R24EY032440

Immunotherapy for Ocular Surface Diseases - Abstract

We have discovered a new mechanism for inflammation on the ocular surface. First, we discovered the presence of neutrophil extracellular traps (NETs) on the ocular surface of dry eye disease (DED) patients. Subsequently, we found the presence of citrullinated proteins and anti-citrullinated protein antibodies (ACPAs). ACPAs not only cause ocular surface disease but also stimulate the formation of NETs, creating a self-perpetuating cycle of chronic inflammation on the ocular surface.

We present an innovative pathophysiological concept: DED is characterized by a breach of self-tolerance towards citrullinated antigens, leading to the generation of autoantibodies (ACPAs). NETs could represent a source of citrullinated antigens that fuel the ACPA autoimmune response over the ocular surface.

We performed a first-in-human pilot clinical trial and demonstrated that ocular surface immune globulin (OSIG) eye drops, formulated from pooled human immune globulin products (IVIG), were safe and effective in treating DED patients. Our findings shift the current paradigm, which focuses on T-cell mediated inflammation as central to the pathophysiology of DED, to also include autoimmune inflammation driven by post-translational modifications in self-proteins (citrullination) and autoantibodies (ACPAs).

The purpose of this R24 application is to produce preclinical data that supports a commercial investigational new drug (IND) application to the U.S. Food and Drug Administration (FDA). The longer-term goal is to test the efficacy of OSIG eye drops in clinical trials and position them as a new topical biologic immunotherapy for DED patients.

Therefore, in Aim A, we seek to develop an optimum OSIG eye drop formulation using Quality by Design (QBD) principles, test critical quality attributes (CQAs), and manufacture clinical supplies following Good Manufacturing Practices (GMP). In order to use the OSIG ophthalmic formulation in humans, an FDA IND is a prerequisite. Therefore, in Aim B, we propose to perform preclinical in vitro and in vivo toxicology and efficacy studies using the OSIG ophthalmic formulation to meet regulatory requirements for IND studies.

In Aim C, we propose to conduct a clinical study to identify DED subtypes, clinical presentations, and patient characteristics that are most associated with ACPAs or NETs, and hence most likely to show therapeutic benefit with OSIG therapy.

To successfully achieve these three aims, we have established a highly qualified, multi-disciplinary team experienced in ophthalmic drug development, FDA processes, and regulations.

If the aims of this grant proposal are successfully achieved, we will be one step closer to introducing the first immunotherapy for ocular surface diseases into clinical practice.

University Of Illinois

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]

Illinois United States

State-Wide

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

Amendment Since initial award the End Date has been extended from 12/31/25 to 12/31/26 and the total obligations have increased 284% from $2,163,291 to $8,312,140.