Tissue Collection for Disease Modeling
Age-related macular degeneration (AMD), primary open-angle glaucoma (POAG), and proliferative diabetic retinopathy (PDR) are the major causes of irreversible vision loss worldwide. Although the exact causes and mechanisms of these diseases are not completely understood, it is known that genetic and environmental factors contribute to the development of these diseases. Recent scientific advances have enabled the reprogramming of already-differentiated tissues such as skin cells back to cells called induced pluripotent stem cells (iPSCs). iPSCs have the potential to be programmed into different cells in the eye, which are lost in degeneration. We therefore propose to obtain skin biopsies from patients with the above mentioned eye disease. The goals are to provide samples from a well-characterized patient population whose members exhibit the target eye diseases. Although there are animal models of eye diseases, retinal cells derived from iPSC will provide a better and faster way for disease modeling in the dish, novel tools for drug screening. The iPSC-derived retinal cells can also be used to replace degenerated or damaged retinal cells to restore vision for millions of patients, such as retinal pigment epithelium (RPE) cells to treat AMD and retinal ganglion cells to treat glaucoma.
Statement of Benefit to California:
Blindness or impaired vision affects 3.3 million Americans ages 40 and over, or one in 28, according to a study sponsored by NIH. This figure is projected to reach 5.5 million by the year 2020. The rate of low vision and blindness increases significantly with age, particularly in people over age 65. California has the largest population in the United States. With the aging of the population, the number of Californians with age-related eye diseases is increasing, and vision loss is expected to remain a major public health and societal economic concern in addition to its substantial effect on individual living quality. Our proposed study of tissue collection from patients with major eye diseases will provide new means and materials to understand mechanisms of susceptibility to ocular diseases. It is innovative and promises a number of unique contributions to the field of regenerative medicine. By integration of clinical and genome-wide association datasets, we will be able to perform a comprehensive and coordinated study designed to identify and understand the complex interplay of genetic, developmental and environmental factors, and their contributions to the development and progression of major eye disorders. This should open a new avenue for future functional studies and could eventually help facilitate the prediction, development of improved treatment, and prevention of devastating blindness-causing diseases.
The objective of this proposal is to collect biological samples from individuals suffering from severe eye disorders that lead to vision loss or blindness. In particular, the applicants will focus on Age-related Macular Degeneration (AMD), including both the wet and dry forms of this disease, Primary Open-Angle Glaucoma (POAG), and Proliferative Diabetic Retinopathy (PDR), which together represent the leading causes of irreversible vision loss in the aging population. Although the exact causes and mechanisms of these diseases are not completely understood, it is known that genetic as well as environmental factors contribute to the development of disease and effective treatments that address the causes are lacking. The goal of the proposal is to establish a collection of samples from clinically well-characterized patient populations whose members exhibit the target eye diseases. This will provide new means and materials to understand mechanisms of susceptibility to ocular diseases and allow development of novel cell-based models for these disorders. Additionally, most of the samples will have associated genetic data such as genotype analysis and exome sequencing, some of which has already been gathered, allowing for integration of clinical and genetic datasets. Impact and Significance - Patient-derived human induced pluripotent stem cells (hiPSCs) represent a unique resource for modeling these complex eye disorders and there is a strong likelihood that it will accelerate research on these pathologies. - All three disease groups are common and important ophthalmologic problems that should be better understood. hiPSC lines are a good approach to study underlying disease mechanisms and there is potential for discovering innovative interventions. An ophthalmologic hiPSC collection would be important and of wide interest. - Each disease could require a substantial number of cell lines to identify consistent results, so including three diseases may be a relative weakness of the proposal. Rationale - It is difficult to model these ocular diseases in animals and therefore critical to find alternate methods; hiPSCs would provide such an alternative model. - Because there is a significant body of work showing that hiPSCs can be differentiated into multiple relevant ocular cell types, there is a strong rationale for modeling these three eye disorders using hiPSC. - The investigators do not comment directly on whether the number of proposed donors is sufficient to address key questions about the genetics and mechanisms of the proposed diseases, nor do they comment on how they decided on the number of samples to be collected for each disease. Reviewers felt that due to the complexity of AMD, inclusion of a higher number of tissue donors than proposed my be warranted. Quality of the Proposed Protocols - The comprehensive medical assessment and associated clinical data are strengths of the proposal. Reviewers highly appreciated the existence of genetic data for most tissue donors. - Reviewers criticized the data sharing plan, and were unclear whether the intent is to transfer the existing genetic data, in principle a strength of this proposal, to the Repository. - The proposed consent form has been approved by the institutional review board (IRB) and is consistent with the guidelines suggested by CIRM. - Safeguards for coding information and protecting confidentiality are described; patient information will be protected. - The plan for cell shipment to the Deriver is not sufficiently described in the protocol, which is a shortcoming. Feasibility - The proposal already has IRB approval to collect samples from patients. - Many pieces are already in place; the applicant should be able to enroll the required subjects. - The phenotypic and genotypic data to be included from the study subjects seems to be extensive and well organized; much of the characterization has already been done which was viewed as a major strength of the proposal. Budget - Personnel costs are in line with the needs of the project. - A relatively high amount of money is requested for a specific piece of equipment without a justification for its requirement. - The medical data, including genetic data, will need to be annotated so that it can be shared. Reviewers suggested reallocating the funds proposed for the unnecessary piece of equipment to this activity. - The cost per sample was considered reasonable. - The applicants propose to derive the fibroblast lines themselves but this is not part of this RFA and should come out of the budget. Qualifications of the Principal Investigator (PI) and Team Members, Resources - The investigators are established, highly qualified researchers in the field of ophthalmology. They are without doubt qualified to conduct the proposed activities. - The applicants are well-recognized investigators in the genetics of age-related eye disorders and are based at a leading institution in the biomedical field. - The plan does not identify needed personnel for data management.
- PROGRAMMATIC DISCUSSION
- A motion was made to move this application into Tier 1, Recommended for Funding. Reasons given were: it addresses an unmet medical need, it increases the diversity of tissue samples, and the scientific merit was high. The proposed genome sequencing, although valuable, is an expensive item and is not part of the RFA. The motion carried with specific recommendations (i) that the proposed sequencing not be funded by this grant and that this component be removed from the budget and (ii) that CIRM confirm that the existing genetic data described in the proposal will be transferred to the Repository.
- CIRM contacted the applicant and confirmed that, if funded, the genetic data associated with tissue donors will be transferred to the Repository.