Funding opportunities

Funding Type: 
Disease Team Planning
Grant Number: 
Principle Investigator: 
Funds requested: 
$37 367
Funding Recommendations: 
Grant approved: 
Public Abstract: 

The targeted disease is retinitis pigmentosa (RP), a severe form of blindness that runs in families. This disease is not common, yet represents an attractive near term target for stem cell therapy for a number of reasons: 1) RP destroys the light detecting cells of the retina but generally leaves the rest of the visual system and body unharmed, so the clinical goal is circumscribed; 2) RP is prototypical of degenerations of the nervous system, so a cure for this less common disease would accelerate progress towards new therapies for a range of more familiar conditions; 3) scientific research has shown that the rods and cones can be spared in animals by either delivering molecules known as growth factors or by transplanting particular types of stem cells, so the scientific feasibility of treating RP has already been established in principle.

The therapeutic approach is to save the light sensing cells of the eye using modified stem cells. The problem with the molecules (“growth factors”) that are capable of saving the light detecting cells (rods and cones) is that they are rapidly degraded in the body, so a method of long term delivery in needed. Stem cells can be genetically modified to manufacture and secrete the desired growth factors and thereby save the rods and cones, following transplantation to the eye. In addition, there is evidence that the stem cells themselves might help preserve the cone photoreceptors. Furthermore, recent work has shown that stem cells can to some extent develop into photoreceptors and directly replace the dying cells of the patient’s retina. Thus, transplanted stem cells could treat the targeted disease of RP in multiple ways simultaneously. Importantly, there are a host of reasons why clinical trials in the eye are easier and safer than most locations in the body. The eye is an important proving ground for stem cell-based therapies and provides a stepping stone to many incurable diseases of the brain and spinal cord.

Statement of Benefit to California: 

Benefits to the state of California and its citizens are both direct and indirect. The direct benefit is medical in that there is currently no cure or established treatment for the individuals and families that suffer from the dreadful hereditary blindness known as retinitis pigmentosa. In addition, there are many people in California and throughout the world that suffer from degenerative diseases of the retina and central nervous system that could benefit from the type of stem cell therapy proposed in the current application. The rapid progress that could be achieved via this proposal would help legitimize the use of stem cells and should thereby accelerate the development of stem cell-based therapeutics for a wide range of other diseases. In so doing there would be an indirect benefit to California by making our state a focal point for stem cell breakthroughs. This would increase medical capabilities, strengthen the {REDACTED} system, and energize local biotechnology companies with outside investment and a payoff in jobs and tax revenues.

Review Summary: 

Executive Summary

This proposal is focused on retinitis pigmentosa, a disease that causes photoreceptor and retinal degeneration leading to reduced vision or blindness. The goal of the proposed disease team will be to develop a therapeutic approach to protect photoreceptor cells by engineering the localized expression of beneficial growth factors. These growth factors will be produced by stem cells delivered as encapsulated cells or as transplants into the retina. The proposal outlines essential basic research, translational evaluation in animal models, and near-term clinical trials in humans.

This proposal outlines a well organized plan to develop neuroprotection therapy for a form of hereditary blindness. Although the target disease is relatively rare, the treatments developed in the proposed project may be applicable to more common conditions such as age-related macular degeneration or diseases of neural degeneration.

The proposed approach has a strong rationale, and its feasibility is supported by preclinical studies in animals. This feasibility and the maturity of the concept are key strengths of the proposal. Reviewers noted the particular advantage of the eye as a site for stem cell-based therapy, since the retina is accessible for implantation, manipulation, and ready assessment and is an immune privileged site. Although one reviewer felt that the proposal lacked adequate focus and was concerned that the applicant had not considered issues of appropriate developmental stage of donor cells and recipient tissue, others were confident that approaches would be refined and gaps in knowledge explored adequately during the planning process.

The PI is a stem cell neurobiologist and an ophthalmologist with specialization in retinal degenerative diseases. He/she has published extensively on retinal progenitor cells. He/she has translational experience in taking neuroprotection projects into the clinic and has collaborated previously with biologists, surgeons, and engineers in medical treatment development. Additionally, the PI has previous experience in organizing multidisciplinary research consortia, which is a clear strength of the proposal.

The planning approach appears highly collaborative and well thought out. Team members with impressive credentials and appropriate expertise have been identified, and some of these researchers have already met to discuss the concept and approach. Planned teleconferences and further meetings and the extensive institutional support for this effort should facilitate the preparation of a strong disease team proposal.

Reviewer Synopsis

This proposal targets retinitis pigmentosa, a disease of photoreceptors that causes reduced visual acuity or blindness in otherwise healthy individuals. The majority of cases represent genetic mutations and, despite being responsible for a significant degree of visual disability, there are no effective treatments at the present time for the condition.

The aim here is to protect photoreceptors by engineered expression of growth factors released by transplanted stem cells. The stem cells will be delivered either as encapsulated cells or transplanted into the retina. Those transplanted into the retina may also integrate and differentiate, but this is not essential for the therapeutic benefit of this trial.

Reviewer One Comments

This proposal address retinitis pigmentosa, a form of hereditary blindness that progressively destroys the photoreceptor cells in generally healthy people. While this disease is relatively rare, stem cell-based treatments developed for RP might be applicable to more common conditions such as age-related macular degeneration and glaucoma and even to neurological degeneration of the brain or spinal cord. Thus, the approach proposed, the generation of retinal pigment epithelial cell lines to deliver cytokines that promote neuroprotection of photoreceptors, is of considerable significance. Cytokine-mediated neuroprotection of photoreceptors was first reported by collaborators on this proposal, Matthew LaVail et al. This phenomenon has been reproducibly demonstrated in multiple species. However, cytokines are rapidly degraded in the eye by endogenous proteases, resulting in the need for a method of sustained intraocular delivery. Thus, cell-based delivery is a rational approach. Clinical trials are already underway using introduction of encapsulated genetically modified cells secreting CNTF introduced into the vitreous cavity. Retinal progenitor cells can be generated from embryonic stem cells, permitting the investigators’ strategy of using ES-derived retinal precursors that are specified but not fully differentiated as cells that can integrate into the host retina and differentiate into photoreceptors. They will perform basic research to introduce cytokine genes into ES and induced pluripotent stem cells (iPS) using inducible promoters, followed by the generation of RPCs and RPE cells and extensive characterization. A second translational element will be implantation of encapsulated cells and transplantation in animal models, with the expectation of near-term clinical trials in humans. The idea appears to be quite mature, as the scientific feasibility of stem cell-mediated neuroprotection in RP has been demonstrated in animals. The Stem Cell Consortium of the Foundation Fighting Blindness concluded in a meeting in 2006 that the approach of stem cell-mediated neuroprotection represented the stem cell-based method closest to clinical application for RP. RP is often predictable on genetic grounds, and implantation of cells will not require any new technology. Thus, the procedure is feasible. Moreover, the retina is an immune privileged site and it is not expected that immune suppression will be required. Moreover, neural progenitor cells appear to lack immunogenecity and resist destruction as allografts. The investigators have identified the appropriate gaps in knowledge that will be addressed during the final process, including optimal cytokine gene and vector construction, use of multiple genes, choice of promoters, additional studies of stem cell proliferation and differentiation, encapsulation options, choice of cell population, etc.

Principal Investigator:
Dr. Klassen is a stem cell neurobiologist at UC Irvine who is fully trained in opthalmology with specialization in retinal degenerative diseases. He is a member of the Stem Cell Consortium of the Foundation Fighting Blindness and a founding member of the Southern California Consortium for Regenerative Eye Research. He has focused his career on this approach to degenerative retinal disease. He has personally envisioned the specifics of this project and pursued the development of novel regenerative treatments. He has played a central role in a retinal neuroprotection project that has recently been approved for a clinical safety trial in patients with end-stage RP in Brazil. He is leading a multi-disciplinary consortium directed at the development of regenerative strategies for treatment of AMD. This team includes retinal stem cell biologists, visual electrophysiologists, vitreoretinal surgeons, chemical engineers, a pig geneticist and a veterinary ophthalmologist and involves multiple institutions across the country. Thus, Dr. Klassen has considerable experience in assembling disease teams for translational therapies of retinal degenerative diseases and is well qualified to lead this effort.

Planning Approach:
Dr. Klassen has submitted his proposal on behalf of a multi-institutional group of investigators who have already met, discussed the concept of the retinal disease-oriented translation effort, and have expressed interest. This includes a large group of investigators at multiple California institutions, all of whom have provided letters of support. The effort is supported by the Department of Ophthalmology at UCI and the UCI Stem Cell Center. Members of the Stem Cell Consortium of the Foundation Fighting Blindness provide out-of-state support. Corporate interest has also been expressed. Dr. Klassen will begin by presenting an overall therapeutic goal to interested parties and each will formulate a specific role and sub-project contributing towards the goal. Frequent teleconferences will be followed by another group meeting and a series of meetings leading to the development of a draft, which will then be reviewed and critiqued by the entire group. The process seems collaborative and well thought out.

Reviewer Two Comments

Plausibility of target
The Author argues that diseases of the eye represent particularly applicable targets for stem cell medicine, given ease of access, the fact that only one of the two eyes is targeted and the limited movement of cells outside the eye should the therapy not succeed or complications develop. Also, the Authors argue that the immune privileged nature of the eye means that it is not necessary to use autologous cells.

I agree that the eye represents an excellent site for early applications of stem cell medicine to disease. The evidence that photoreceptor degeneration can be influenced by growth factors is solid, although the extent of benefit may be rather small. However I do not accept that integration and differentiation into photoreceptors following transplantation is likely; studies performed thus far suggest that this requires rather precise matching of developmental stage of transplanted cells and recipient retina. Nonetheless, delivery of neuroprotective factors by encapsulated stem cells represents a valuable concept worth exploring.

Evidence in support of therapeutic concept: see above.

Can it go to clinic in 5 years? Yes, given the range of ophthalmological surgical expertise available to this group. Injections into the eye are used routinely for therapy, e.g. for macular degeneration, and I see no objections in principle to the approach proposed. However more attention to the types of cell to be used would be necessary to convince me that this team can get to the clinic in this time.

Importance of problem and ability to advance stem cell medicine to the clinic: see above.

Principal Investigator
Dr Klassen has worked in stem cell biology for some years and has published a number of papers in specialist journals on neural stem cells. He is clearly committed to stem cell research as it applies to visual disease, and has clinical experience in ophthalmology. Significantly, he does have translational experience in taking neuroprotection projects into the clinic and has also worked with biologists, surgeons and engineers in developing treatments for adult macular degeneration. He therefore does have the necessary leadership qualities for this project.

Translational expertise of Principal Investigator: see above.

Leadership qualities of Principal Investigator: see above.

Planning Approach:
Merit of planning process proposed; is it well thought out? The planning approach has an impressive list of names, with expertise that covers most of the areas required. However, the proposal simply details three meetings and gives no insights into likely pathways, problems and gaps that need to be addressed etc. So, while I have no doubt that the collective expertise is available, there must be a concern as to how it will be brought together. For this reason, I am not convinced by this application that a truly competitive proposal can emerge, even though I feel that the concept is excellent and the clinical feasibility is high.

How good is the team? See above.

Will an award enable the team to prepare a competitive application? See above.

Reviewer Three Comments

Retinitis pigmentosa is a form of hereditary blindness in which the photoreceptors are progressively destroyed in otherwise healthy people. It provides a prototype for retinal neurodegeneration disease and is thus proposed for stem cell therapy. The goal of this project is to introduce cytokine genes in to ES cells and induced pluripotent stem cells (iPS) under inducible promoters and to differentiate these ES cells to retinal progenitors or retinal pigment epithelial cells and to characterize them. The second component would then be to encapsulate these cells and transplant them into animal models as preclinical studies leading to clinical trials. Preclinical studies have shown that: 1) human neural progenitor cells transplanted subretinally in a genetic rat model of retinal degeneration could preserve the photoreceptors and that this was enhanced by genetically engineering the expression of GDNF; initiatives or clinical trials, though he/she has published extensively on breast cancer tumorogenesis. 2) 8um microsphere delivery of GDNF in to the vitreal chamber was neuroprotective in a rat model of glaucoma; and 3) several groups have derived retinal progenitor cells from ES cells. The immune privileged site of the chambers of the eye also lends support for this approach. The proposal lists the knowledge, which provides strong support for this approach, and the gaps that will be explored in the planning stage.

Principal Investigator:
Dr. Klassen is an MD-PhD ophthalmologist who since 2006 is Assistant Professor and Director of Stem Cell and Retinal Regeneration Program at UC Irvine. He has published extensively on retinal progenitor cells. He has private foundation research funding. He has been centrally involved in a retinal neuroprotection project in which GDNF-laden microspheres are used to rescue injured retinal neurons, particularly the ganglion cells in models of glaucoma; this project has progressed through preclinical trials and currently has been approved for a clinical safety trial (Phase I) in Brazil. He has organized and secured funding (for 1 year so far) for a multidisciplinary consortium for development of regenerative strategies for age related macular degeneration (AMD). Additionally he is a founding member of the Southern California Consortium for Regenerative Eye Research, which forms the basis of this Disease Team. A weakness is that he has not had much experience in orchestrating large groups of independent investigators as yet.

Planning Approach:
The disease team has a number of interested parties and is being orchestrated by Dr. Klassen. The Southern California Consortium for Regenerative Eye Research is said to form the basis of this Disease Team. The organization of the final project seems more based on what each member formulates as a role and subproject than on what is needed to reach the goal and then how and who is needed to do that. Even so, there does seem to be widespread interest and expertise and the final application may encompass all the steps needed to bring to the clinic.