Intra-Articular Treatment of Disease-Modifying Nanomedicines for Osteoarthritis
Abstract
FY20 PRMRP Topic Area: Arthritis/Osteoarthritis • Basic and translational research to identify treatments to mitigate and/or reverse osteoarthritis. • Intra-articular treatments that offer sustained (two or more months) relief of symptoms and/or disease-modifying effects. Osteoarthritis (OA) is the most common form of arthritis, affecting more than 30 million in the U.S. alone. It is a substantial burden among Veterans of the U.S. Armed Forces: the military population is associated with a significantly elevated OA incidence; OA is a leading cause of disability and of medical discharge after injury in the military population; OA imposes an annual economic burden exceeding $60 billion. Worse, clinically accepted treatment strategies are often ineffective, and there is over-reliance on opioids. Recent insurance claim data indicate that >50% of OA patients are treated with opioids, and many have become opioid-dependent. Because no OA disease-modifying drug is currently available, there is an urgent need to develop an effective treatment strategy for OA. Local treatment using intra-articular administration of drugs is appropriate and ideal for OA treatment to minimize potential adverse effects that are commonly associated with systemic drug exposure. However, to meet the requirement of local injection in clinical settings, it is essential to reduce the frequency of drug injections. An ideal OA disease-modifying drug should elicit two simultaneous effects: (i) rapid joint pain reduction and (ii) inhibition of cartilage degeneration and OA disease progression. Recent results from our group and others show a dramatic increase in vascular endothelial growth factor (VEGF) expression and new blood vessel formation in joints, both of which strongly correlate with the severity of OA joint pain. Genomic studies reveal that VEGF expression is an OA marker that is strongly associated with painful OA progression in humans. There are multiple VEGF ligands that share redundant and compensatory roles that may contribute to OA progression and pain. Thus, targeting the receptors on which ligands converge may be more effective than targeting individual ligands. Our novel preliminary data show strikingly distinct pathologic roles for VEGF receptors (VEGFRs) during OA progression: VEGFR-1 (known as Flt1) is the major driver of joint pain transmission, and VEGFR-2 (known as Flk1) is primarily responsible for cartilage tissue degeneration in OA, and simultaneous inhibition of Flt1 and Flk1 using pazopanib, a U.S. Food and Drug Administration-approved small molecule inhibitor for both Flt1 and Flk1 showed dual effects: (i) rapid joint pain reduction and (ii) inhibition of cartilage degeneration that promotes gradual cartilage regeneration in our established OA model. We hypothesize (1) that intra-articular administration of drugs targeting both Flt1 and Flk1 simultaneously will elicit dual effects eliciting (a) rapid pain reduction and (b) inhibition of cartilage degeneration, and (2) that a single intra-articular administration of nano-PAZ (nanotechnology-based drug formulation of pazopanib) will provides prolonged drug efficacy for >16 weeks controlling pain and OA disease progression, simultaneously, in our preclinical OA animal models. We will rigorously test our hypotheses with three specific aims. In Aim 1, we will evaluate rapid pain reduction and halted joint pathology by targeting Flt1 and/or Flk1 by weekly intra-articular treatment with either individual monoclonal antibodies (mAbs) or combinations of mAbs over the course of disease progression (inflammatory, early, and advanced OA) in our murine OA models. Our study will validate our initial findings using transgenic mouse model and pharmacologic studies that Flt1 (pain) and Flk1 (cartilage degeneration, pathology) exert distinct roles during OA disease progression. In Aim 2, we will validate the effect of a single intra-articular nano-PAZ treatments as OA disease-modifying drug at
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110549
Entities
People
- Hee-jeong Im Sampen
Organizations
- United States Army
- University of Illinois at Chicago