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 1 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 1 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. However this 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 benefit to risk ratio for the planned trial is very high.
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 first 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 clincial trial design that we are developing could have far-reaching impact on the treatment of other neurodegenerative disorders.
The goal of the applicant is to file an Investigational New Drug (IND) application with the Food and Drug Administration (FDA) and complete a Phase I clinical trial using mesenchymal stem cells (MSCs) modified to express brain-derived neurotrophic factor (BDNF) to treat Huntington’s disease (HD) patients. HD is a fatal, heritable neurodegenerative disorder in which cognition, mood, and movement are gradually affected. Patient death occurs, in general, due to complications of immobility, and only palliative therapy is currently available. The applicant proposes that BDNF-expressing MSCs delivered into the brain will provide neurorestorative effects and slow neural decline.
Significance and Impact
- There is a significant unmet medical need in the proposed patient population.
- Although this therapy is unlikely to be curative, it has the potential to meaningfully delay disease progression. Any treatment that meaningfully delays disease progression would represent a significant advance in the treatment of this disease.
- The proposed cell and gene therapy approach is clinically competitive as cell migration provides a huge delivery advantage over similar non-cell based gene therapy approaches currently in development for treatment of HD.
- The target product profile (TPP) is reasonable, and this is a well-developed project supported by basic science with a clear path to the clinic.
- The application is entirely responsive as a single development candidate is proposed that is at the appropriate development stage, meets the criteria set forth in the RFA, and is appropriate for the treatment of the designated disease.
Project Rationale and Feasibility
- The proposal is sufficiently advanced to meet the proposed milestones and timelines.
- It is likely that the proposed clinical trial can be executed and that meaningful positive and/or negative results will be obtained after completion of the study.
- Though not the major defect in HD, BDNF deficiency is well described and is an appropriate therapeutic target supported by reasonable preclinical efficacy data including behavioral benefit in animal models. Further, it is clear that cell therapy offers a clear therapeutic advantage over direct injection of BDNF. However, it is not clear that BDNF-expressing MSCs offer an advantage over treatment with unmodified MSCs, which naturally secrete some BDNF. Should a full application be submitted, the clear advantage of MSC gene modification should be demonstrated in preclinical studies that include control groups treated with unmodified MSCs.
- The rationale is based partially on the assumption that neurotrophic factors will be intrinsically beneficial. However, neurotrophic factors have multiple functions, and BDNF plays a significant role in memory function and has been associated with psychoses and schizophrenia. Should a full application be submitted, reviewers would like acknowledgement of the potential adverse effects of BDNF and a clear plan to monitor and manage such potential adverse events as it will be problematic to eliminate cells should adverse events occur.
- Safety studies are ongoing and pre-IND feedback has been received and is being acted upon.
- The feasibility of the therapeutic approach depends upon demonstration of reasonable cell migration in the preclinical animal model studies that are ongoing.
- The applicant does address MSC persistence, but this should be considered in the context of an immune competent animal and potential immune suppression regimens (or lack thereof) appropriate for an allogeneic MSC should be discussed. In a full application, the issues of cell persistence and immune suppression should be clearly addressed, as some persistence will be required for the proposed therapy to be efficacious.
- The details of the clinical study are vague and need bolstering and should be developed more fully during the planning phase if a full application is submitted.
- Reviewers suggested that a less advanced patient population be considered both due to surgical risk factors for the proposed patient population and since trophic support mechanisms may be too late if significant fixed degeneration has already occurred. There is an emerging international consensus that for both safety and efficacy purposes, such trials should be done in earlier stage patients.
- It was not clear why fetal transplant experiments were performed in the relevant preclinical animal model.
Principal Investigator (PI) and Planning Leader
- The PI is expert in HD clinical neurology and has a strong publication record in movement disorders. S/he has participated in many clinical trials but does not appear to have initiated his/her own studies and has little translational cell therapy experience.
- The application indicates a lack of expertise in clinical cellular transplantation and neurosurgical cell therapy translational issues with relation to patient selection, safety, and surgical delivery/volumetric issues. Reviewers strongly recommended that during the planning period the applicant seek advice from and include as a collaborator an investigator with direct experience in developing cell therapy trials in HD or Parkinson’s disease.
- The team is well qualified in the clinical treatment of HD, translational neuroscience, cell biology, and GMP issues.
- Andrew Balber
- Charles S. Cox