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, saliva, urine, 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, saliva, urine, and/or blood samples to study three eye diseases that affect the retina: Best disease, L-ORD, and AMD.

Eligibility:

• Individuals affected with ocular condition is one year of age or older.
• Individuals affected with Best disease, L-ORD, or AMD is 18 years of age or older.
• Unaffected individuals are seven years of age or older.

Design:

• The study requires one visit to the National Eye Institute.
• Participants will be screened with a medical and eye disease history. They may also have an eye exam.
• Participants will provide a hair sample, saliva sample, urine sample, blood sample, and/or 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 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.

• INCLUSION CRITERIA:

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

1. Have the ability to understand and sign an informed consent or have a parent/legal guardian to do so if they are minor children or have a legally authorized representative if they are adults without consent capacity.

2. Participant meets one of the following criteria:

   1. Participant has been diagnosed with an ocular condition of interest including but not limited to: degenerative retinal diseases, optic atrophy, microphthalmia/anophthalmia, ciliopathy, and other ocular developmental or degenerative conditions.
   2. Participant is free of eye diseases and could serve as an unaffected control. Participant's age, sex, and ethnicity must match an existing participant with one of the eye diseases under study. 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. Healthy, unaffected children will only have one skin punch biopsy done 3mm or less in size. In affected participants, an additional punch may be gathered if the initial sample does not contain adequate cells. This will be taken from children ages seven years and older. Sampling of ten occipital hairs and/or saliva may be pursued at the investigator's discretion. Participants not able to provide a skin biopsy or blood sample may opt to provide 100-200 ml of fresh urine. As a rule, samples will be collected on non-sedated/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, urine sample or 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 an ocular condition 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.

1. Participant is unable to comply with study procedures.
2. 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.

ADDITIONAL CRITERIA FOR CLNICAL-GRADE CELL LINE GENERATION:

The additional eligibility criteria must be met for participants donating samples for the generation of clinical-grade cell lines.

Inclusion Criteria

1. Participant must be greater than 18 years of age, as of the date of enrollment. There is no upper age limit for donor enrollment.
2. Participant is able to provide a punch skin biopsy and 200 ml of peripheral venous blood.
3. Participant is willing and eligible to co-enroll in NEI protocol 15-EI-0128.

Exclusion Criteria

1. Participant has medical history that includes any of the following:

   1. Thrombocytopenia or other blood dyscrasias

   2. Bleeding diathesis

   3. Antibiotic use within the prior 48 hours

   4. Active cancer or history of cancer within the past five years

   5. History of exposure to transfusion transmitted diseases including HIV and hepatitis B and C as defined by the Standards for Blood

      Banking and Transfusion Services, American Association of Blood Banks.

   6. Travel to an area where malaria is endemic as defined by the CDC (www.cdc.gov/travel)

   7. At risk for the possible transmission of Creuzefeldt-Jackob Disease (CJD) and Variant Creuzefeldt-Jackob Disease (vCJD) as described in the FDA Guidance for Industry, January 9, 2002, "Revised Preventive Measures to Reduce the Possible Risk of Transfusion of Creuzefeldt-Jackob Disease (CJD) and Variant Creuzefeldt-Jackob Disease (vCJD) by Blood and Blood Products"

2. Participant is currently febrile (temperature > 38 degrees C)

3. Participant has Hemoglobin level:

   • African American women <11.5 grams/dL
   • Other women < 12.0 grams/dL
   • Men <12.5 grams/dL

4. Participant has low hematocrit (HCT):

   • African American women < 34%
   • Other women <36%
   • Men <38%

5. Participant has Platelets <150 x 103/microL

6. Participant has Absolute neutrophil count <1.0 x 103/microL.

7. Participant has positive tests for blood borne pathogens (as required by the Standards for Blood Banks and Transfusion Services, American Association of Blood Banks. The currently required tests include anti-HIV1/2, anti-HCV, anti-HBc, Anti-HTLV I/II, anti-T. Cruzi, HBsAg, syphilis, and molecular testing for West Nile virus, HCV, HBV, and HIV-1).

465 participants with ocular conditions and 465 participants without any ocular disease