Inherited retinal degenerations result in visual loss in patients as early as in their adolescence. 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 by now a number of gene mutations which can cause these disorders, we do not understand how these mutations ultimately lead to loss of the cells. Recent advances in stem cell technologies now have provided us with the opportunity to gain a better understanding of the disorders.
In this proposal, we plan to study the degenerative process by creating an eye-like structure in a dish using a combination of stem cell and bioengineering approaches. We plan to use 3D scaffolds to grow eye cells generated from pluripotent stem cells. We will directly compare normal retinal cells with cells derived from patients with Retinitis Pigmentosa. This approach will allow us to identify the processes that ultimately lead to the death of the photoreceptor cells int he eye and blindness. In the future, we could then extend this work to identify new drugs which will help halt or at least slow down the degeneration in these patients.
Photoreceptor degenerations, including Retinitis Pigmentosa (RP), cause visual impairment for millions of patients in the United States and a number of patients in the state of California being one of the most populous states in the US. RP encompasses a group of retinal degeneration with a prevalence of 1 in 4000 and 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. Most people with RP are legally blind by age 40. There are no effective forms of treatment for a majority of these patients. Thus results in a tremendous stress on the state of CA's resources. In addition, there is both monetary and psychological stress on the families esp. in cases of Retinitis Pigmentosa as multiple family members are affected.
The only way to potentially help these patients will be to either replace the dead cells with new photoreceptors or find ways to better understand the degenerative process in order to identify novel drugs to delay the progression of degeneration. The proposed research in this application is to generate eye tissue in a dish from patients with severe forms of Retinitis Pigmentosa in order to gain a better understanding of the disease. This will in turn help us in the future to identify new drugs to delay or stop the visual loss and this will attract new biotechnology partners in the state of CA.
This proposal is focused on understanding biological mechanisms underlying retinitis pigmentosa (RP), a degenerative disorder that affects the retinal photoreceptor cells and ultimately leads to vision loss. The applicant proposes to employ a bioengineered scaffold in concert with pluripotent stem cells to create an eye-like structure that will serve as an in vitro, three-dimensional (3D) retinal model. To achieve this goal, the applicant will first optimize an in vitro 3D patterned biomaterial scaffold for use in deriving an organized and fully differentiated retina-like structure from human embryonic stem cells (hESCs). Next, the applicant will study the formation of the retinal outer segment using induced pluripotent stem cell (iPSC)-derived retinal photoreceptors from patients with early RP. Finally, the applicant will restore the defective gene in patient-derived cells and evaluate the 3D photoreceptor structure formed from these corrected cells.
Significance and Innovation
- The proposed project could have a major impact on understanding RP disease mechanisms.
- The 3D-retinal model could provide a fundamentally different and improved approach for developing novel therapeutic strategies for RP.
- Although other studies have used biomaterials and tissue-engineering scaffolds for the retina, the proposed scaffold design is novel and represents a potentially innovative breakthrough for retinal modeling.
Feasibility and Experimental Design
- Reviewers viewed the proposal as “high risk-high gain”, with challenging experiments and a model that will be difficult to develop, but potentially yielding tremendous value and utility if successful.
- The proposal included substantial preliminary data. However, there were some concerns regarding if mature and functional photoreceptor cells had been successfully derived.
- Reviewers found the overall approach logical but suggested that the project could be carried out with only iPSCs and that experiments with hESCs were unnecessary.
- The choice of scaffold was considered logical and appropriate. However, some of the experimental methodology was poorly defined and not adequately referenced. Additionally, alternative methods were not well discussed.
Principal Investigator (PI) and Research Team
- The applicant is a talented young investigator with expertise in stem cells and photoreceptor cell derivation.
- The co-investigator is an expert in tissue engineering scaffolds and cell-materials interactions.
- The research facilities, environment and budget were considered appropriate for the proposed research.
Responsiveness to the RFA
- No relevant concerns were highlighted by reviewers under this review criterion.
- Programmatic REVIEW
- A motion was made to raise this application into Tier 1, Recommended for Funding. Programmatic reasons for this move included recognition of the applicant as an exceptionally promising and talented young scientist who has already made important contributions to the field and the importance of retinal disease. Reviewers briefly summarized the key technical aspects of the proposal and noted that research on the retina was not represented in applications recommended for funding. The motion carried.