There is currently no effective treatment to restore or improve vision for patients suffering from incurable blinding diseases such as dry age-related macular degeneration and retinitis pigmentosa, which need both new photoreceptors and retinal pigment epithelium. However, a unique method to transplant fetal retinal progenitor sheets together with its supporting retinal pigment epithelium (RPE) has been shown to improve vision in animal models of retinal degeneration and in patients. Differentiation of human embryonic stem cells (hESCs) into sheets of retinal progenitor tissue that contain photoreceptor progenitors and RPE cells could create an unlimited supply of donor tissue. Our lab has generated retinal progenitor tissue from hESCs in 3-D constructs (“layers”), and a new immunodeficient model of retinal degeneration. Recently, several laboratories have shown that hESCs can “self-assembly” into early stages of eye development and develop into laminated structures. The hypothesis of the proposed project then is that hESCs can be consistently differentiated into sheets of retinal tissue, which can restore visual responses after transplantation to a new immunodeficient rat model of retinal degeneration that does not reject human cells. In the final year, we will standardize methods to increase the production of these sheets in a way that complies to good manufacturing practice. This project will ultimately help to restore vision in patients suffering from retinal diseases.
Retinal diseases reduce the quality of life of patients who suffer from vision loss and at significant cost to the health care system. Age-related macular degeneration (AMD) destroys the central vision and is the most common cause of blindness among people over 65. In 2010, AMD affected 2.1 % of the general population which means 2.1 million in the U.S. and about 240,000 in California, with these numbers projected to grow to 5 million (in the U.S.) in 2050 as the population ages. Ca. 20-35% of AMD cases develop irreversible geographic atrophy with local loss of RPE and photoreceptors in the macula. Another incurable disease, retinitis pigmentosa (RP) which is inherited (1:3500) and occurs in younger people, affects the light-sensing photoreceptors first, but also the supporting RPE layer beneath the retina following photoreceptor degeneration. Thus, both AMD and RP patients will need both new RPE and photoreceptors. The proposed replacement therapy is the only one that targets more mature disease stages of both AMD and RP, for which no other therapy exists. An effective treatment will keep afflicted individuals productive, enhance State tax revenues and defray the healthcare cost burden to taxpayers. It will also lead to robust industry developments in the fields of clinical transplantation, drug screening, and predictive toxicology, effectively leading to job creation and tax benefits to the State as a result of consumption of research and clinical goods and services.
The objective of this Development Candidate award (DC) proposal is to develop sheets of human embryonic stem cell (hESC)-derived retinal progenitor cells and hESC-derived retinal pigment epithelium (RPE) for the treatment of the late stage of retinal degenerative diseases such as retinitis pigmentosa and the dry form of age-related macular degeneration (AMD). The applicant will derive sheets of retinal tissue from hESC, then test them in rat models for the restoration of visual responses. In addition, methods will be developed for scale-up and eventual GMP production of the proposed candidate. If successful, this approach could restore or stabilize vision in patients suffering from retinal diseases.
Objective and Milestones
-The Target Product Profile (TPP) is scientifically and clinically reasonable.
-The project milestones are realistic and well thought out. The outcome measures for these milestones are very clearly defined.
Rationale and Significance
- A hESC-derived retinal transplant would offer a substantial improvement for retina restoration over the existing options; however, currently there are already several clinical programs that are using a similar approach.
- The novelty of this study is that it will transplant a combination of retinal progenitor cells and RPE into a damaged retina to replace both layers. If successful this could have a big impact in the treatment of late stage retinal degenerative diseases.
- The 3-D structures have potential to restore visual function not just preserve visual performance.
Feasibility and Design
- Although the preliminary data provides evidence that the team can achieve the project milestones, there was a real concern that the investigators had not yet demonstrated sufficient feasibility with the proposed candidate.
- The research/development plan is well thought out and addresses key hurdles with sufficiently high bars for success.
- Reviewers were skeptical about the feasibility of achieving the requirements for a development candidate award and being ready to advance to IND-enabling studies given that the actual development candidate had not yet been achieved.
- Most of the studies proposed are morphological analyses of transplanted retinal cells; there are not enough functional readouts to assess efficacy.
Qualifications of the PI and Research Team
- The PI has expertise in transplantation of retinal sheets to restore visual function in animal models of retinal degeneration and has worked with both hESCs and retinal progenitors.
- The Co-PI is strong; the research team has the combined expertise to conduct the proposed technically challenging studies.
- The budget is appropriate.
Collaborations, Assets, Resources and Environment
-The investigators have sufficient lab facilities, access to cores and a great academic environment.
-The applicant organization is highly supportive of translational research and has provided a strong letter of institutional commitment.
Responsive to the RFA
- This application is responsive to the RFA since the proposed candidate is novel, requires human stem cells and the disease indication has been identified.
- FINAL DISCUSSION
- A motion was made to move this application to tier 1, Recommended for Funding, with a condition. The condition is to demonstrate, within 12 months, the ability to make the hESC – derived 3-D sheets. This is a go no/go milestone for the project. The motion carried.