This project aims to use a powerful combined neural progenitor cell and growth factor 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. Human neural progenitor cells found early in brain development can be isolated and expanded in culture to large banks of billions of cell. When transplanted into animal models of ALS they have been shown to mature into support cells for dying motor neurons called astrocytes. In other studies, growth factors such as glial cell line-derived growth factor (or GDNF) have been shown to protect motor neurons from damage in a number of different animal models including ALS. However, delivering GDNF to the spinal cord has been almost impossible as it does not cross from the blood to the tissue of the spinal cord. The idea behind the current proposal is to modify human neural progenitor cells to produce GDNF and then transplant these cells into patients. There they act as “Trojan horses”, arriving at sick motor neurons and delivering the drug exactly where it is needed. A number of advances in human neural progenitor cell biology along with new surgical approaches have allowed us to create this disease team approach.
The focus of the proposal will be to perform essential preclinical studies in relevant preclinical animal models that will establish optimal doses and safe procedures for translating this progenitor cell and growth factor therapy into human patients. The Phase 1/2a clinical study will inject the cells into one side of the lumbar spinal cord (that supplies the legs with neural impulses) of 12 ALS patients from the state of California. The progression in the treated leg vs. the non treated leg will be compared to see if the cells slow down progression of the disease. This is the first time a combined progenitor cell and growth factor treatment has been explored for patients with ALS.
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 $200,000-300,000 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 progenitor cell and gene transfer of a growth factor, 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.
This applicant proposes to develop and test Glial cell-Derived Neurotrophic Factor (GDNF)-expressing human neural progenitor cells (hNPC) as a therapy for Amyotrophic Lateral Sclerosis (ALS). ALS is a lethal disease that is characterized by severe loss of brain and spinal cord motor neurons and their associated support cells, called astrocytes. This cell loss leads to muscle weakness, paralysis, respiratory failure and death, usually within four years. The rationale behind this combination therapy is that the hNPC will differentiate to replace degenerating astrocytes, while expression of the growth factor will have a neuroprotective effect. The goals of this proposal are to perform preclinical safety and efficacy studies in relevant animal models, and to carry out Phase 1 clinical studies in ALS patients to establish safety and feasibility of this therapeutic.
Significance and Impact
- There are approximately 5,600 new cases of ALS in the USA each year and as many as 30,000 Americans may currently be affected by ALS.
- Currently, there is only one approved therapy for ALS and it has limited efficacy. If successful, this proposed therapy could have a ground-breaking impact on the treatment of ALS.
- Reviewers noted a similar study being carried out in ALS patients by another group. However, differences include the fact that the other group’s cells are not engineered to secrete GDNF, and they differentiate into neurons rather than astrocytes after transplantation.
- Some reviewers questioned the potential therapeutic efficacy of GDNF, referring to previous clinical trial data. One key issue is that GDNF appears only important in early stages of disease onset.
- Reviewers commented that ALS is a diffuse disease and questioned whether this focal therapy would actually impact the disease.
Therapeutic Development Readiness
- Reviewers were concerned about the lack of convincing preclinical data. In the figure measuring a functional endpoint (BBB score) there was minimal difference between the GDNF and non-GDNF groups.
- The investigators have not fully described the potential immunogenicity of allogeneic hNPCs in the context of the suggested immunosuppressive regimen. There was no significant description how this immunosuppressive regimen compares with the animal studies.
- GDNF expression was confirmed in vitro for up to 14 weeks of expansion but there are inadequate data addressing in vivo expression levels or whether gene silencing occurs in vivo.
- The applicants discuss development of a tracking method, however this was not detailed in the proposed clinical trial synopsis.
- The investigators conducted a pre-pre IND meeting with FDA in 2005 and a pre IND meeting in February of 2011 resulting in detailed suggestions for pivotal IND-enabling studies.
Feasibility of the Project Plan
- Reviewers expressed concerns about the aggressive timelines, noting that there is very little time built in between the pivotal nonclinical studies and the start of the clinical trial, thus not allowing any time should the FDA impose a clinical hold.
- There was concern about the lack of information on how the clinical sites would be trained, and how the variability between sites would be addressed. For example, there was no mention of a standardized assay for assessing cell viability prior to administering to patients.
- It was suggested that the patient follow up be longer than 12 months to look for potential tumorigenicity, immunogenicity and other safety issues.
- The use of the proposed tracer was questioned as it is taken up by host cells when transplanted cells die.
Principal Investigator (PI) and Development Team
- 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 team is excellent. The clinical trial physicians are outstanding members with direct clinical expertise and experience in ALS clinical trials.
Collaborations, Resources and Environment
- The investigators have not fully described how they will access Intellectual Property needed for product development.
- The preclinical CRO is well established and will do the mixed GLP/non-GLP tox studies.
Budget (Assessment of the budget was conducted separately from the overall scientific evaluation and points or concerns raised in this section did not contribute to the scientific score. This section highlights items that must be addressed should the application be approved for funding. )
- It was felt that a budget of close to $300K per patient for the clinical sites was high, and that it should be closer to $50,000 - $80,000 per patient.
- A motion was made to move this application into Tier 3, Not Recommended for Funding. Reviewers felt the applicant failed to show behavioral efficacy data, and that it was premature to move this therapy into the clinic. It was suggested that there are well-known animal models that could be used for further testing to better develop the product. The motion carried.
- Russell Lonser