Funding opportunities

Funding Type: 
Disease Team Therapy Development - Research
Grant Number: 
Principle Investigator: 
Funds requested: 
$18 950 061
Funding Recommendations: 
Grant approved: 
Public Abstract: 

One in every ten thousand people in the USA has Huntington's disease, and it impacts many more. Multiple generations within a family can inherit the disease, resulting in escalating health care costs and draining family resources. This highly devastating and fatal disease touches all races and socioeconomic levels, and there are currently no cures. Screening for the mutant HD gene is available, but the at-risk children of an affected parent often do not wish to be tested since there are currently no early prevention strategies or effective treatments.

We propose a novel therapy to treat HD; implantation of cells engineered to secrete Brain-Derived Neurotrophic factor (BDNF), a factor needed by neurons to remain alive and healthy, but which plummets to very low levels in HD patients due to interference by the mutant Huntingtin (htt) protein that is the hallmark of the disease. Intrastriatal implantation of mesenchymal stem cells (MSC) has significant neurorestorative effects and is safe in animal models. We have discovered that MSC are remarkably effective delivery vehicles, moving robustly through the tissue and infusing therapeutic molecules into each damaged cell that they contact. Thus we are utilizing nature's own paramedic system, but we are arming them with enhanced neurotrophic factor secretion to enhance the health of at-risk neurons. Our novel animal models will allow the therapy to be carefully tested in preparation for a phase I clinical trial of MSC/BDNF infusion into the brain tissue of HD patients, with the goal of restoring the health of neurons that have been damaged by the mutant htt protein.

Delivery of BDNF by MSC into the brains of HD mice is safe and has resulted in a significant reduction in their behavioral deficits, nearly back to normal levels. We are doing further work to ensure that the proposed therapy will be safe and effective, in preparation for the phase I clinical trial. The significance of our studies is very high because there are currently no treatments to diminish the unrelenting decline in the numbers of medium spiny neurons in the striata of patients affected by HD. Our biological delivery system for BDNF could also be modified for other neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS), spinocerebellar ataxia (SCA1), Alzheimer's Disease, and some forms of Parkinson's Disease, where neuroregeneration is needed. Development of novel stem cell therapies is extremely important for the community of HD and neurodegenerative disease researchers, patients, and families. Since HD patients unfortunately have few other options, the potential benefit to risk ratio for the planned trial is very high.

Statement of Benefit to California: 

It is estimated that one in 10,000 CA residents have Huntington’s disease (HD). While the financial burden of HD is estimated to be in the billions, the emotional cost to friends, families, and those with or at risk for HD is immeasurable. Health care costs are extremely high for HD patients due to the long progression of the disease, often for two decades. The lost ability of HD patients to remain in the CA workforce, to support their families, and to pay taxes causes additional financial strain on the state’s economy. HD is inherited as an autosomal dominant trait, which means that 50% of the children of an HD patient will inherit the disease and will in turn pass it on to 50% of their children. Individuals diagnosed through genetic testing are at risk of losing insurance coverage in spite of reforms, and can be discriminated against for jobs, school, loans, or other applications. Since there are currently no cures or successful clinical trials to treat HD, many who are at risk are very reluctant to be tested. We are designing trials to treat HD through rescuing neurons in the earlier phases of the disease, before lives are devastated.

Mesenchymal stem cells (MSC) have been shown to have significant effects on restoring synaptic connections between damaged neurons, promoting neurite outgrowth, secreting anti-apoptotic factors in the brain, and regulating inflammation. In addition to many trials that have assessed the safety and efficacy of human MSC delivery to tissues via systemic IV infusion, MSC are also under consideration for treatment of disorders in the CNS, although few MSC clinical trials have started so far with direct delivery to brain or spinal cord tissue. Therefore we are conducting detailed studies in support of clinical trials that will feature MSC implantation into the brain, to deliver the neurotrophic factor BDNF that is lacking in HD. MSC can be transferred from one donor to the next without tissue matching because they shelter themselves from the immune system. We have demonstrated the safe and effective production of engineered molecules from human MSC for at least 18 months, in pre-clinical animal studies, and have shown with our collaborators that delivery of BDNF can have significant effects on reducing disease progression in HD rodent models.

We are developing a therapeutic strategy to treat HD, since the need is so acute. HD patient advocates are admirably among the most vocal in California about their desire for CIRM-funded cures, attending almost every public meeting of the governing board of the California Institute for Regenerative Medicine (CIRM). We are working carefully and intensely toward the planned FDA-approved approved cellular therapy for HD patients, which could have a major impact on those affected in California. In addition, the methods, preclinical testing models, and clinical trial design that we are developing could have far-reaching impact on the treatment of other neurodegenerative disorders.

Review Summary: 

This proposal is focused on a genetically modified cell therapy for Huntington’s disease (HD), an inherited neurodegenerative disorder. The applicant has developed mesenchymal stem cells (MSCs) that are modified to secrete brain-derived neurotrophic factor (BDNF) as a potential treatment for HD. BDNF is a protein that promotes the growth and survival of neurons and is expressed at low levels in the HD brain. The applicant proposes to complete the preclinical safety, efficacy and manufacturing work required to submit an Investigational New Drug (IND) application to the FDA. The applicant also proposes the completion of two clinical trials. The first would be an observational trial to establish a clinical baseline for each HD patient enrolled, which would be completed in Years 1 and 2 of the award. The second trial would be a Phase I study to determine the safety of transplantation of BNDF-secreting MSCs in HD patients, which would be completed in Years 3 and 4.

Significance and Impact
- HD is a devastating disease with a significant unmet medical need. Although BDNF therapy would not be expected to cure HD, it has the potential to slow disease progression. There are currently no treatments available that slow the progression of HD, so the proposed therapeutic could have a major impact on the disease.

- BDNF has been implicated in a number of other neurological diseases and so a successful trial of BDNF-secreting MSCs in HD could also have a broader impact.

- The Target Product Profile (TPP) is focused on the Phase I trial when it should instead reflect the aspirational attributes of an FDA approved product. Clinically meaningful efficacy endpoints should be described in the TPP and the potential for cell overgrowth or tumor formation should be listed under safety, even though the risk is slight.

Project Rationale
- The scientific rationale is compelling. It is based on multiple studies that have shown that BDNF levels are reduced in HD and that restoring BDNF can reduce cell death and improve function in animal models of the disease.

- The applicant has demonstrated preclinical proof-of-concept for the therapeutic approach in a rodent model of HD.

Therapeutic Development Readiness
- The project appears ready for clinical translation. It is likely to result in an IND application at the beginning of Year 3 and completion of the Phase I trial by the end of Year 4.

- The team has already interacted with the FDA and received feedback, manufactured GMP grade BDNF-secreting MSCs and performed initial safety studies.

- The manufacturing strategy and timeline are reasonable and feasible.

Feasibility of the Project Plan
- The project plan is well thought out and feasible.

- The proposed observational trial is a strength of the project plan. The course of HD can be highly variable among patients and the observational trial will provide an important clinical baseline.

- Reviewers recommended that the applicant increase the size of the observational patient cohort significantly. They noted that the anticipated percentage of patients carrying over from the observational trial to the interventional trial is overly optimistic given the many reasons patients may drop out or become ineligible.

Principal Investigator (PI) and Development Team
- The PI has a great deal of experience managing HD patients and has been involved in a number of HD clinical trials.

- The Co-PI has demonstrated success in translating discovery research into first-in-human clinical trials.

- The clinical team is strong and has worked together on previous clinical projects.

- There is some overlap and redundancy in some of the staff roles proposed, for example among the clinical fellow, nurse practitioner and research associate for clinical operations. In addition, there is overlap in the expertise of some of the consultants, both between the consultants and with other members of the team.

Collaborations, Resources and Environment
- The resources and environment are excellent. In particular, the team has access to a GMP facility that has demonstrated the ability to produce GMP grade lentiviral vectors.

- The international collaboration with neural transplantation experts is a strength.

- Consultants with cell and gene therapy experience have been identified.

- The team’s intellectual property strategy is not well described and freedom to operate is not presented.

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. )

- CIRM staff recommended that the team parallel track activities to reduce the proposed 12-month gap between IND filing and initial patient dosing.

- Justification should be provided for the GLP validation study.

  • Boro Dropulic
  • Charles S. Cox
  • Darin Weber
  • David Pepperl
  • Russell Lonser