Osteoarthritis (OA) is a disabling, degenerative disease characterized by progressive cartilage and bone damage. There remains a need for local therapies that, following a single injection, can provide long-term pain relief and functional improvement and potentially delay disease progression. FX201 is a novel, intra-articular (IA), interleukin-1 receptor antagonist (IL-1Ra) gene therapy in development for the treatment of OA. In this study, we assessed the efficacy, biodistribution, and safety of helper-dependent adenovirus (HDAd)-ratIL-1Ra, the rat surrogate of FX201, and the biodistribution of FX201, in the anterior cruciate ligament transection (ACLT) rat OA model. A single IA injection of HDAd-ratIL-1Ra administered 7 days post-ACLT mitigated OA-related changes to cartilage, bone, and the synovial membrane at week 12 following surgery. Furthermore, FX201 and HDAd-ratIL-1Ra persisted for at least 92 days in the injected joint and proximal tissues with minimal evidence of vector spreading peripherally. Finally, HDAd-ratIL-1Ra showed a favorable safety profile without any local or systemic adverse effects. In conclusion, HDAd-ratIL-1Ra demonstrated local therapeutic and disease-modifying effects and was well tolerated, supporting further clinical development of FX201.
Low back pain affects 80% of the population with half of cases attributed to intervertebral disc (IVD) degeneration. However, the majority of treatments focus on pain management, with none targeting the underlying pathophysiological causes. PCRX-201 presents a novel gene therapy approach that addresses this issue. PCRX-201 codes for interleukin-1 receptor antagonist (IL-1Ra), the natural inhibitor of the pro-inflammatory cytokine IL-1, which orchestrates the catabolic degeneration of the IVD. Our objective here is to determine the ability of PCRX-201 to infect human nucleus pulposus (NP) cells and tissue to increase the production of IL-1Ra and assess downstream effects on catabolic protein production.Degenerate human NP cells and tissue explants were infected with PCRX-201 at 0 or 3000 multiplicities of infection (MOI) and subsequently cultured for 5 days in monolayer (n=7), 21 days in alginate beads (n=6) and 14 days in tissue explants (n=5). Cell culture supernatant was collected throughout culture duration and downstream targets associated with pain and degeneration were assessed using ELISA.IL-1Ra production was increased in NP cells and tissue infected with PCRX-201. The production of downstream catabolic proteins such as IL-1β, IL-6, MMP3, ADAMTS4 and VEGF was decreased in both 3D-cultured NP cells and tissue explants.Here, we have demonstrated that a novel gene therapy, PCRX-201, is able to infect and increase the production of IL-1Ra in degenerate NP cells and tissue in vitro. The increase of IL-1Ra also resulted in a decrease in the production of a number of pro-inflammatory and catabolic proteins, suggesting PCRX-201 enables the inhibition of IL-1-driven IVD degeneration. At present, no treatments for IVD degeneration target the underlying pathology. The ability of FX201 to elicit anti-catabolic responses is promising and warrants further investigation in vitro and in vivo, to determine the efficacy of this exciting, novel gene therapy.
using a two-way ANOVA with significance evaluated at p < 0.05 for both bulk tissue and depth-dependent results. Results: Bulk tissue analysis revealed that individually, impact and sliding caused increased chondrocyte death and damage for all assessments, with impact having the greater effect, however the combination further increased cell damage and death (Figure 1A-C). For cell death and apoptosis, the effects of impact and sliding were additive, while for MT depolarization the effect was more than additive (Figure 1C) (p ¼ 0.016 for interaction via two-way ANOVA). Examining the spatial patterns of chondrocyte damage and death (Figure 2A-C) revealed that all treatments resulted in cell damage and death that was highest near the articular surface and decreased with depth from the surface. In controls cell death, apoptosis, and MT depolarization were unaffected deeper in the tissue. Sliding alone resulted in levels of cell death, apoptosis, and MT depolarization that were not different from controls deeper into the tissue (p > 0.05). Impact alone increased cell death, and MT depolarization in the deeper regions of the cartilage compared to controls (p < 0.05). The combination of impact and sliding was nominally higher than either impact or sliding alone, but the interaction was only statistically higher for MT depolarization (Figure 2C). This combination resulted in dramatically higher MT depolarization deeper in the tissue compared to the impact only group (~60% vs~30%, p ¼ 0.005). Conclusions: The goal of this study was to assess the combined effects of two types of loading experienced in joints after trauma. The data show that both impact injury and sliding affect chondrocyte damage. Damage was primarily concentrated at the articular surface, which indicates the surface acts as a protective layer to limit damage propagation deeper into the tissue. Assessments of cell death and apoptosis show additive effects of the combination treatment. However, this combination causes synergistic damage in the assessment of MT depolarization, particularly deeper in the tissue. This population of cells with MT depolarization represents a possible mechanism by which damage propagates to other areas of the tissue and joint. As such this cell population represents a potential target for therapy.
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