Improving Tendon Repair via Sensory Nerve NGF-TrkA Signaling for Retention on Duty
Abstract
The proposed project directly relates to the FY19 PRORP ARA Focus Area of Retention on Duty Strategies, including “Interventions and/or rehabilitation strategies that can facilitate retention on duty for common combat-related musculoskeletal injuries.” Major tendon injuries represent a significant source of morbidity for military trainees, combat casualties, and military Veterans. Tendonitis or other tendon injuries represent a significant source of delay in military training. For example, in one long-term observational study following 80,106 active-duty personnel for 1 year, 450 cases of Achilles tendonitis and 584 cases of patellar tendinopathy were identified. Furthermore, once injured, a tendon is predisposed to further injury, which sets up the patient for risk of chronic pain, psychosocial distress, and future disability. Better understanding of the pathophysiology of tendon repair will lead to more efficacious treatment strategies. This would represent a high impact on both individual and socioeconomic levels among military and civilian populations. Nerve fibers terminate at the surfaces of tendons and interact with the tendon during homeostasis and repair. The most familiar and best-understood function of sensory nerves is pain sensation, which is profoundly apparent following tendon injury. The central mediator of pain sensation is NGF (nerve growth factor), which transmits nociceptive signals either by directly activating TrkA (Tropomyosin receptor kinase A) sensory neurons or through indirect mechanisms. In addition to pain sensation, a body of literature suggests an evolutionarily conserved role of nerves in tissue regeneration. For example, the regeneration of a starfish appendages, fish fins, amphibian limbs, and deer antlers are all critically dependent on concomitant nerve regeneration. Clinical observations suggest that an important neural influence on tendon repair, for example in patients with spinal cord injury, sciatica, or diabetic neuropathy who exhibit higher rates of tendon degeneration or tendon rupture. Our new preclinical animal models suggest a paradigm where NGF signaling after tendon injury elicits TrkA-expressing nerve ingrowth, which is essential for later stages in tendon repair. Applicability and Impact: Potential clinical applications of this proposal include prevention of tendon degeneration, as well as improvements in tendon repair. Gambogic amide (GA) is a naturally occurring TrkA agonist and has been used for years in humans, as it is the major active ingredient within a traditional Chinese herbal preparation. It was only recently that a chemical-genetic screen identified the mechanism of action of GA via TrkA agonism. We hypothesize that this novel intervention will improve extremity reinnervation and tendon regeneration and repair. Second, if our hypothesis regarding the role of tendon-associated nerve fibers is correct, another class of drugs may be opened up that prevents the progression of peripheral neuropathy (such as in diabetes). Thus, at-risk tendon-injury populations based on the presence of existing neuropathy would undergo prophylactic treatment, especially during injury-prone time periods such as military training. Overall, better treatment options for tendon and ligamentous injuries would impact approximately 17 million individuals yearly in the U.S. alone, with an estimated economic cost of over $40 billion. Timeline for Clinical Application: GA is a naturally occurring, readily translatable, selective TrkA agonist that has already demonstrated preclinical safety and efficacy across several mouse and rat models. As such, IND-enabling studies would be expected to commence at the termination of the proposed study. Both Drs. James and Levi have experience with the patent process, as demonstrated by previously filed patents for therapies to improve extremity healing in military relevant processes.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010795
Entities
People
- Aaron W James
Organizations
- Johns Hopkins University
- United States Army