Universal Rare Gene Study: A Registry and Natural History
Study of Retinal Dystrophies Associated with Rare Disease-Causing Genetic Variants

Inherited retinal degenerations (IRDs) affect approximately 2 to 3 million
people worldwide.The rise of promising treatment approaches has increased
rapidly in recent years, include gene editing and augmentation (early-stage
disease), neuroprotection (mid-stage disease), prosthetics,
optogenetics, and cell therapy to restore some light sensation (late-stage
disease). Despite advancements in therapy development, and a growing number of
interventional trials (https://www.clinicaltrials.gov/) for IRDs, there remain
significant hurdles to designing trials and moving therapy through the
development process. Several papers have reviewed unmet needs and identified
top priorities to move the promise of treatment forward amongst a complex
landscape of IRD research. The common theme among the recommendations is the
vital need for natural history studies, the foundational basis for trial design
and drug development.

IRDs are genetically diverse (280 causative genes have been identified to date)
(https://sph.uth.edu/retnet/) and have vastly different clinical
manifestations, including age of onset, severity of disease, rate of
progression, and structural and functional abnormalities. Understanding this
phenotypic heterogeneity is a major challenge for potential therapy developers.
It is critical to identify genetic factors impacting disease severity and
progression, including the impact of mutation-specific variations within genes.
Natural history data, both longitudinal and cross-sectional, within each gene
population is needed to understand these differences, and ideally these studies
would include enough cases to evaluate a variety of
subgroups across genetic, phenotypic, and environmental factors. The
cornerstone of good trial design is a good endpoint. Identifying the best
candidate endpoint for evaluating progression of disease, and ultimately
treatment effects in a trial, requires consideration of many properties. These
include sensitivity, reproducibility, correlation with other measures of
disease progression, how much within-person change is beyond measurement
variability, and whether within-person change is clinically meaningful. For a
given treatment, the best measure also depends on the expected benefit;
restoration of vision versus slowing of progression. Since IRDs are genetically
diverse, understanding these properties within each gene
is important.

Individual natural history studies for each rare RD gene are not feasible. Many
centers have as few as one (1) - two (2) patients for a particular RD gene and
may not be able to devote resources needed to implement each study. Individual
studies also require considerable startup time (e.g., contracts, IRB/Ethics
Committee approvals) and study management expenses regardless of the number of
patients. A single, universal protocol under which all rare RD genes may be
enrolled would address these inefficiencies. Because of the vast phenotypic
diversity, simultaneous open enrollment of all rare RD genes directly into a
longitudinal natural history study is problematic. Unfocused enrollment efforts
spread across hundreds of genes will dilute timelines for data collection and
analysis objectives within targeted genes. A solution is to create a universal
registry open to all rare RD genes, to cross-sectionally characterize patients
within all rare RD genes (mild, moderate, and severe vision loss) so they are
ready to be enrolled into a subsequent universal longitudinal natural history
study as their gene is selected. This two-phase platform will (1) eliminate
repetitive processes like certification, training, regulatory approval,
contract agreements, (2) reduce costs and accelerate timelines for longitudinal
studies and (3) leverage a large sample size and standardized data collection
in the cross-sectional study to explore the extent to which genes with common
mechanisms of disease have similar clinical manifestations (e.g., determine if
and how some genes may be pooled in some analyses).

Known Potential Risks
Most examination procedures are considered part of standard care for retinal
degenerations. This study will be capturing some information about participants
that include identifiable, personal information, like date of birth (will be
collected if permitted by site*s regulatory bodies). The study has procedures
in place to protect that information. However, there is a chance that a loss of
that protection could occur. This would be a loss of confidentiality. There are
special efforts being made to ensure that this does not happen.
The sections below summarize the risks and discomforts that may be occur during
the period of prospective data collection.
• Risks associated with testing VA, KP, SP, MP, FST, ERG, OCT, and PROs may
include boredom and frustration, but no lasting adverse effects are associated
with these noninvasive tests
• Dilating eye drops will be used as part of the ophthalmic examination and
before some tests. Dilating eye drops may sting, cause light-sensitivity, or an
allergic reaction. There is a small risk of inducing a narrow-angle glaucoma
attack from the pupil dilation. However, all participants will have had prior
pupil dilation usually on multiple occasions and therefore the risk is
extremely small. If glaucoma occurs, treatment is available.
• In rare instances, the cornea may be scratched during measurement of IOP or
use of a contact lens electrode. An abrasion like this may be painful, but it
heals quickly with no lasting effects. If a participant experiences a corneal
abrasion, a tear ointment may be administered, and an eye patch or gauze may be
placed over the eye.

Known Potential Benefits
Study participants are not expected to benefit directly from participation in
this study. Study participants participating in this study may benefit from
close attention from the study personnel and Investigator(s). The risks of
participating in the study are outweighed by the benefits. Benefits include
increased attention from the study personnel and the ability to contribute to
increased understanding of the cross-sectional description and natural history
of retinal degenerations due variants in rare genes, which may contribute to
future development of treatments.

The risk level for this protocol is considered no greater than minimal risk. A
risk-based monitoring approach will be followed, consistent with the FDA
*Guidance for Industry Oversight of Clinical Investigations * A Risk-Based
Approach to Monitoring* (August 2013).