Early Translational IV
$1 960 790
Recommended if funds allow
Inherited retinal degenerations result in loss of vision in patients as early as few months after birth. Retinitis Pigmentosa includes a group of such degenerations which run in families and can result in legal blindness by 40 years of age. Even though we know a number of gene defects which can cause these disorders, gene therapy is not available to help most of these patients. In this application, we are proposing to make new light-sensing cells called photoreceptors from stem cells to take up the function in the eye. We have shown that these cells once generated in the lab have the potential to restore some vision in mice with visual impairment secondary to inherited retinal degeneration. Another way these cells could also potentially help is by preventing the remaining cells in the eye from dying and thereby preserve native vision. Cellular replacement strategy could help all patients with vision disorder including age-related macular degeneration is used with the supporting pigment epithelial cells. The work proposed here will be carried out using cells that have been generated in clean facilities so that they can then be fast-tracked to the clinic.
Statement of Benefit to California:
Photoreceptor degenerations, including Retinitis Pigmentosa (RP) and Leber Congenital Amaurosis (LCA), cause visual impairment for millions of people in the United States including a number of patients in the state of California as it is one of the most populous states in the US. RP and LCA encompass a group of retinal degeneration with a prevalence of up to 1 in 4000 and they often runs in families. Typical symptoms include night blindness followed by decreasing vision, and eventually legal blindness or, in many cases, complete blindness. RP is usually diagnosed in adolescents and young adults and most of these patients are legally blind by age 40. LCA on the other hand is much more severe affecting young children who often go blind very early in life. There are no effective forms of treatment for a majority of these patients. Thus, it results in a tremendous stress on the state of CA's resources. In addition, there is both monetary and psychological stress on the families especially as multiple family members are affected. One way to potentially help these patients will be to replace the dead cells with new photoreceptors derived from stem cells. In this proposal, we will look into the feasibility of using pluripotent stem cells to generate the replacement photoreceptors and test their effectiveness in restoring vision. This proof of concept could eventually be applied to other retinal degenerative conditions like age-related macular degeneration in association with RPE.
This application for a Development Candidate Feasibility (DCF) award proposes to investigate the feasibility of developing human embryonic stem cell (hESC)- and human induced pluripotent stem cell (hiPSC)-derived photoreceptor cells as a potential therapy for patients with inherited retinal degeneration disorders. Inherited retinal disorders occur earlier in life compared to the more common macular degeneration, but both inherited and acquired degeneration can result in blindness. The applicant proposes to optimize the differentiation protocol to achieve photoreceptor cells, select the most appropriate hESC and / or iPSC lines, develop enrichment methods and assays, and then test the optimal transplantation parameters in two laboratory models of inherited retinal degeneration. Objective and Milestones - The objective of the proposal, to generate a source of photoreceptor cells, is significant and important. While others are making progress in translating cell therapies utilizing different progenitor cell types for treatment of retinal degeneration, this proposal focuses on developing and testing photoreceptor cells. - The milestones are presented in a logical fashion and are reasonable for achieving preclinical proof-of-concept. Rationale and Significance - Clinical results using a different approach suggest that even an incremental increase in photoreceptor restoration could make a significant clinical difference. - The rationale to pursue photoreceptor replacement strategies is strong. - A reliable, well-characterized source of retinal cells will be needed for replacement purposes. - While this project is likely to incrementally advance the field, there are few treatments and no cures for retinal degeneration. Feasibility and Design - The applicant presents strong data showing the induction of cells expressing retinal markers, and that a small proportion of the cells progress to express photoreceptor markers. A challenge for the project will be to increase the efficiency of this process, and improve stability of the cell phenotype. - The PI has observed anatomical integration in previous experiments; a key goal of this project is to demonstrate functional integration. Reviewers cautioned that the planned readout will be inadequate for a measurement of functional donor cell integration and should be bolstered by other functional tests. - The first milestone, to optimize differentiation, is a significant amount of work and is critical to the success of the project. Therefore, the project carries risk. - The proposed markers for retinal cells are insufficiently specific to achieve the enrichment goals stated in the application. However, reviewers noted that the applicant is right to consider that a mix of cell types might be most desirable to achieve integration and functional benefit. Qualification of the PI (Co-PI, Partner PI, if applicable) and Research Team - The applicant has performed much of the preliminary work in his / her previous lab with a highly accomplished retinal researcher. - The applicant is a newly-appointed investigator (2011) and since then productivity has been modest. - A number of key project team members are to be hired. Reviewers questioned whether this could be accomplished and new staff adequately trained in the timeframe needed to make the 3-year timeline. - The Co-investigator is well accomplished in hESC and iPSC research and can provide necessary support in his / her area of expertise. Collaborations, Assets, Resources and Environment - The PI and previous mentor hold a key patent for this approach. - All necessary materials are available to the project. - The resources at the applicant institution are sufficient to conduct the proposed research. Responsiveness to the RFA - Reviewers judged the application to be responsive to the RFA. A target for intervention is identified.