Funding opportunities

hESC-Derived Motor Neuron Progenitors for the Treatment of Spinal Muscular Atrophy

Funding Type: 
Disease Team Research I
Grant Number: 
Funds requested: 
$4 745 168
Funding Recommendations: 
Not recommended
Grant approved: 
Public Abstract: 
Our goal is to obtain FDA-approval for a stem cell-based therapy to treat the leading genetic killer of infants under 2 years of age, spinal muscular atrophy (SMA) Type I. SMA is a disease that first causes dysfunction of and then destroys motor neurons controlling all movement, including swallowing and breathing. There is no known treatment. The diagnosis of SMA Type I is usually made before 3 months of age and >95 percent die or require full-time respiratory support in infancy. Of all motor neuron diseases, SMA is the easiest to obtain FDA approval for, and presents the greatest clinical need given the certain death of afflicted infants. The information that we obtain will be directly relevant to SMA Type II and III, ALS, chronic spinal cord injury, and polio, all of which are characterized by motor neuron loss. The treatment involves transplantation of high-purity populations of human motor neuron cells derived from human embryonic stem cells (hESC-MNPs). We have already completed many steps towards FDA approval, including 1) production of a motor neuron manufacturing facility to make the cells in a manner compatible with human use, which has been audited and shown to be compliant with FDA guidelines for cell production, 2) small animal proof-of-concept studies which show that transplantation of our cells, made under FDA-compliant conditions, restores lost motor neurons in models of motor neuron loss, 3) FDA-reviewed safety studies which show that transplantation of our cells, made under FDA-compliant conditions, does not cause tumors, pain or any adverse events, and 4) multiple meetings with expert researchers and doctors resulting in a final clinical plan. Our team has been preparing for this clinical trial for 3 years, and has already held formal meetings with the FDA, so we do not require all 4 years of support. In this proposal, we are requesting 18 months of support for, 1) scale up of the cell manufacturing facility to prepare for the large volumes required for human treatment, and confirm that the scaled up production process produces the same quality cells as the current production process, 2) replication of small animal proof-of-concept studies which show that transplantation of our cells, made under FDA-compliant conditions, restores lost motor neurons in models of motor neuron loss, 3) large animal safety studies to test the accuracy of our cell delivery with available instrumentation, determine survival and differentiation rate of transplanted cells, and make sure that transplantation does not result in tumor formation or any adverse event, and 4) hire the staff to complete the pre-IND and IND filings.
Statement of Benefit to California: 
The treatment and care of individuals with motor neuron diseases represents a significant social and economic burden to the State of California. Specific to the first target indication, there are approximately 1,500 individuals affected by SMA currently living in the State of California and nearly 1,000,000 carriers of the SMA gene. Additionally, the Families of SMA Research Director, Dr. Jill Jarecki, is headquartered in San Diego. If successful, our clinical strategy will improve the function and quality of life of individuals with motor neuron diseases, which will lessen the cost that citizens and the State bear in terms of patient care. This program will position California for international competitiveness in this emerging area of biotechnology, as our clinical trial development strategy addresses critical barriers limiting the development of this sector in California and abroad. High purity cultures of hESC-derivatives enable transplantation approaches to disease, drug discovery, and predictive toxicology. This research plan will lead to the development and thorough characterization of a renewable source of human motor neurons that enables these 3 strategies as they pertain to spinal muscular atrophy, amyotrophic lateral sclerosis, polio, and spinal cord injury. Our program is within 18 months of being presented to the FDA for an IND. Thus, it will provide precedent in California for subsequent stem cell-based clinical trials, {REDACTED}. Thus, California will benefit from ‘hosting’ the discovery of what will become the first and second human embryonic stem cell-based clinical trials in the world. This will result in California being a focus of the stem cell industry, including large pharmaceutical companies that will eventually participate in the latter stage stem cell clinical trials. Clinically relevant scientific advances lead to the development of biotechnology companies, creating jobs and taxation. Funding for this proposal will directly create 11 new jobs. In these challenging economic times, we feel that any award should be spent in a manner which enhances the local and state economy, in essence returning direct value to the citizens of California. To this end, we have purposely selected suppliers of equipment and services that are located in the state of California. In addition, due to the booming medical device and biotechnology industries in California, we feel that all new hires can be obtained from within the state of California.
Review Summary: 
The goal of this proposal is to develop a cellular therapy for spinal muscular atrophy (SMA) Type 1, a genetic disease of infants that causes motor neuron dysfunction and death. The proposed therapeutic candidate is human motor neuron progenitor cells (hMNPs) derived from human embryonic stem cells. The applicant’s hypothesis is that hMNPs transplanted into the spinal cord will mature in vivo into functional motor neurons, which could restore motor function in two ways: hMNPs could rescue diseased neurons via growth factor secretion and trophic support; or replace diseased neurons via axonal growth and reinnervation of target muscle. The applicant has completed a number of steps in preparation for an Investigational New Drug (IND) filing and requests 18 months of funding. Specifically, the applicant proposes to scale up production of hMNPs, confirm efficacy in a mouse model of motor neuron loss and perform safety studies in other relevant animal models. The reviewers raised significant concerns about the proposed therapeutic strategy. Specifically, they cited a lack of preliminary data demonstrating disease-modifying activity of hMNPs. Reviewers also raised questions about the proposed clinical approach and generally felt that an IND filing in 18 months would be premature. Reviewers questioned the scientific rationale for this proposal. They noted the enormous challenge posed by transplanting cells that will have to not only survive and replace dying motor neurons but also extend axons that exit the spinal cord, find the appropriate targets and functionally innervate muscles. Reviewers cautioned that while the distances required for axonal growth in infants are shorter than in adults, they are still much greater than in a rodent. More importantly, reviewers could not find evidence in the application for the efficacy of the proposed therapeutic in an animal model of the disease. While there is a figure displaying locomotor behavior following hMNP transplant, the animal model is not indicated. Reviewers felt that evidence for preclinical efficacy was a vital missing piece of this proposal. Reviewers appreciated the significance of the proposal and agreed that SMA is a devastating disease desperately in need of a treatment. However, they did not feel that the proposed approach is likely to cure or halt the disease. Reviewers cautioned that transplanted hMNPs may be unable to rescue motor neurons in a disease where much of the damage may be done before birth. They also doubted whether full spinal cord motor neuron replacement is clinically feasible. Reviewers agreed that there is a tremendous unmet medical need in SMA and the development of any treatment option would have a major impact on patients. However, they raised concerns about the clinical readiness of this particular approach, since an incomplete rescue of motor neuron function may not result in a positive overall outcome for patients. The reviewers raised a number of issues surrounding the preliminary data that lead them to doubt the project’s feasibility. They were concerned that much of the hMNP characterization and axonal outgrowth data was obtained in vitro, a setting that may have little bearing on the behavior of these cells in vivo. Reviewers noted that preclinical safety data is described but not presented, making it impossible to evaluate. They also would have appreciated the inclusion of data addressing lot-to-lot variability of hMNPs as well as safety testing with dead or lysed cells. Reviewers thought that some percentage of cells is likely to die after transplant, potentially resulting in secondary inflammation and neurotoxic injury. Reviewers found the research plan to be logical and detailed with appropriate regulatory considerations. They appreciated that the applicant has already held a pre-pre-IND meeting with the FDA, established cGMP manufacturing processes and performed some preclinical safety studies. However, they did raise one major concern with the clinical plan, which proposes to use a hand-held Hamilton syringe for multiple cell injections into the infant spinal cord. Reviewers strongly suggested rethinking this cell delivery approach. They cautioned that hand-held syringe is uncontrolled in terms of targeting and pressure dynamics and recommended an injection frame and syringe pumps for standardization and reproducibility. The reviewers praised the research team and noted that the PI has an established track record in stem cell and motor neuron biology. They agreed that the team has a good understanding of regulatory issues and has established the proper collaborations to maximize the likelihood of success. Reviewers did feel that an ethics committee was noticeably missing from the team. They were concerned about the ethical issues surrounding complex, high-risk surgeries on infants incapable of providing consent. Reviewers also noted that while there is one pediatrician on the external advisory board, there are none on the research team and recommended that one be added. Overall, reviewers were not convinced of the scientific maturity of this proposal. They did not find the preliminary data compelling and specifically noted a lack of evidence for disease-modifying activity of the therapeutic candidate. Reviewers also raised a number of concerns with the scientific rationale and proposed therapeutic strategy which caused them to question the project’s clinical readiness.
  • Darin Weber

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