Treatment of knee osteoarthritis via intra-articular delivery of an immunosuppressive enzyme
Active Project Grant Awarded Last action
- Award ID
- R01AR079874
- Recipient
-
University Of Florida UEI NNFQH1JAPEP3
- Awarding agency
-
National Insititue of Arthritis and Musculoskeletal and Skin Diseases
National Institutes of Health, Department of Health and Human Services
- Obligated
- $6,057,670
Award facts
- Assistance listing
- 93.846 Arthritis, Musculoskeletal and Skin Diseases Research
- Completion date 91% complete
- Place of performance
- Gainesville, FL 32611, USA
Award details come from USAspending.gov.
Description
- Abstract
- In osteoarthritis (OA), intra-articular inflammation is a key mediator of joint destruction and chronic joint pain. Unfortunately, current strategies to control joint inflammation have largely failed. 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 immunosupressive 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 and thereby create 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 via a novel tissue anchoring approach. Morever, because tissue-anchored IDO does not need to release to generate anti-inflammatory signals, the anchored IDO will continue to produce anti-inflammatory kyneurenines 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? And, 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.
Transactions
| Action | Obligated | Date |
|---|---|---|
| Amendment | $30,448 | |
| Amendment | $548,041 | |
| Amendment | $548,041 | |
| Amendment | $601,474 | |
| Amendment | $44,033 | |
| Amendment | $44,033 | |
| Amendment | $566,158 | |
| Amendment | $566,158 | |
| Amendment | $566,158 | |
| Amendment | $630,406 | |
| Amendment | $630,406 | |
| Amendment | $630,406 | |
| Original award | $651,908 |
Show all 13
Subawards
| Subrecipient | Amount | Awarded |
|---|---|---|
| Montana State University | $77,928 | |
| North Florida Foundation For Research And Education, Inc. | $68,196 | |
| Montana State University | $77,928 | |
| North Florida Foundation For Research And Education, Inc. | $40,422 | |
| Montana State University | $252,550 |
Quick answers
Who received award R01AR079874?
R01AR079874 was awarded to University Of Florida by National Insititue of Arthritis and Musculoskeletal and Skin Diseases (National Institutes of Health) on April 1, 2022.
How much is award R01AR079874 worth?
$6,057,670 has been obligated on R01AR079874.
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