Reformulating NT-Z001 and its delivery route to treat rheumatoid arthritis

PROJECT ABSRACT A significant proportion of rheumatoid arthritis (RA) patients—30-70%—continue to report pain despite treatment with disease-modifying antirheumatic drugs (DMARDs). This persistent pain may be attributed to incomplete inflammation control, post-inflammatory or neuropathic conditions, or mechanisms such as central sensitization. The objective of this SBIR transition grant is to reformulate NT-Z001, an epigenetic gene therapy, to better address the needs of RA patients by enabling localized joint injections instead of the more invasive intrathecal (IT) route. NT-Z001 targets the NaV1.7 sodium channel, a key mediator of pain, offering a novel approach to chronic pain management that could reduce reliance on opioids and other analgesics. By downregulating NaV1.7 expression through AI-designed zinc finger (ZF) proteins fused to a repressor domain, NT-Z001 aims to provide durable pain relief and address inflammation, macrophage infiltration, nerve sprouting, and joint remodeling in RA. NT-Z001's mechanism of action directly interferes with the pain transmission process, offering a targeted alternative that could significantly improve patient quality of life. Preliminary studies have demonstrated NT-Z001's ability to alleviate pain and inflammation in preclinical models mimicking RA pathology. These studies highlight NT-Z001's potential to modulate pain and inflammatory pathways and, importantly, to reduce peripheral nerve sprouting, which contributes to chronic pain in RA. This proposal outlines a plan to reformulate NT-Z001 for intra-articular delivery, evaluating viral (AAV and HSV) approaches to ensure effective localization in the dorsal root ganglia (DRG) after joint injections. The best-performing formulation will be tested in the collagen-induced arthritis (CIA) model of RA, assessing its impact on mechanical allodynia, inflammation, and joint pathology. If successful, this work will enhance NT-Z001's therapeutic potential by offering RA patients a less invasive and more effective option for pain management. Additionally, it could open the door to developing therapies for other chronic pain conditions where intrathecal administration is not a suitable approach.