This study will establish a repository of biospecimens to generate induced pluripotent stem (iPS) cells, which will be used to determine molecular mechanisms for potentially blinding eye diseases including but not limited to: Best Vitelliform Dystrophy (Best Disease); Late-Onset Retinal Degeneration (L-ORD); Age-Related Macular Degeneration (AMD); Leber congenital amaurosis (LCA); Joubert syndrome; X-linked retinitis pigmentosa (RP); oculocutaneous albinism; Stargardt s with ABCA4 gene mutations; Waardenburg syndrome, coloboma, Enhanced S-Cone syndrome (ESCS), Spinocerebellar Ataxia, Type 7 (SCA7) and eye diseases associated with MITF, PAX2, or PAX6 gene mutations. Skin fibroblasts, saliva, hair keratinocytes, urine, and/or blood cells may be collected from participants with retinal diseases and from age, sex, and ethnicity-matched healthy participants.
Although research involving multiple different ocular cell types from these patients may be performed, the vast majority of the work will be centered on the retinal pigment epithelium (RPE) and neural retina. RPE and/or neural retinal cells generated from the iPS cells of participants with retinal diseases and healthy volunteers will be used to analyze molecular mechanisms involved in disease initiation and progression. In addition, the iPS cell-derived ocular cells will be used to perform high throughput (HTP) drug screens aimed at suppressing the molecular phenotypes of the disease and to identify potential therapeutic agents for these diseases.
Objectives: The primary objective of this study is to generate participant-iPS cells that can be differentiated into ocular cell types, to be used to study the molecular mechanisms of and to develop treatments for ocular conditions. This objective will be carried out in three phases. First, this study will establish a repository of fibroblasts, keratinocytes, urine-derived cells and/or blood cells collected from participants with eye diseases and from matched controls without any eye diseases. Second, the somatic cell repository will be used to generate iPS cells, which will be differentiated into RPE, neural retinal and/or other ocular cells. These cells will be used to elucidate molecular pathways that have led to disease pathogenesis. In the third phase, the participant-specific ocular cells will be used to perform high throughput drug screens to identify novel potential therapeutic compounds. The cells obtained in this protocol may be genetically modified, may be transplanted into animals in the laboratory, and, if used in the development of cell-based therapies, may be transplanted into humans. Transplantation into humans will be done as a part of a different study.
Study Population: We plan to recruit 465 participants with ocular conditions including but not limited to: degenerative retinal diseases, optic atrophy, microphthalmia/anophthalmia, ciliopathy, and other ocular developmental or degenerative conditions, and 465 healthy volunteers without any eye disease. If possible, unaffected siblings and relatives of participants with eye diseases will be included as healthy volunteers.
Design: In this basic science, research-oriented study, skin, saliva, hair, urine, and/or blood samples may be collected from affected participants with the eye diseases and/or genetic mutations under study, and from control participants matched for age, sex, and ethnicity. The sample collection procedures will incur only minimal risk to adult participants. This study will typically require only one visit by each participant. Participants may be requested to return if their initial sample(s) did not produce adequate cells for study in the laboratory. Participants who were previously enrolled to provide samples for research-grade iPS cell generation may return for an additional visit to provide samples for clinical-grade iPS cell generation, if eligible. The skin fibroblast, keratinocyte, urine-derived cells and/or blood samples will then be used to generate participant-specific iPS cells, and these cells will then be differentiated into RPE, neural retinal and/or other ocular cell types. iPS cells may not be made from all samples. The investigators will use the samples for research studies aimed at identifying molecular and signaling pathways underlying disease onset and progression and for developing potential therapeutic treatments for the eye diseases under study.
Outcome Measures: The outcome measures for this study include the creation of iPS cells from at least one of the three types of somatic tissues collected from each participant, the differentiation of iPS cells into RPE, neural retinal cells and/or other ocular cells, and the identification of molecular and physiological phenotypes in these cells that may be linked to the onset or progression of the ocular conditions being studied. This analysis may lead to the discovery of therapeutic interventions for these diseases. There are no specific participant-based clinical outcomes for this protocol. Participants will, in general, be seen only once for this protocol. In rare cases, participants may be requested to return to the clinic if their initial sample(s) did not produce adequate cells for study in the laboratory.
