R01AR079874

Treatment of Knee Osteoarthritis via Intra-Articular Delivery of an Immunosuppressive Enzyme - Project Summary

In osteoarthritis (OA), intra-articular inflammation plays a crucial role in joint destruction and chronic joint pain. Unfortunately, current strategies to control joint inflammation have been largely unsuccessful. To address this challenge, our team is developing an innovative metabolic reprogramming strategy for the treatment of knee OA.

In our strategy, indoleamine 2,3-dioxygenase (IDO), an immunosuppressive enzyme, will be intra-articularly delivered to catabolize tryptophan into kynurenines. Based on IDO's effect in other tissues, this redirection of tryptophan metabolism will likely drive the polarization of joint-level immune cells toward an anti-inflammatory state. Importantly, our strategy differs from other intra-articular delivery strategies for protein and synthetic drugs, as our enzyme will continuously produce anti-inflammatory metabolites in the OA-affected joint, creating prolonged anti-inflammatory effects that potentially reset immune homeostasis in the joint.

However, while IDO can continuously produce anti-inflammatory metabolites, free IDO is subject to joint clearance. To address this challenge, we will also fuse IDO to a carbohydrate-binding protein, thereby extending IDO's joint residence time through a novel tissue anchoring approach. Moreover, because tissue-anchored IDO does not need to release to generate anti-inflammatory signals, the anchored IDO will continue to produce anti-inflammatory kynurenines without the need for our 'drug' (IDO) to release and bind a specific target.

Our preliminary data demonstrate that tryptophan metabolism is altered in both human OA and rodent models, our tissue anchoring strategy can extend the residence time of an enzyme from a few days to over 4 weeks, and that intra-articular delivery of an IDO fusion protein can shift tryptophan metabolism, reduce inflammation, and reverse pain-related behaviors in a rat knee OA model.

As such, this R01 proposal seeks to evaluate intra-articular delivery of an IDO fusion protein as a therapeutic strategy to control joint inflammation and reduce OA-related pathological remodeling after trauma (Aim 1) and after the onset of chronic OA symptoms (Aim 2). To achieve these aims, our team will integrate expertise in metabolic profiling, immune engineering, joint histology, and rodent behavioral analyses.

Specifically, this R01 will address the following scientific questions:

1) How is joint metabolism altered by intra-articular delivery of an IDO fusion protein?
2) How is the local regulation of the immune system within the joint altered by an intra-articular injection of an IDO fusion protein?
3) Do IDO-induced metabolic shifts affect other joint tissues as well?
4) Can intra-articular injection of an IDO fusion protein stall the onset of post-traumatic OA after medial meniscus injury?
5) Can intra-articular delivery of an IDO fusion protein reverse OA-related pain and disability, even in the context of irreparable joint damage?

Answering these questions will be important for understanding the translational risks of our IDO fusion protein, as well as for refining metabolic reprogramming strategies for OA treatment in the future.

University Of Florida

THE NATIONAL INSTITUTE OF AND MUSCULOSKELETAL AND SKIN DISEASES (NIAMS) MISSION IS TO SUPPORT RESEARCH INTO THE CAUSES, TREATMENT, AND PREVENTION OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES, TRAINING OF BASIC AND CLINICAL SCIENTISTS TO CARRY OUT THIS RESEARCH, AND DISSEMINATION OF INFORMATION ON RESEARCH PROGRESS IN THESE DISEASES. THE EXTRAMURAL PROGRAM PROMOTES AND SUPPORTS BASIC, TRANSLATIONAL, AND CLINICAL STUDIES OF SYSTEMIC RHEUMATIC AND AUTOIMMUNE DISEASES, SKIN BIOLOGY AND DISEASES, BONE BIOLOGY AND DISEASES, MUSCLE BIOLOGY AND DISEASES, AND JOINT BIOLOGY AND DISEASES AND ORTHOPAEDICS. NIAMS SYSTEMIC RHEUMATIC AND AUTOIMMUNE DISEASES PROGRAMS ADDRESS BASIC, TRANSLATIONAL, AND CLINICAL RESEARCH, INCLUDING CLINICAL TRIALS AND OBSERVATIONAL AND MECHANISTIC STUDIES, FOCUSED ON IMMUNE-MEDIATED ARTHRITIS AND AUTOIMMUNE-RELATED ACUTE AND CHRONIC DISORDERS IN ADULTS AND CHILDREN. NIAMS SKIN BIOLOGY AND DISEASES PROGRAMS SUPPORT BASIC, TRANSLATIONAL, AND CLINICAL RESEARCH IN SKIN, INCLUDING BOTH COMMON AND RARE SKIN DISEASES. THESE PROGRAMS INCLUDE INVESTIGATIONS OF THE BASIC MOLECULAR, CELLULAR, AND DEVELOPMENTAL BIOLOGY OF SKIN, AS WELL AS STUDIES OF SKIN AS AN IMMUNE, SENSORY, ENDOCRINE, AND METABOLIC ORGAN. NIAMS BONE BIOLOGY AND DISEASES PROGRAMS SUPPORT RESEARCH ON THE CONTROL OF BONE FORMATION, RESORPTION, AND MINERALIZATION AS WELL AS THE EFFECTS OF SIGNALING MOLECULES ON BONE CELLS. THEY SUPPORT CLINICAL STUDIES OF INTERVENTIONS TO PREVENT FRACTURES ASSOCIATED WITH OSTEOPOROSIS AND RESEARCH INTO LESS COMMON BONE DISEASES. NIAMS MUSCLE BIOLOGY AND DISEASES PROGRAMS ENCOURAGE RESEARCH ON MUSCLE DEVELOPMENTAL BIOLOGY, GROWTH, MAINTENANCE, AND HYPERTROPHY, PHYSIOLOGY OF CONTRACTION, STRUCTURAL BIOLOGY OF THE CONTRACTILE APPARATUS, DISEASE MECHANISMS, BIOMARKERS AND OUTCOME MEASURES, AND DEVELOPMENT AND CLINICAL TESTING OF THERAPIES FOR CONDITIONS INCLUDING THE MUSCULAR DYSTROPHIES. NIAMS JOINT BIOLOGY, DISEASES, AND ORTHOPAEDICS PROGRAMS SUPPORT A BROAD SPECTRUM OF RESEARCH CENTERED ON THE INTERPLAY AMONG THE BODY'S MUSCLES, BONES, AND CONNECTIVE TISSUES. THEY ENCOURAGE TISSUE ENGINEERING AND REGENERATIVE MEDICINE RESEARCH, MOLECULAR BIOLOGY, IMAGING, AND CLINICAL RESEARCH, AND THE TREATMENT AND PREVENTION OF ORTHOPAEDIC CONDITIONS. NIAMS PARTICIPATES IN THE SMALL BUSINESS INNOVATION RESEARCH (SBIR) AND SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAMS. THE SBIR PROGRAM IS INTENDED 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. THE STTR PROGRAM IS INTENDED 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.

93.846 - Arthritis, Musculoskeletal and Skin Diseases Research

National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) [HHS - NIH]

Gainesville, Florida 326110001 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 367% from $651,908 to $3,042,020.