This study will use Ataxia-Telangiectasia (A-T), an early-onset inherited neurodegenerative disease of children, as a model to study the mechanisms leading to cerebellar neurodegeneration and to develop a drug that can slow or halt neurodegeneration. We will start with skin cells that were originally grown from biopsies of patients with A-T who specifically carry “nonsense” type of mutations in the ATM gene. We will convert these skin cells to stem cells capable of forming neural cells that are lacking in the brain (cerebellum) of A-T patients; presumably these neural cells need ATM protein to develop normally. We will then test the effects of our most promising new “readthrough compounds” (RTCs) on the newly-developed neural cells. Our lab has been developing the drugs over the past six years. At present, there is no other disease model (animal or in a test tube) for evaluating the effects of RTCs on the nervous system and its development. Nor is there any effective treatment for the children with A-T or other progressively-deteriorating ataxias. Success in this project would open up at least three new areas for understanding and treating neurodegenerative diseases: 1) the laboratory availability of human neural cells with specific disease-causing mutations; 2) a new approach to learning how the human brain develops and 3) a new class of drugs (RTCs) that correct nonsense mutations, even in the brain, and may correct neurodegeneration.
This project seeks to merge the expertise of two major research cultures: one with long-standing experience in developing a treatment for a progressive childhood-onset disease called Ataxia-telangiectasia and another with recent success in converting skin cells into cells of the nervous system. California citizens will benefit by finding new ways to treat neurodegenerative diseases, like A-T, Parkinson and Alzheimer, and expanding the many possible applications of stem cell technology to medicine. More specifically, we will construct a new “disease in a dish” model for neurodegeneration, and this will enable our scientists to test the positive and negative effects of a new class of drugs for correcting inherited diseases/mutations directly on brain cells. These advances will drastically decrease drug development costs and will stimulate new biotech opportunities and increase tax revenues for California, while also training the next generation of young scientists to deliver these new medical products to physicians and patients within the next five years.
This proposal is focused on the development of an induced pluripotent stem cell (iPSC)-derived model for Ataxia-Telangiectasia (A-T), an early onset pediatric neurodegenerative disease. The applicant identifies the lack of “disease-in-a-dish” or animal models for this disease as a bottleneck to the development of therapies. There are three Specific Aims: (1) to generate and characterize iPSCs from A-T patient fibroblasts; (2) to model A-T neurodegeneration by differentiating these iPSCs into neural stem cells and cerebellar neurons; and (3) to use A-T iPSCs and their differentiated progeny to screen a new class of drug compounds designed to correct the disease mutation.
The reviewers agreed that this proposal addresses a significant translational bottleneck and, if successful, could have a major impact on the treatment of A-T and other similar genetic disorders. They noted that the tools and methodologies developed during the project would be valuable to the field as a whole. The reviewers also praised the applicant’s logical approach and strong scientific rationale. They did not find proposal to be particularly innovative, but they did note that the development of an iPSC model of A-T and the use of a new class of drug compounds would be novel.
Reviewers found the research plan to be well-written and carefully designed. They described the preliminary data as compelling and noted that these data demonstrate the ability of the research team to generate iPSCs from several groups of patients and differentiate these cells along the neural lineage. In addition, the applicant has already completed a high-throughput screen, identified promising drug compounds and synthesized 60 analogs for testing. Given these preliminary data and the well-crafted Specific Aims, the reviewers were highly confident in the project’s feasibility. They were also impressed by the applicant’s thorough consideration and discussion of potential pitfalls and alternative approaches. Two minor concerns were that differentiation of iPSCs into cerebellar neurons may be difficult, and that the reporter specified for identifying Purkinje cells is also expressed in other neuronal cells.
The reviewers described the Principal Investigator (PI) as a world authority on A-T and highly qualified to oversee the project. They noted that the PI has published many relevant and high impact articles and has an outstanding track record in the field. Reviewers also appreciated the contributions of a Co-Investigator with considerable expertise in the generation and characterization of iPSCs. They described this collaboration as integral and critical to the success of the project.
Overall, reviewers were enthusiastic about this highly significant proposal to develop an in vitro model of A-T. They praised the focused and feasible research plan as well as the strong research team. Reviewers were convinced that this proposal could have a major impact on the development of novel therapies for A-T and related genetic disorders.