UG3NS142998

A small molecule PROTAC for macular degeneration - Abstract

Age-related macular degeneration (AMD) and related macular dystrophies (MDS) are leading causes of adult blindness with limited treatment options.

AMD/MDS can present in two forms, geographic atrophy/GA (dry form) and choroidal neovascularization/CNV (wet form).

There is strong evidence linking sterile inflammation to AMD/MD pathogenesis and two complement pathway inhibitors are already approved by FDA for treating GA in the dry form of AMD.

However, due to limited therapeutic impact and adverse effects of complement inhibitors and other approved drugs for both dry AMD and wet AMD, there is a significant need for novel therapies for AMD/MDS.

Our recently published data and preliminary studies identified secretory phospholipase A2-IIA (SPLA2-IIA), a pro-inflammatory enzyme, as a key molecular player in AMD/MD pathogenesis.

AMD/MD primarily affect the retinal pigment epithelium (RPE) cells in the eye and patient-derived induced pluripotent stem cell-RPE (iRPE) from AMD and 2 distinct MDS showed elevated levels of SPLA2-IIA.

Furthermore, AMD/MD iRPE cultures and AMD donor eyes showed elevated SPLA2-IIA levels in drusen, a pathological hallmark of early AMD/MD that is the key driver of later stage pathologies in AMD/MDS.

Notably, pharmacological modulation of SPLA2-IIA activity in AMD and MD iRPE cultures led to reduced drusen.

In addition, directly linking elevated SPLA2-IIA activity to AMD/MD pathology, SPLA2-IIA overexpression led to AMD-associated pathological alterations (drusen, Bruch’s membrane thickening, RPE thinning, CNV and visual deficits) in C57BL/6J mice.

Altogether, these studies provide a strong rationale for targeting SPLA2-IIA activity in AMD/MDS.

Toward this goal, we propose to develop proteolysis-targeting chimeras (PROTAC) compounds for specific inhibition of SPLA2-IIA in AMD/MDS.

In initial experiments, we have synthesized a ‘lead‘ PROTAC (UR-00059) that can induce degradation of SPLA2-IIA in iRPE cells with half-maximal degradation concentration DC50 of 295.5 nM.

The following milestone-driven aims will allow us to develop an effective PROTAC-based therapy targeting SPLA2-IIA for AMD/MDS.

Aim 1: Optimize UR-00059 structure and activity and characterize the target engagement in vivo;

Aim 2: Conduct in vivo efficacy studies and non-GLP absorption, distribution, metabolism, and toxicology of UR-00059;

Aim 3: Perform IND enabling studies and obtain FDA approval for human testing.

Ultimately, the proposed studies will develop a novel PROTAC-based therapy for targeting inflammation, drusen and consequently late stage pathologies of AMD and related MDS.

University Of Rochester

(1) TO SUPPORT EXTRAMURAL RESEARCH FUNDED BY THE NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE (NINDS) INCLUDING: BASIC RESEARCH THAT EXPLORES THE FUNDAMENTAL STRUCTURE AND FUNCTION OF THE BRAIN AND THE NERVOUS SYSTEM, RESEARCH TO UNDERSTAND THE CAUSES AND ORIGINS OF PATHOLOGICAL CONDITIONS OF THE NERVOUS SYSTEM WITH THE GOAL OF PREVENTING THESE DISORDERS, RESEARCH ON THE NATURAL COURSE OF NEUROLOGICAL DISORDERS, IMPROVED METHODS OF DISEASE PREVENTION, NEW METHODS OF DIAGNOSIS AND TREATMENT, DRUG DEVELOPMENT, DEVELOPMENT OF NEURAL DEVICES, CLINICAL TRIALS, AND RESEARCH TRAINING IN BASIC, TRANSLATIONAL AND CLINICAL NEUROSCIENCE. THE INSTITUTE IS THE LARGEST FUNDER OF BASIC NEUROSCIENCE IN THE US AND SUPPORTS RESEARCH ON TOPICS INCLUDING BUT NOT LIMITED TO: DEVELOPMENT OF THE NERVOUS SYSTEM, INCLUDING NEUROGENESIS AND PROGENITOR CELL BIOLOGY, SIGNAL TRANSDUCTION IN DEVELOPMENT AND PLASTICITY, AND PROGRAMMED CELL DEATH, SYNAPSE FORMATION, FUNCTION, AND PLASTICITY, LEARNING AND MEMORY, CHANNELS, TRANSPORTERS, AND PUMPS, CIRCUIT FORMATION AND MODULATION, BEHAVIORAL AND COGNITIVE NEUROSCIENCE, SENSORIMOTOR LEARNING, INTEGRATION AND EXECUTIVE FUNCTION, NEUROENDOCRINE SYSTEMS, SLEEP AND CIRCADIAN RHYTHMS, AND SENSORY AND MOTOR SYSTEMS. IN ADDITION, THE INSTITUTE SUPPORTS BASIC, TRANSLATIONAL AND CLINICAL STUDIES ON A NUMBER OF DISORDERS OF THE NERVOUS SYSTEM INCLUDING (BUT NOT LIMITED TO): STROKE, TRAUMATIC INJURY TO THE BRAIN, SPINAL CORD AND PERIPHERAL NERVOUS SYSTEM, NEURODEGENERATIVE DISORDERS, MOVEMENT DISORDERS, BRAIN TUMORS, CONVULSIVE DISORDERS, INFECTIOUS DISORDERS OF THE BRAIN AND NERVOUS SYSTEM, IMMUNE DISORDERS OF THE BRAIN AND NERVOUS SYSTEM, INCLUDING MULTIPLE SCLEROSIS, DISORDERS RELATED TO SLEEP, AND PAIN. PROGRAMMATIC AREAS, WHICH ARE PRIMARILY SUPPORTED BY THE DIVISION OF NEUROSCIENCE, ARE ALSO SUPPORTED BY THE DIVISION OF EXTRAMURAL ACTIVITIES, THE DIVISION OF TRANSLATIONAL RESEARCH, THE DIVISION OF CLINICAL RESEARCH, THE OFFICE OF TRAINING AND WORKFORCE DEVELOPMENT, THE OFFICE OF PROGRAMS TO ENHANCE NEUROSCIENCE WORKFORCE DEVELOPMENT, AND THE OFFICE OF INTERNATIONAL ACTIVITIES. (2) TO EXPAND AND IMPROVE THE SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE 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. TO UTILIZE THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM, TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND 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 Institute of Neurological Disorders and Stroke (NNDS) [HHS - NIH]

National Eye Institute (NEI) [HHS - NIH]

Rochester, New York 146113847 United States

Single Zip Code

Blueprint Neurotherapeutics Network (BPN): Small Molecule Drug Discovery and Development of Disorders of the Nervous System (UG3/UH3 Clinical Trial Optional) (PAR-25-051)