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. HD is a challenging disease to treat. Not only do the affected, dying neurons need to be salvaged or replaced, but also the levels of the toxic mutant protein must be diminished to prevent further neural damage and to halt progression of the movement disorders, physical, mental, and emotional decline that is associated with HD.
Intrastriatal implantation of mesenchymal stem cells (MSC) has significant neurorestorative effects, 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 new tools to also reduce mutant protein levels and 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 infusion into the striata to restore the health of neurons that have been damaged by the mutant htt protein. Additional proposed trials building upon the initial trial are designed to reduce harmful levels of the mutant htt protein, to provide additional factors to restore function to damaged neurons, and finally, to replace the damaged striatal neurons with new ones.
The significance of our studies is very high because there are currently no treatments to diminish the amount of toxic mutant htt protein in the neurons of patients affected by Huntington’s disease. There are no cures or successful clinical trials to reverse the decline in striatal neuron number and striatal volume. Our therapeutic strategy is initially examining models to treat HD, since the need is so acute. But this biological delivery system for siRNA and 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 and reduction of the levels of a mutant or disease-activating protein could be curative.
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 trials is extremely 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. The lost ability of HD patients to remain in the CA workforce and to support their families 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. Since there are currently no cures or successful clinical trials to treat HD, many are reluctant to be tested. We are designing trials to treat HD through healing neurons in the earlier phases of the disease and replacing them in later stages.
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, either alone or as supporting cells for astrocytes or NSC and hESC-derived medium spiny neurons. MSC can be transferred from one donor to the next without tissue matching because they shelter themselves from the immune system. Also, by engineering MSC to secrete siRNA to reduce levels of the mutant protein through RNA destruction, we hope to provide the patients with a long-term therapy for their disease. We have demonstrated the safe and effective production of engineered molecules from human MSC for at least 18 months, in pre-clinical animal studies.
Our therapeutic strategy will initially examine models 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 ICOC meeting. This would be the first approved cellular therapy for HD patients and would have a major impact on those affected in California. In addition, the methods and preclinical testing that we are developing will have far-reaching impact on the treatment of other neurodegenerative disorders.
This proposal seeks to investigate neuroprotective and neurorestorative strategies for the treatment of Huntington’s disease (HD) using four different approaches involving human mesenchymal stem cells (hMSCs). Medium spiny neurons in the straitum are the most susceptible to destruction in HD, which is the result of a mutation in the huntingtin (htt) protein that renders it dysfunctional and pathogenic. The applicant proposes to conduct a total of four preclinical trials of intracerebral hMSCs transplantation in animal models of HD. Trial #1 will compare transplantation of unmodified hMSCs and hMSCs engineered to produce brain derived neurotrophic factor (BDNF). Trial #2 will compare transplantation of unmodified hMSCs with hMSCs engineered to produce siRNA against mutant htt. Trial #3 will involve transplantation of unmodified hMSCs together with engineered hNSC-derived astrocytes that produce BDNF. Trial #4 will use hMSCs co-delivered with hESC or hNSC-derived striatal medium spiny neurons (MSNs). The transplantation experiments will be conducted in rodents as well as in a large animal model. The applicants also plan to develop a large animal model of HD as part of this project. The applicants expect to achieve an Investigational New Drug (IND) filing at the conclusion of each trial, the first of which will be for testing unmodified hMSCs in HD within eighteen months of the start of the project.
The significance of the proposal was judged to be high, as HD is a devastating neurological condition that has no cure and there is an unmet need for treatment of patients with this disease. Although the incidence of HD is less than other neurodegenerative diseases such as Parkinson’s disease, the severity of the motor and cognitive symptoms of HD in relatively young individuals is overwhelming. Reviewers agreed that the use of hMSCs as neuroprotective and restorative agents for the treatment of HD is attractive since these cells can be employed as vehicles to deliver specific therapeutic agents to damaged striatal cells in the HD brain. The present approach would be unlikely to halt the condition indefinitely, but if successful could provide a major impact on the lives of patients by potentially improving both life-span and quality of life. However, reviewers noted that this proposal is positioned in a highly active field that is populated by established collaborative initiatives. The proposed therapeutic cell-therapy candidates would have to compete with direct anti-sense therapies, which were judged to be more feasible, better controlled in study design, and likely to have a far better safety index than the proposed cell-therapy candidates.
The feasibility of the plan was judged to be questionable. Specifically, the plan was found to be overambitious in its multiple research thrusts, and most reviewers agreed that the scientific underpinnings of several the proposed approaches were not sufficiently supported by compelling preliminary data. For example, minimal data demonstrating efficacy of human MSC in the murine model was presented in the application, and such data would be critical to warrant moving into the second preclinical model, or any of the other more complex proposed therapeutic research thrusts. Similarly, the proposed concept to modify MSC to produce BDNF is based on the prior use of astrocytes that overexpress BDNF in murine models of HD, but data supporting the premise that MSC producing the same molecule would be equally or more efficacious are not presented in the application. While these proposed therapeutic concepts all constitute intriguing basic science concepts, reviewers unanimously agreed that all are much too early in their stage of development to achieve the proposed IND filings within the four-year timeframe. Of note, all reviewers agreed that the proposal for developing a large animal model of HD was unique and potentially could be a very valuable resource, but details of development were not yet sufficiently convincing to the review panel (and do not directly address the objective of this RFA).
Overall reviewers found this a poorly focused and premature proposal. Given the importance of demonstrating efficacy, in the first preclinical trial (unmodified versus BDNF-engineered MSCs), the parameters under investigation, specification of behavioral tests, and long-term follow up should be detailed. These critical details are only presented in outline. Additionally, a detailed functional assessment is mandatory and exploration of mechanism of action should also be undertaken. The preclinical research is distributed into four different preclinical trials that utilize several animal models. Reviewers commented that some of the animal models may not adequately reflect the clinical setting, as the various models utilize different cell delivery methods and sites of injection, as well as different strategies to minimize immune rejection. Finally, reviewers challenged the applicants’ apparent assumption that the MSC IND application could simply be amended to allow for the use of the genetically modified MSC. It seems much more likely the FDA would request a whole new IND application, with additional safety and toxicology data because of the genetic modification of the MSC and the potentially unregulated release of a potent growth factor in the brain.
The project milestones are defined for each preclinical trial, but most reviewers found that the timelines were generally over ambitious given that efficacy has not been robustly demonstrated in any of the approaches. One reviewer questioned the parallel timing for the planning of large animal and rodent studies and suggested it would be more reasonable to obtain proof of efficacy at least in the rodent studies before proceeding to large animals. Furthermore the team has yet to demonstrate that they can produce the large animal model of HD required for some crucial experiments. Reviewers agreed that milestones need to be much better defined in terms of outcome measures. For example, outcomes of efficacy need to be clearer and the go/no-go point should be based on efficacy as well as safety.
In general, reviewers found that the team assembled is capable of carrying out all aspects of the proposed project, but not in the proposed timeframe. Some reviewers expressed concern regarding the PI‘s ability to lead such a large project team, despite a solid track record and expertise in the field. Moreover, some reviewers felt the governance structure of the project is not clearly defined in the proposal and they found it to be a weakness especially in view of the scope of the project and the large number of research partners and collaborators. Reviewers agreed that the Collaborative Funding Patner team’s contribution is crucial for several aspects of the project.
In summary, although the panel found the significance of the proposal to be high, they had concerns about the scientific maturity and feasibility of the plan. The panel did not judge the complex, multifaceted plan to be achievable in the four-year timeframe, and it was not recommended for funding.