Disease Team Research I
ICOC Funds Committed:
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.