R24EY032434

Restoring Vision with High-Fidelity Nonsense Codon Correction - Project Summary/Abstract

Nonsense mutations cause approximately 15% of genetically inherited retinopathies and inherited human diseases in general, accounting for 2.5 to 3 million patients in the U.S. For certain specific genes, nonsense mutation incidences can be as high as 40%. Because nonsense mutations cause premature termination (PTC) of protein translation, the disease phenotype is often severe.

Currently, there are only a limited number of therapies for nonsense mutations being tested in human clinical trials, including gene therapy, small molecule read-through drugs, or genome editing. Associated challenges equal the promises of each of these therapeutic options. Looking forward, newer technologies may address these hurdles and provide more safe and efficacious treatments for patients.

During protein translation, tRNA functions at the ribosomal site to incorporate a specific amino acid into the polypeptide sequence. We aim to develop the next generation of nucleic acid therapy based on anticodon encoding transfer RNA (ACE-TRNA) that incorporates the correct wild type amino acid at the site of a disease-causing nonsense mutation.

Because of the many anatomical advantages afforded by the eye, we seek to test the broad applicability of ACE-TRNA therapeutics for nonsense mutations that cause retinopathies and related blindness due to defects in a variety of genes, including those encoding ion channel proteins. Specifically, we will focus on nonsense mutation in ion channels expressed in photoreceptors (PR) which convert retinal light inputs and retinal pigment epithelium (RPE), which provide support for PR. These two cell types are primarily the site of blindness pathogenesis.

In this project, we will:
1) Develop ACE-TRNA therapeutics that target specific nonsense mutations across several PR and RPE ion channels.
2) Engineer both viral and non-viral ACE-TRNA delivery systems for long-term editing. Using these, we will determine the functional outcome of ACE-TRNA treatment using cultured cells and human iPSC-derived RPE and iPSC-PR retinal organoids.
3) Test both our viral and non-viral ACE-TRNA in vivo using mice harboring genetic defects that cause blindness in humans; and
4) Assess the safety and bioavailability of ACE-TRNA therapeutics in our preclinical NHP model systems.

There are no FDA-approved therapeutic drugs that target channelopathies because of the complexities associated with precise post-translational modifications, carefully regulated expression, and assembly. Our team's combined expertise in ACE-TRNA development, nanomaterial synthesis, human pluripotent stem cell biology, ion-channel physiology, and pathophysiological model systems is unique and ideally suited to advance ACE-TRNA technology toward clinical trials for a wide range of genetic diseases that cause blindness.

University Of Wisconsin System

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]

Madison, Wisconsin 53715 United States

Single Zip Code

NEI Translational Research Program (TRP) on Therapy for Visual Disorders (R24 Clinical Trial Optional) (PAR-18-707)

Amendment Since initial award the total obligations have increased 437% from $1,454,844 to $7,812,597.