U24EY033275

Accelerating Photoreceptor Replacement Therapy with In-Vivo Cellular Imaging of Retinal Function - Abstract

To restore high-quality, usable vision in patients, it is important to develop regenerative therapies in models that share key features of the human visual system, particularly a fovea, the retinal area specialized for high acuity vision.

Pre-clinical testing has been challenging due to both the absence of models of foveal vision loss and the difficulty of demonstrating restored function. Under previous AGI funding, the Advanced Retinal Imaging Alliance at the University of Rochester has recently overcome these challenges to create a pre-clinical testing platform leveraging adaptive optics technology. This platform aims to:

1. Create localized regions of photoreceptor ablation in the fovea that are axially confined.
2. Optically read out restored retinal ganglion cell function by performing cellular-scale calcium imaging in the living eye.

This system was developed to meet the needs of photoreceptor replacement therapy, which requires photoreceptor loss with preserved host retinal circuitry. Furthermore, a high-resolution in vivo imaging approach is well-suited for pre-clinical evaluation of regenerative therapies where the timescales of restored connectivity are unknown and functional integration occurs on the cellular scale.

In this proposal, we will use our platform to generate pre-clinical data that will inform future clinical trials of photoreceptor replacement therapy in patients.

Functional integration of transplanted photoreceptors with the host retina requires both high-density delivery of high-quality donor photoreceptors and a host retina with the capacity for synaptogenesis. We have assembled a consortium that can explore and optimize both sides of this interaction.

In continued collaboration with a team at the University of Wisconsin led by David Gamm, a clinician and expert in photoreceptor replacement therapy, we will evaluate survival and functional integration of transplanted photoreceptor precursors delivered to the sub-retinal space as aggregates or following incorporation into custom biodegradable scaffolds.

In collaboration with a team at the University of California, Berkeley led by Teresa Puthussery, an expert in retinal remodeling in retinal degeneration models and retinal histology, we will examine the impact of the loss of photoreceptor signaling on the inner retina. We will explore whether deafferented cone bipolar cells can remodel and functionally integrate with donor photoreceptors and whether retinal hyperactivity develops in the fovea as it does in rodents.

To make meaningful progress toward restoring vision in patients who have lived with vision loss for many years, we will examine how these phenomena develop in the fovea over time and whether the regenerative potential of the host can be improved by therapeutic interventions such as retinoic acid blockers.

These studies will allow us to fully characterize our novel photoreceptor ablation model and deploy it with photoreceptor replacement therapies to advance the field toward clinical trials.

University Of Rochester

1) TO SUPPORT EYE AND VISION RESEARCH PROJECTS THAT ADDRESS THE LEADING CAUSES OF BLINDNESS AND IMPAIRED VISION IN THE U.S. THESE INCLUDE RETINAL DISEASES, CORNEAL DISEASES, CATARACT, GLAUCOMA AND OPTIC NEUROPATHIES, STRABISMUS, AMBLYOPIA, AND LOW VISION AND BLINDNESS REHABILITATION. 2) TO INCREASE UNDERSTANDING OF THE NORMAL DEVELOPMENT AND FUNCTION OF THE VISUAL SYSTEM IN ORDER TO BETTER PREVENT, DIAGNOSE, AND TREAT SIGHT-THREATENING CONDITIONS, AND, TO ENHANCE THE REHABILITATION, TRAINING, AND QUALITY OF LIFE OF INDIVIDUALS WHO ARE PARTIALLY-SIGHTED OR BLIND. 3) TO SUPPORT A BROAD PROGRAM OF BASIC VISION RESEARCH THROUGH GRANTS AND COOPERATIVE AGREEMENTS, TO ENCOURAGE HIGH QUALITY CLINICAL RESEARCH, INCLUDING CLINICAL TRIALS, OTHER EPIDEMIOLOGICAL STUDIES, AND HEALTH SERVICES RESEARCH, TO ENCOURAGE RESEARCH TRAINING AND CAREER DEVELOPMENT IN THE SCIENCES RELATED TO VISION, AND TO SPONSOR SCIENTIFIC WORKSHOPS IN HIGH PRIORITY RESEARCH AREAS TO ENCOURAGE EXCHANGE OF INFORMATION AMONG SCIENTISTS. 4) SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO ENCOURAGE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.867 - Vision Research

National Eye Institute (NEI) [HHS - NIH]

New York United States

State-Wide

NEI Audacious Goals Initiative: Translation-Enabling Models to Evaluate Survival and Integration of Regenerated Neurons in the Visual System (U24 Clinical Trial Not Allowed) (RFA-EY-20-001)

Amendment Since initial award the total obligations have increased 365% from $1,233,185 to $5,733,511.