This project aims to use a powerful combined stem cell and gene therapy approach to treat patients with amyotrophic lateral sclerosis (ALS or Lou Gehrig’s Disease). ALS is a devastating disease for which there is no treatment or cure. Progression from early muscle twitches to complete paralysis and death usually happens within 4 years. Every 90 minutes someone is diagnosed with ALS in the USA, and every 90 minutes someone dies from ALS. In California the death rate is one person every one and a half days.
Stem cells have been shown to produce support cells for dying motor neurons called astrocytes which may slow down disease progression. Furthermore, many studies have shown that growth factors such as glial cell line-derived growth factor (or GDNF) can protect motor neurons from damage in a number of different animal models including those for ALS. However, delivering GDNF to the spinal cord has been almost impossible as it does not cross from the blood to the brain tissue. The idea behind the current proposal is to modify stem cells to produce GDNF and then transplant these cells into patients. A number of advances in human stem cell biology along with new surgical approaches has allowed us to put together this disease team approach – a first in man study to deliver cells modified to release a powerful growth factor that are expected to slow down the death of motor neurons and paralysis in patients.
The focus of the proposal will be to perform essential preclinical studies in both small and large animals that will establish optimal doses and safe procedures for translating this stem cell and gene therapy into human patients. The Phase 1 clinical study will include 30 ALS patients from the state of California. This will be the first time this type of stem cell and gene therapy has been available to any ALS patients in the world.
ALS is a devastating disease, and also puts a large burden on state resources through the need of full time care givers and hospital equipment. It is estimated that the cost of caring for an ALS patient in the late stage of disease while on a respiration is $200,00-300,000 per year. While primarily a humanitarian effort to avoid suffering, this project will also ease the cost of caring for ALS patients in California if ultimately successful. As the first trial in the world to combine stem cell and gene therapy it will make California a center of excellence for these types of studies. This in turn will attract scientists, clinicians, and companies interested in this area of medicine to the state of California thus increasing state revenue and state prestige in the rapidly growing field of Regenerative Medicine.
The proposed project aims to use a human stem/progenitor cell line modified to release glial cell line-derived neurotrophic factor (GDNF) to treat amyotrophic lateral sclerosis (ALS), a lethal disease for which effective treatment is lacking. During the research award, the applicant proposes to conduct all necessary preclinical studies and manufacturing activities, file the Investigational New Drug (IND) application and complete a first in human Phase I clinical study. The goal of the Phase I study is to establish the safety and feasibility of this approach in ALS patients.
Significance and Impact
- Currently, there is only 1 approved therapy for ALS and it has limited efficacy. If successful, the proposed combined cell/neurotrophic factor therapy could have a revolutionary impact on the treatment of ALS.
- There are a number of cell and/or cell and gene therapy approaches to ALS under development. A potential competitive advantage of the applicant’s approach is the long-term delivery of a potent trophic factor for motor neurons and the differentiation propensity of this stem cell line.
- The TPP is appropriate for the developmental stage of this product, but is lacking a compelling description of the applicant’s vision for the final product or alternatively, the product at the end of this project. The applicant should consult the FDA guidance document (Guidance for Industry and Review Staff Target Product Profile — A Strategic Development Process Tool for instructions on how to prepare a TPP) in preparing the TPP should a full application be submitted.
- This proposal is responsive to the RFA
Project Rationale and Feasibility
- While the mechanism underlying ALS is not known, the scientific rationale must be based largely on evidence for potential amelioration of motor neuron death by cell therapy augmented by engineered secretion of GDNF. There is a significant body of published work, including publications from the PI, supporting the potential benefits of stem/progenitor therapy and/or local neurotrophic factor delivery.
- The preclinical data presented in the application (not done with the proposed cell line) were supportive of the proposed cell therapy approach but did not convince reviewers that the addition of GDNF conferred additional benefit. This issue was pivotal to the reviewers. Should the applicant submit a research award application, it is critical that the applicant include data clearly demonstrating the additional benefit of GDNF to stem cell treatment alone
- When reviewers considered the weaknesses in the preclinical efficacy data supporting the use of GDNF, it was noted that animal models may or may not predict functional improvements in humans and this is a severe disease where treatment option are badly needed. However, it is still incumbent on the investigators to provide convincing efficacy data before moving forward into human studies.
- It is unclear what the IND-enabling studies will be but the investigators have clear knowledge of this from the FDA feedback so a more complete description of these studies should be incorporated into the research award application.
- It is unclear if immunosuppression will be required in the clinical study, and the need for immunosuppression was not discussed.
Principal Investigator (PI) and Planning Leader
-The PI is ideally suited to lead this effort, and has the required experience in translational neuroscience that is focused on cell and growth factor therapy.
-The Planning Leader has an extensive track record in regulatory affairs and R&D in areas directly relevant to the proposed application, both as an executive in the biotech industry and as a consultant.
- Jonathan Glass
- Thomas Freeman