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 would create an unlimited supply of donor tissue. Our lab has generated retinal progenitor tissue from hESCs in 3-D constructs (“layers”) and implanted sheets of ESC-derived neuronal progenitors into a rat model of retinal degeneration where they survived and continued to develop in the subretinal space. 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. We will also determine whether this tissue is safe to use in patients by testing it in an immunodeficient rat strain. This project will ultimately help to restore vision in patients suffering from retinal diseases.
Statement of Benefit to California:
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. Over a 15-year period, late AMD will affect 3.1 % of the general population which means 9.6 millions in the U.S. and about 1.15 millions in California, with these numbers growing as the population ages. Another incurable disease, retinitis pigmentosa (RP) which is inherited (1:4000) 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.
Patients with degenerative retinal diseases lose both retinal pigment epithelium (RPE) and photoreceptors. The applicants for this Development Candidate (DC) Award propose to develop a composite replacement tissue derived from human embryonic stem cells (hESCs) differentiated separately into RPE and photoreceptor progenitors and then grown together as a retinal sheet for transplantation to restore or improve vision in degenerative retinal diseases. They propose to test these hESC-derived retinal sheets in an immunodeficient rodent model. The aims of the study are 1) to test the hypothesis that sheets of hESC-derived photoreceptor progenitors, transplanted together with a hESC-derived RPE sheet into a rat model of retinal degeneration, will develop mature photoreceptor markers and integrate with the degenerated host retina; 2) to test whether these transplants improve visual function in the rat model, with stable retinal cell marker expression and long-term survival and 3) to develop a safety profile of hESC-derived retinal layers in pilot studies in immunodeficient rats.
Objective and Milestones
- The work is at a fairly early stage of development; considerable characterization and development work may be needed prior to selection of optimal conditions and a clinically applicable product.
- A serious concern is the inability to show any expression of mature retinal markers in the composite hESC-derived retinal sheets; it is unclear what additional optimization will successfully accomplish the goal of differentiation or how long it might take.
- Strengths of the proposal include the possible benefits of providing both RPE as well as photoreceptors as transplanted tissue and the availability of an animal model to address proof-of-concept.
- An important weakness of the proposal is that the applicant did not adequately consider the possibility of observing improved retinal and visual function after transplantation by promoting survival of endogenous neurons versus replacement of degenerated neurons. A tangible flaw is that they did not propose a specific plan to distinguish these effects and may mistake replacement for trophic effects.
- Other weaknesses include the lack of a plan to assess distant migration of the transplanted cells from the site of transplantation and lack of a rigorous plan to assess integration between donor and host neural tissue.
- The TPP should focus on a single disease indication.
Rationale and Significance
- The scientific rationale and impetus for pursuing this approach are compelling.
- The significance is high as there are currently no effective therapies for restoring visual function once retinal degeneration advances in age-related macular degeneration (AMD) and retinitis pigmentosa (RP). The proposed therapy has potential to impact both of these diseases.
Research Project Feasibility and Design
- The main weakness is the research plan, which was not sufficiently developed and lacked critical details; in particular, outcome measures are insufficiently described.
- There is insufficient description of the visual acuity test which is particularly important for evaluating the success of the transplants, and there are no details on how the data will be interpreted.
- There are no electrophysiology (ERG) measurements included in the outcome testing despite inclusion of focal ERG equipment in the budget.
- Potential negative effects include pain, but there are no tests included to measure pain; cell migration to ectopic sites is listed as a concern, but tissues to be evaluated for this are not included.
- The feasibility of transplant survival is questionable.
- Interpretation of descriptive data from the preparation of the retinal sheets is unclear as there does not appear to be a quantitative assessment of various cell types over time.
- The research plan is designed with clear rationale, methods, and expected outcomes and appreciation of dose and dose extrapolation.
- The immune privilege of the subretinal space may be overstated; immunogenicity may be a concern
Qualification of the PI (Co-PI and Partner PI, if applicable) and Research Team
- The investigative group is very strong.
- The PI is a leader in the progenitor transplantation field; there is no information provided as to direct experience in product development.
- It is not clear that the PI's effort is justified satisfactorily at 40%.
- There are a number of concerns regarding the budget, which is inadequately justified and inflated; the budget includes numerous staff personnel whose roles are not well-defined and seem to overlap; in view of past and ongoing work in the laboratory, it is not clear why equipment requested is not already available and no justification is provided for why this additional equipment is needed.
Collaborations, Assets, Resources and Environment
- The environment for the proposed work is excellent;
- The institutional support is excellent
Responsiveness to the RFA
- Human stem cells are necessary to achieve the outcomes of the proposed research and an appropriate target for intervention has been identified. No relevant concerns.