborate in a disease research team award. Overall assessment from reviewers is that this is a superb proposal from a leading developmental researcher in motor neuron biology. The disease in question, ALS, is important and a therapy is badly needed. Likewise the juvenile version of the disease, SMA, is an incurable disorder of the neonate with a clear genetic cause. Overall, the review panel agreed that there is a high likelyhood that this plan and group will lead to valuable information useful for putting together a disease-targeted team. The overall plan of this award is well worked out: the applicant identifies clear workshop goals, including detailed sub-topics, and includes a plan for follow up. Reviewers commented on the strong team-based nature of the plan, which involves highly collaborative researchers. The strengths of this proposal were in the applicant PI, the team particpants, and the clear and collaborative planning approach. The applicant, a leading developmental neurobiologist and an expert in motor neuron disease, proposes to gather well-regarded local and national experts, including stem cell biologist and experts in both the therapeutic approach to ALS and other motor neuron disorders, to participate in a workshop. This is an outstanding group of investigators who are well versed in the basic and clinical biology of motor neuron disease. The goals of the workshop are to develop a plan to tackle the disease and to design a clinical trial. The concept to be tested here is that the current experimental approaches for ALS are lacking because they are based on studies in mutant mice and not on studies using human tissues. Being able to generate relevant cell types from human embryonic stem cells (for instance, generating astrocytes expressing mutant SOD1 in non-sporadic ALS, or human motor neurons from similar sources) will allow treatment strategies to be tested in human cells in vitro. Although ALS might be considered an immature field, a lot of work is being done and appropriate cell-therapy instrumentation is being developed for the field. Furthermore, axons can effectively connect to muscle in animal models of cell therapy, although it remains to be shown that this will be functionally achieved in humans. The major concern expressed by reviewers was that this proposal is based on a single meeting of (albeit outstanding) scientists without much clinical experience. The clinical experience is mostly from outside of California. The panel commented that California may lack clinical infrastructure in this area - it will be necessary for project success to develop a means of funding out-of-state collaborations with clinical groups. Finally, one reviewer asked whether this meeting will be sufficient to foster the collaborative effort required to generate a treatment strategy through stem cell technology. There is no doubt that the group is extremely strong, but as the applicant acknowledges they are all extremely busy and may not have the time to contribute significantly to this project beyond the meeting. Overall, reviewers were highly enthusiastic about the proposal due to it’s scientific strengths and it’s strong, collaborative plan. Reviewer One Comments This is a superb proposal from Dr. Pfaff who is a leading developmental researcher on motor neuron biology. In his plan he will bring together experts from the San Diego community including stem cell biologist which is Dr. Snyder and Marsala as well as experts in both the therapeutic approach to ALS and other motor neurons including Larry Goldstein, Don Cleveland, Inder Verma, Mark Tuszynski as well as outside experts including Tom Jessell for developmental biology, Chris Henderson for developmental biology and motor neuron disease, Douglas Kerr, Michael Sendtner, Arthur Burghes and others. This is an outstanding group of investigators who are well versed in the basic and clinical biology of motor neuron disease. The overall plan is well worked out including identification workshop goals, the organization of the workshop with sub topics a plan for follow up. This is a highly collaborative plan and involves highly collaborative researchers. There is a high likely hood that this plan and group will lead to valuable information eventually for putting together a disease targeted group. The principal investigator is excellent, and his qulifications are perfect for this proposal. Reviewer Two Comments Concept: The goal of the proposal is to hold a workshop at the Salk Institute that will include scientists, clinicians and patient advocates, working on or having a personal interest in ALS. Out of this meeting they propose that a plan will evolve to tackle the problem and lead to a clinical trial. The disease in question, ALS, is important and a therapy is badly needed. Likewise, the juvenile version of the disease, spinal muscular atrophy is an incurable disorder of the neonate with a clear genetic cause. The concept to be tested here is that the current experimental approaches for ALS are based on studies in mutant mice and not on human tissues. Being able to generate cells from human ESCs, e.g. astrocytes expressing mutant SOD1 in non-sporadic ALS, human motor neurons from similar sources etc. will allow treatment strategies to be tested in these. Principal Investigator: Dr. Pfaff is an expert in motor neuron development. He is very well funded both by the NIH and CIRM and he has a first rate publication record. He is truly a leader in the field. Planning Approach: The whole effort here will be with the workshop planned for the Salk Institute. The invited participants included practically all of the national experts in the field. The big question however is whether this meeting will truly lead to a collaborative effort that will generate a treatment strategy through stem cell technology. There is no doubt that the group in San Diego is extremely strong but as Dr. Pfaff acknowledges, they are all extremely busy and may not have the time to contribute significantly to this project beyond the meeting. Also, it can be said that the basic science is first-class but the clinical application does not have the same depth.
Conflicts: 

© 2013 California Institute for Regenerative Medicine