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RN1-00573-1: Immune Regulation of Retinal Stem Cell Migration and Survival

Recommendation: Not recommended for funding

Public Abstract (provided by applicant)

Our goal is to speed the development of stem cell treatments for the many blinding diseases that affect the eye and specifically the retina, such as age-related macular degeneration (AMD). Cell transplantation has been attempted for 2 decades without real success. This scientific project will help fill gaps in our knowledge in two areas. 1) It will help us answer how the stem cells get to where they where they need to be to help the eye. 2) How do we make the cells stay (for a long time) and work where need to be. We feel the immune systems reaction to the cells will play a big role in answering these two question. Plus we will do our research in such a way we will meet the standards mandated by the Food and Drug Administration for use in human treatments. This will help us move forward quickly to the treatment of real vision loss in patients. Lastly we will compare stem cells from different sources to find out which source will be the best for eye and retina disease.

To answer the question how do the cells get to where they need to be, we have found a way to study cell movement in the eye. This new model allows us to study cells as the move to the retina. Using this model, we can figure out how our delivery of the cells to the eye affects where they ultimately end up in the retina. Also we will see how different types of stem cells may travel more appropriately than others, which will help us chose the best ones for patients. Plus we feel that the immune system whose job it is to keep bad germs away from us, also will influence how these cells travel.

We also want to find what keeps the cells where they need to be. We think the stem cell type may make a difference and again we think the immune system will play a role in their long-term survival. Our studies will be aimed at understanding these things that keep the cells from staying where they need to be. We will take steps to figure out the specific proteins or molecules that are involved. If we can figure this out we can take action to change those factors, and provide a way for long-term survival of the cells in the retina.

Blindness is tragedy, which more and more Americans suffer with.  We believe that stem cell transplantation to the eye and retina could prevent and in some cases reverse blindness.  Filling these gaps in our knowledge regarding stem cell movement and how the immune system affect both movement and survival will allow us to advance towards our goal of treating blind patients in the near future.

Statement of Benefit to California (provided by applicant)

Vision loss to an individual can be catastrophic. Blindness can be overwhelming, robbing one of independence, hindering communication, and worsening other health care problems. Vision loss can also prevent gainful employment, as only 1 out of 3 visually impaired people of employment age are in the workforce. In the United States, blindness is one of the public’s biggest health fears only behind cancer and AIDS. Vision loss increases with age as over 20% of those over 65 of age report vision loss. In California, 16% (1.7 million) over 45 years of age have vision loss, and as the Baby Boomers generation continues to age, these numbers are expected to greatly increase. In fact, the Eye Diseases Prevalence Research Group estimates that by the year 2020 the percent of Americans blind will increase by 70%.

Problems with the retina encompass the great majority of the reasons for blindness and vision loss in the American population. For those 60 years and over, age-related macular degeneration is the leading cause of vision loss. For people between the age of 25 and 74, the leading cause of blindness is damage to the retina caused by diabetes (diabetic retinopathy). Even for infants, the leading cause of blindness is retinopathy of prematurity.

We believe our proposed studies will be of significant value to Californians. Our goal is to speed the development of stem cell therapies for the many blinding diseases of the retina. First, funding this project will help establish California as a leader in retinal stem cell therapies. These advances will allow Californian patients with many blinding disorders to benefit by directly participating in the clinical trials. In addition, answers found in these studies of the eye will apply to other stem cell treatments. Moreover, as retinal problems are common in Californians, the number of Californians that could directly benefit is great. Our proposed projects are focused on the application of human stem cells towards human retinal disease, specifically addressing how stem cells get to where they need to be in the eye what keeps them from staying there. In addition, we will study how the immune system affects the transplantation of these cells and how cell changes (differentiation) makes them more or less successful in migration and survival. Understanding these immune responses will be critical for the success of most future stem cell treatments.

Finally, many physicians and even moreso retinal specialists do not stay in academics and research because the financial and personal benefits of private practice are great and research funding continues to decline. These realities mean that there is not an abundance of physicians that commit their careers towards improving eye care in fields such as retinal stem cell therapies. This type of funding of a physician-scientist in the study of retinal disease will help reverse this trend here in California.

Review

SYNOPSIS: The goal of this project is to gain a better understanding of how adult and human embryonic stem cells (hESCs) integrate and survive in the retina, and to repair the retinal pigment epithelium (RPE) in mouse models. The proposal explores the potential of stem cells to treat retinal degeneration, and compares adult and embryonic stem cells as a source of cells that are capable of delaying or diminishing neuronal loss in the retina.

STRENGTHS AND WEAKNESSES OF THE RESEARCH PLAN: These studies aim to contribute to the development of stem cell therapies for diseases such as age related macular degeneration (AMD) and retinitis pigmentosa. It is thus an interesting proposal in a clinically relevant area. The major strengths of this proposal are that the candidate has the potential to become a well-qualified scientist/clinician, s/he is working with a strong group of colleagues, and the clinical target is of major importance.

Unfortunately, the research plan suffers from a number of weaknesses. Although the hypothesis and goals are well articulated, the experiments are poorly designed. In many cases, it is not clear what model system is being used for which experiments, and precise quantitative endpoints are not identified. It is apparent that the investigator has little direct experience with these model systems, as the comparisons between hESC-derived and adult stem cell derived cells are unclear at times. In addition, in the use of abbreviations and model systems there is an unwarranted assumption of knowledge, and the background material related to model systems and gene products are not provided in enough detail for the reviewer to gain an appreciation of the rationale behind certain experiments and methodologies. The preliminary data are quite limited in their ability to support the proposed studies. A question could also be raised about whether the RPE might be the best cell to replace. One reviewer commented that there is no evidence to date that these cells are useful in neuroprotection, as noted by the applicant. The reviewer also noted that, in the clinical scenario, delivery or transplantation of cells designed to give rise to RPE might be too late.

The Principal Investigator (PI) is relatively untested scientifically to take on such a large series of ambitious experiments, and has a limited scientific background. Some of the data presented in the preliminary results section seems to parallel similar experiments published by others, yet it is interesting that the PI does not reference these papers. There also appears to be significant other literature reporting transplantation of neural progenitor cells to replace the RPE, yet most of these references are not cited and this potential cell type derived from hESCs to repair the retinal epithelium is not considered in this project.

The experiments evaluating the role of a specific receptor in determining the ability of stem cells to migrate or home to the RPE are not well-designed. They are based on the premise that hypoxia will upregulate the receptor’s expression. Of course, hypoxia may induce many changes other than this particular receptor’s expression which may affect migration, and therefore these experiments are not designed in a way that will determine a precise role of the indicated receptor in homing and migration to the RPE. Also, it is proposed that expression of a specific factor would be used as a maturational marker. Although the literature appears to suggest that this factor is a signaling molecule that can increases RPE maturation, it is not clear which cells express this factor or that increased expression would indicate a more mature state of the RPE itself (the fact that it is expressed does not necessarily indicate the maturational effects of the factor have been achieved). Also, the investigators propose to select cells expressing another protein in differentiating cultures. However, the feasibility of this is not described. Although the applicant’s colleagues are working on these cells, more detail of how they are obtained, sorted, etc., would have been appropriate. In many cases, the experimental endpoints are descriptive, non-quantitative, and based on histology and immunostaining.

The research proposal is poorly organized, imprecisely written and contains non-quantitative, poorly defined endpoints. The preliminary data is weak and does not reassure reviewers that the project is feasible.

QUALIFICATIONS AND POTENTIAL OF THE PRINCIPAL INVESTIGATOR: The applicant is a young clinical investigator with good training and background. S/he completed an MD/PhD and ophthalmology residency and just recently completed a vitreo-retinal surgery eye fellowship at an institution within California. From 2003 to 2005 s/he was involved with clinical ophthalmology as an attending physician at this institution. From 2003 to 2005 the candidate was involved with clinical ophthalmology as an attending physician at the same institution. Since 2005, s/he has been an Assistant Professor of clinical ophthalmology at another institution. The candidate has received awards for teaching and has been heavily involved in medical school activities while publishing several clinical papers.

A concern could be raised about the PI’s scientific expertise and training to take on the proposed research. The applicant will rely heavily on colleagues, from whom the applicant has garnered a number of letters of support. The applicant has no experience in culturing ES cells as of yet.

The mentoring plans seem appropriate. The applicant has strong letters of support from the institution and from senior colleagues working in stem cells and vision, upon whom s/he will be reliant. The applicant has established both clinical and basic science mentors.

Thus, this is a clinical scientist with good potential addressing a clinically-important question in ophthalmology within a strong visual sciences department. S/he appears to be establishing strong basic science mentorship relationships, but has a limited scientific background at present.

INSTITUTIONAL COMMITMENT TO PRINCIPAL INVESTIGATOR: There is a strong stem cell research program and visual science group at the applicant’s institution, with numerous stem cell faculty and a commitment on the institution’s part to building an infrastructure core, developing resources, and recruiting new faculty. In the ophthalmology group, there are many vision scientists with NIH-funded grants. Significant stem cell core facilities are available at the institution through the established stem cell program, and include a FACS sorting core, an immunodeficient mouse core, human ESC karyotyping and teratoma services, and plans to build a new state-of-the-art GMP facility. In addition, a vector core and automated cell sorting technologies are available. The infrastructure in the applicant’s lab and the core facility at the institution all seem appropriate to carry out the work.

The applicant has a limited amount of extramural funding currently, but letters from the institution demonstrate a strong commitment to his/her development as a clinician-scientist. An NIH K30-mentored clinical research training program is potentially available to the applicant as formal mentorship training, conditional on receipt of CIRM funding.

It is not clear that independent lab space is available to the applicant at this time, and institutional resources may be controlled by other investigators. It appears the applicant has been provided research space in the labs of two collaborators. Additional lab space for the PI may be assigned in the new state-of-the-art GMP facility that is scheduled to be completed in 2008. There appears to be a commitment to expand stem cell research at the institution, both through recruiting new faculty (adding to an already-strong, stem cell investigator-rich program) and new building infrastructure.

DISCUSSION: Reviewers commented that this is an accomplished physician in a strong environment with good institutional support, doing research on a clinically-important problem. Unfortunately, the applicant does not have the research background to undertake this ambitious proposal, and the research proposal suffers from lack of scientific rigor. For instance, the receptor experiments are poorly designed – hypoxia does many things other than increase expression of this receptor. Furthermore, use of murine bone marrow stem cells is problematic as it is unlikely to yield any useful output; it isn’t always clear why the applicant uses both adult and embryonic cells, and the experiments as designed will not elucidate the role of chemokines in homing, which was seen by reviewers as an interesting question. Failure to reference the literature contributed to the feeling that the candidate is very new to the field. Finally, the proposal was poorly written and organized, heavy in acronyms, and had typographical errors, all of which made it difficult to read.

On the whole, the panel was supportive of the applicant and the idea being addressed in this application, and felt that the proposal should be re-written with more preliminary data and more careful advice from scientific mentors.

The following Working Group members had a conflict of interest with this application and were therefore recused from participating in review of, discussion of, and voting on the application:

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