Albumin-binding RNAi Conjugate for Carrier Free Treatment of Arthritis

Osteoarthritis (OA) and rheumatoid arthritis (RA) are joint diseases that are associated with pain and lost quality of life. No disease modifying OA drugs are currently available. RA treatments are better established but are not always effective and can cause immune suppression. Here, an MMP13-selective siRNA conjugate (Albumin-binding siMMP13<(EG18L)2) was developed that, when delivered intravenously, docks onto endogenous albumin and promotes preferential accumulation in articular cartilage and synovia of post-traumatic OA (PTOA) and RA (K/BxN) joints. MMP13 expression was diminished upon intravenous delivery of MMP13 siRNA conjugates, consequently decreasing multiple histological and molecular markers of disease severity, while also reducing clinical manifestations such as swelling (RA) and joint pressure sensitivity (RA and OA). Importantly, MMP13 silencing provided more comprehensive OA treatment efficacy than standard of care (steroids) or experimental MMP inhibitors. These data demonstrate the utility of albumin ‘hitchhiking’ for drug delivery to arthritic joints, and establish the therapeutic utility of systemically delivered anti-MMP13 siRNA conjugates in OA and RA. For the Osteoarthritis treatment studies, groups are either healthy mice (no osteoarthritis) or subjected to an acute PTOA model of noninvasive, repetitive joint loading by subjecting the knee joints of 8-week-old C57BL/6 mice to 250 cycles of compressive mechanical loading at 9N (adapted from Poulet B, et al. Arthritis and rheumatism. 2011. PubMed PMID: 20882669). This procedure was repeated three times per week over a period of 1 week. PTOA groups were either left untreated or treated with MMP13-specific albumin-binding small interfering RNA (siRNA) conjugate. The knee joints were studied 10 days after treatment with subsequent loading cycles still occurring. For the Rheumatoid Arthritis treatment studies, groups are either healthy mice (no arthritis) or injected with K/BxN serum. K/BxN groups were either left untreated or treated with MMP13-specific albumin-binding small interfering RNA (siRNA) conjugate 2 days after serum transfer. 10 days after serum transfer (8 days after treatment), the hindpaw joints were studied.