Cell Collection to Study Eye Diseases

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, hair
keratinocytes, and/or blood cells may be collected from participants with retinal diseases
and from age, gender 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, 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, hair, 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, gender and ethnicity. The sample
collection procedures will incur only minimal risk to adult participants. For on-site minor
participants, the skin biopsy procedure is a minor increment over minimal risk. Offsite minor
participants will not undergo the skin biopsy. 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, 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, as they will be ascertained and/or receiving standard care under
the NEI Ocular Natural History Protocol (16-EI-0134) or other NEI protocols. 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. 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 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, gender, 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. Sampling of ten occipital hairs
may be pursued at the investigator s discretion. 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 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 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. History of cancer

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 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 HCT:

- African American women < 34%

- Other women <36%

- Men <38%

5. Participant has plateleys <150 x 10(3)/(micro)L

6. Participant has Absolute neutrophil count <1.0 x 10(3)/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).