Through this project, we will develop human stem cell models for a rare disorder known as spinocerebellar ataxia type 7 (SCA7). Although SCA7 is rare, it shares important features with very common neurological disorders, including Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS). All these diseases are caused by proteins that misfold to form toxic proteins that damage and kill neurons. We are yet to fully understand how this occurs, but we think that misfolded proteins derail normal processes that the disease protein usually regulates. SCA7 patients display an unique disease symptom – they go blind due to retinal degeneration. In this project, we will create stem cell models for SCA7 retinal degeneration to understand how the SCA7 disease protein causes retinal neurons to die. Our studies will establish the best method for creating retinal neurons from human stem cells made from a patient’s skin. This advance will be important for future experiments on all eye diseases that cause blindness due to retinal disease, including common disorders such as age-related macular generation. By figuring out how the SCA7 disease protein leads to degeneration of retinal neurons, we will gain insights into how disease proteins in AD, PD, and ALS cause neuron toxicity and death. Finally, the knowledge that we acquire from this project will allow us to develop new treatments for SCA7 and for these other more common neurological diseases.
Statement of Benefit to California:
Neurodegenerative diseases, such as Alzheimer’s disease (AD) and Parkinson’s disease (PD), take a great toll on the health, productivity, and emotional well-being of affected patients and their families. With our population aging, we need to make progress in understanding how such diseases occur so that we can come up with new therapies. Decades of biomedical research has taught us that we can learn a great deal from studying rare diseases that are closely related to more common disorders. Indeed, in the late 1990's, studies of spinocerebellar ataxia type (SCA7) coalesced with studies on prion diseases (that causes mad-cow disease), PD, and AD to lead to the realization that all neurodegenerative diseases share a common feature of being caused by a misfolded protein that becomes toxic. We believe that a careful study of SCA7 through stem cell modeling will provide important information for how to approach more common disorders, such as AD and PD. We are also convinced that we can use SCA7 as a proof-of-principle to create reliable methods to model eye diseases that cause blindness in people, and expect that this information will fuel advances in understanding more common retinal disorders, such as age-related macular degeneration. It is also possible that therapies discovered for SCA7 will shed light on powerful strategies to treat related neurological disorders, such as AD and PD.
The applicant intends to uncover the pathogenic basis for spinocerebellar ataxia type 7 (SCA7) retinal degeneration by developing human stem cell models. SCA7 is a rare, inherited neurological disorder characterized by cerebellar and retinal degeneration. The applicant proposes to first generate a patient-derived induced pluripotent stem cell (iPSC) model for SCA7. Then, the applicant will differentiate these cells into retinal photoreceptors and confirm that they exhibit SCA7 disease-specific features. Next, the applicant will employ molecular biology and quantitative approaches to determine the nature of SCA7 transcriptional dysregulation. Finally, the applicant will validate results from the previous aim and pursue potential therapeutic targets for the SCA7 pathway.
Significance and Innovation
- Although the application has significance for polyglutamine diseases, like SCA7, it may also provide clues to molecular mechanisms of degeneration in other, toxic protein-dependent diseases, like Huntington’s disease.
- The utilization of differentiated iPSCs from SCA7 patients and unaffected relatives alongside rigorous quantitative approaches is innovative.
Feasibility and Experimental Design
- More detail regarding Aims 2 and 3 would have increased the competitiveness of this application and enhanced the biological relevance. Specifically reviewers would have appreciated a discussion of how the large amount of data generated in Aim 2 would be used to inform subsequent work.
- The preliminary data confirm that the research team can generate iPSC-derived retinal precursor cells. However, no evidence for differentiation into functional photoreceptor cells is presented.
- The small number of SCA7 patients proposed for iPSC derivation is a significant weakness in the proposal.
- Overall, the experimental design is feasible and should produce large amounts of data.
Principal Investigator (PI) and Research Team
- The research team is experienced and the PI has extensive expertise in the field of neurological diseases.
- The co-investigator has considerable experience with iPSC technology and differentiation into neurons.
- The team lacks experience in generating and studying iPSC-derived photoreceptor cells.
Responsiveness to the RFA
- The proposal meets the objectives of the RFA in that it utilizes human iPSCs from SCA7 patients to better understand the cellular and molecular basis of SCA7 disease.