A major medical problem in CA is the growing population of individuals with neurodegenerative diseases, including Parkinson’s (PD) and Huntington’s (HD) disease. These diseases affect millions of people, sometimes during the prime of their lives, and lead to total incapacitation and ultimately death. No treatment blocks the progression of neurodegeneration. We propose to conduct fundamental studies to understand the basic common disease mechanisms of neurodegenerative disorders to begin to develop effective treatments for these diseases. Our work will target human stem cells made from cells from patients with HD and PD that are developed into the very cells that degenerate in these diseases, striatal neurons and dopamine neurons, respectively. We will use a highly integrated approach with innovative molecular analysis of gene networks that change the states of proteins in these diseases and state-of-the-art imaging technology to visualize living neurons in a culture dish to assess cause and effect relationships between biochemical changes in the cells and their gradual death. Importantly, we will test whether drugs effective in animal model systems are also effective in blocking the disease mechanisms in the human HD and PD neurons. These human preclinical studies could rapidly lead to clinical testing, since some of the drugs have already been examined extensively in humans in the past for treating other disorders and are safe.
Neurodegenerative diseases, such as Parkinson’s (PD) and Huntington’s disease (HD), are devastating to patients and families and place a major financial burden on California. No treatments effectively block progression of any neurodegenerative disease. A forward-thinking team effort will allow highly experienced investigators in neurodegenerative disease and stem cell research to investigate common basic mechanisms that cause these diseases. Most important is the translational impact of our studies. We will use neurons and astrocytes derived from patient induced pluripotent stem cells to identify novel targets and discover disease-modifying drugs to block the degenerative process. These can be quickly transitioned to testing in preclinical and clinical trials to treat HD and other neurodegenerative diseases. We are building on an existing strong team of California-based investigators to complete the studies. Future benefits to California citizens include: 1) discovery and development of new HD treatments with application to other diseases, such as PD, that affect thousands of Californians, 2) transfer of new technologies and intellectual property to the public realm with resulting IP revenues to the state with possible creation of new biotechnology spin-off companies, and 3) reductions in extensive care-giving and medical costs. We anticipate the return to the State in terms of revenue, health benefits for its Citizens and job creation will be significant.
This proposal is focused on the development and characterization of in vitro models of Huntington’s disease (HD) and Parkinson’s disease (PD) from patient-derived induced pluripotent stem cells (iPSCs). There are three specific aims: (1) to study the role of specific cellular processes in HD pathology in a human in vitro model and test the ability of drugs to rescue this pathology; (2) to determine the contributions of specific genes that are differentially regulated in HD cells to disease phenotypes; and (3) to study PD patient iPSC-derived neurons to determine if similar mechanisms identified in aims 1 and 2 also play a role in PD pathology.
Significance and Innovation
- The proposal focuses on cellular mechanisms that may be shared by many neurodegenerative diseases and is therefore highly significant and has the potential to impact a large number of patients.
- The project utilizes innovative technologies, some of which are unique to the applicant’s lab.
Feasibility and Experimental Design
- The project is feasible and the goals are achievable in the proposed timeline.
- Substantial and compelling preliminary data are provided to support the aspects of the proposal focused on HD.
- Aim 3, focused on PD, is not as well developed or supported as aims 1 and 2. Reviewers cautioned that tyrosine hydroxylase is not sufficient as a marker of midbrain dopaminergic neurons. The plan for purifying and characterizing these neurons is not well described.
- Reviewers raised concerns about characterization of HD iPSC-derived neurons and the team’s ability to produce enriched populations of human striatal neurons and astrocytes. They noted that differentiation protocols for these cell types are not well established in the field.
Principal Investigator (PI) and Research Team
- The PI is highly accomplished and an expert in the field of HD research.
- The PI and co-investigator have an ongoing collaboration and have together made important contributions to the HD-iPSC field.
- While the PI and co-investigator are not well known for work on PD or directed differentiation of pluripotent cells, they have established strong collaborations to ensure the project’s success in these areas.
Responsiveness to the RFA
- The proposal is highly responsive to the RFA.