Cell Collection to Study Retinal Diseases

Background:

- Best Vitelliform Dystrophy (Best disease), Late-Onset Retinal Degeneration (L-ORD), and Age-Related Macular Degeneration (AMD) all affect the retina, the light sensing area at the back of the eye. Doctors cannot safely obtain retinal cells to study these diseases. However, cells collected from hair follicles, skin, and blood can be used for research. Researchers want to collect cells from people with Best disease, L-ORD, and AMD, and compare their cells with those of healthy volunteers.

Objectives:

- To collect hair, skin, and blood samples to study three eye diseases that affect the retina: Best disease, L-ORD, and AMD.

Eligibility:

• Individuals at least 18 years of age who have Best disease, L-ORD, or AMD in at least one eye.
• Healthy volunteers at least 18 years of age.

Design:

• The study requires one visit to the National Eye Institute.
• Participants will be screened with a medical and eye disease history. They will also have an eye exam.
• Participants will provide a hair sample, a blood sample, and a skin biopsy. The hair will be collected from the back of the head, and the skin will be collected from the inside of the upper arm.

This study will establish a repository of biospecimens to generate induced pluripotent (iPS) stem cells to be used to determine molecular mechanisms for three potentially blinding retinal diseases: Best Vitelliform Dystrophy (Best Disease), Late-Onset Retinal Degeneration (L-ORD), and Age-Related Macular Degeneration (AMD). Skin fibroblasts, hair keratinocytes, and CD34+ blood cells will be collected from participants with Best Disease, L-ORD, and AMD and from age, gender and ethnicity-matched healthy participants.

Retinal pigment epithelium (RPE) cells generated from the iPS cells of patient and healthy volunteers will be used to analyze molecular mechanisms involved in disease initiation and progression. In addition, the iPS cell-derived RPE cells will be used to perform high throughput (HTP) drug screens aimed at suppressing the molecular phenotypes of the disease to identify potential therapeutic agents for Best disease, L-ORD, and AMD.

OBJECTIVES:

The primary objective of this study is to generate participant-specific RPE cells to be used to study the molecular mechanisms of and to develop treatments for Best disease,

L-ORD and AMD. This objective will be carried out in three phases. First, this study will establish a repository for fibroblasts, keratinocytes, and CD34+ blood cells collected from participants with these three diseases and from participants without any retinal diseases. Second, the somatic cell repository will be used to generate iPS cells, which will be differentiated into RPE cells. These RPE cells will be used to elucidate molecular pathways that have led to disease pathogenesis. In the third phase, the patient-specific RPE cells will be used to perform high throughput drug screens to identify novel potential therapeutic compounds.

STUDY POPULATION:

We plan to recruit 25 participants with Best disease, 25 participants with

L-ORD, 50 participants with AMD and 75 healthy volunteers without any retinal disease. If possible, unaffected siblings and relatives of patients will be included as healthy volunteers.

DESIGN:

In this basic science, research-oriented study, skin, hair and blood samples will be collected from participants with Best disease, L-ORD and AMD and from control participants matched for age, gender and ethnicity. The sample collection procedures will incur only minimal risk to participants. This study will typically require only one visit by each participant. The skin fibroblast, keratinocyte and CD34+ blood samples will then be used to generate patient-specific iPS cells and these cells will then be differentiated into RPE cells. 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 Best disease, L-ORD and AMD.

OUTCOME MEASURES:

The outcome measures for this study include the creation of iPS cells from the three types of somatic tissues collected from each patient, the differentiation of iPS cells into RPE cells and the identification of molecular and physiological phenotypes in RPE cells that may be linked to the onset or progression of Best disease, L-ORD and AMD. This analysis may lead to the discovery of therapeutic interventions for these diseases. There are no specific patient-based clinical outcomes for this protocol. Participants will be seen only once for this protocol, as they will be receiving the standard of care under the NEI Evaluation and Treatment Protocol (08-EI-0169) or other NEI protocols.

• Retinal Disease
• AMD
• Retinal Degeneration

• Wu SM, Hochedlinger K. Harnessing the potential of induced pluripotent stem cells for regenerative medicine. Nat Cell Biol. 2011 May;13(5):497-505. Review. Erratum in: Nat Cell Biol. 2011 Jun;13(6):734.
• Stadtfeld M, Hochedlinger K. Induced pluripotency: history, mechanisms, and applications. Genes Dev. 2010 Oct 15;24(20):2239-63. Review.
• Bharti K, Miller SS, Arnheiter H. The new paradigm: retinal pigment epithelium cells generated from embryonic or induced pluripotent stem cells. Pigment Cell Melanoma Res. 2011 Feb;24(1):21-34. Epub 2010 Oct 7.

• INCLUSION CRITERIA:

To be eligible, participants must meet the following inclusion criteria:

1. Participant has the ability to understand and sign an informed consent.

2. Participant meets one of the following criteria:

   1. Participant has been diagnosed with Best disease, defined as the presence of lipofuscin-like deposits in the subretinal space and definitive mutations in the BEST1 gene.
   2. Participant has been diagnosed with L-ORD, defined as problems in dark adaptation and the loss of rod and cone function, subretinal deposits, RPE atrophy and hemorrhage, and long anterior zonules in the lens.
   3. Participant has been diagnosed with AMD, defined as the presence of:

   i. large drusen in both eyes along with pigmentary changes with or without advanced AMD (neovascular AMD), or

   ii. geographic atrophy in at least one eye.

   d. Participant has been diagnosed with LCA, defined as a presentation that is typical of the disease and mutations in the CEP290 or CRX genes.

   e. Participant has been diagnosed with Joubert syndrome, defined as the presence of retinal dysfunction and/or degeneration and mutations in the CEP290 or CC2D2A genes.

   f. Participant has been diagnosed with X-linked RP, defined as a presentation that is typical of the disease and mutations in the RPGR or RP2 genes.

   g. Participant is free of retinal diseases and could serve as an unaffected control. Participant's age (within five years), gender, and ethnicity must match an existing participant with Best disease, L-ORD, AMD, LCA, Joubert syndrome, or X-linked RP. Control participants matched to AMD participants must not have drusen greater than 63 microns in size.

3. Adult participant is able to provide a punch skin biopsy and 30 mL of peripheral venous blood OR child participant is able to provide a punch skin biopsy and the lesser of 5 mL/kg or 30 mL of peripheral venous blood. Sampling of ten occipital hairs may be pursued at the investigator's discretion. As a rule, samples will be collected on nonsedated/ anesthetized participants. Sedation/anesthesia will NOT be used solely for the purpose of sample collection. In rare instances where a minor requires sedation for another medically indicated procedure, samples may be collected at the time of sedation/anesthesia. Because young children may not be able to cooperate with sample collection, those unable to provide a skin biopsy and a blood sample may be excluded from the study, based on the judgment of the examining investigator.

4. Participant meets one of the following criteria:

   1. Participant affected with LCA, Joubert syndrome, or RP is one year of age or older.
   2. Participant affected with Best disease, L-ORD, or AMD is 18 years of age or older.
   3. Unaffected participant is seven years of age or older and willing and able to provide assent.

EXCLUSION CRITERIA:

A participant is not eligible if any of the following exclusion criteria are present:

Participant is unable to comply with study procedures.

Participant has a systemic disease that, in the opinion of the investigator, compromises the ability to provide adequate samples. Examples of co-existing diseases that would exclude a participant include a bleeding diathesis or a genetic susceptibility to infections, particularly cutaneous infections.