Validation of Novel Target for OA Treatment

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ABSTRACT: Osteoarthritis (OA) affects nearly 100 million Americans. It is the most common form of arthritis and a leading cause of pain and disability. Prevalence and incidence of the disorder are predicted to increase because of increased lifespan and obesity. Symptomatic treatments are often ineffective, and/or associated with severe side effects 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. Despite the fact that OA is a leading cause of disability, and imposes an annual economic burden exceeding $60 billion, there is no way as yet to cure OA or prevent its progression. There is an urgent need to identify and validate therapeutic targets for pain (symptom) management and to decrease disease progression. Results from our group and others show a dramatic increase in vascular endothelial growth factor (VEGF) expression and in new blood vessel formation in joints, both of which strongly correlate with the severity of OA joint pain. Also, genomic studies reveal that vegf expression is strongly associated with symptomatic OA progression in humans. FDA approval of several inhibitors of the VEGF pathway (i.e., for cancer treatment) has enabled significant advances in the therapy of diseases related to pathological angiogenesis. However, there are multiple VEGF ligands with redundant and compensatory roles that may contribute to OA progression and pain. Thus, targeting individual ligands may be less efficacious than targeting receptors. Specifically, VEGF ligands signal via two receptors, VEGFR-1 (known as Flt1) and VEGFR-2 (known as Flk1). Our central hypothesis is that because VEGFR-2/Flk1 is primarily responsible for cartilage tissue degeneration in OA, and VEGFR-1/Flt1 is the major driver of joint pain transmission, targeting both Flt1 and Flk1 simultaneously elicits dual function: (i) immediate symptom alleviation and (ii) inhibition of cartilage tissue degeneration. Thus, both disease progression and pain are halted. To rigorously validate our target, we will: 1) Use different types of target inhibitors - mAbs targeting Flt1 (by mAb MF1) and/or Flk1 (by mAb DC101) or pazopanib, an FDA-approved small inhibitor molecule for Flt1 and Flk1 currently being used for cancer treatment; 2) Use different species, different OA models and both male and female subjects using a Tg mouse model, two different mouse and rat OA models, and two different dog OA models; 3) Replicate the work in multiple laboratories; and 4) Test abuse liability of target engagement. The findings from our rigorous validation studies will take the field of OA research a giant step forward by developing a novel strategy for treating OA and joint pain effectively and safely in our pre-clinical OA animal model; and, in the longer term, by providing a rationale for clinical trials targeting Flt1 and Flk1 to treat OA patients.