Development of Nav channel targeting antisense oligonucleotides as chronic pain therapeutics using an integrated platform based on machine learning and optical electrophysiology

About This Grant

Project Summary: Development of Nav channel targeting antisense oligonucleotides as chronic pain therapeutics using an integrated platform based on machine learning and optical electrophysiology Effective treatment of chronic pain, including severe neuropathic pain conditions, such as erythromelalgia (EM) and small fiber neuropathy (SFN), remains a significant unmet medical need. Current therapies often lack full efficacy or come with serious risk, such as addiction associated with opioids. Antisense oligonucleotides (ASOs) offer a promising solution by knocking down specific mRNA transcripts with a long duration of action (~3 months) for sustained relief. ASOs have been successfully applied to patients to treat severe neurological disease. Here, we propose to develop an ASO therapeutic targeting the voltage-gated sodium channel, Nav1.7, which is highly expressed in dorsal root ganglion (DRG) neurons. Nav1.7 is a target with strong human genetics validation in pain transmission, including neuropathic pain. Reduction of channel expression via a therapeutic ASO may overcome the challenges of small molecules by mimicking the mechanism for congenital insensitivity to pain (CIP) resulting from hNav1.7 loss-of-function mutations. Administering the ASO via intrathecal (IT) injection will enable precise knockdown of Nav1.7 expression in DRG tissues in a state-independent manner with minimal risks for autonomic side effects, paving the way for an effective and targeted chronic pain therapy. To enable the selection of a Nav1.7 specific ASO with the desired profiles, Quiver has developed breakthrough technologies: (i) high throughput readout of neuronal excitability based on all-optical electrophysiology, (ii) combination of patient genetics and state-of-the-art human iPSC sensory neuron differentiation protocol for pain therapeutics validation in patient-based models, and (iii) a machine learning-guided ASO design and discovery platform for identifying the best ASO candidates with maximum therapeutic index. As an entry point, Quiver has identified a potent and selective hNav1.7 lead ASO (QV-2421) with confirmed activity in primary DRG neurons from relevant species and a clean in vivo CNS tolerability profile through in sillico prediction and empirical validation. In the UG3 phase, we will apply our breakthrough technology in combination with well-established preclinical assays to optimize the ASO lead. Quiver will collaborate with Boston Children's Hospital (BCH) to validate the functional impact of the lead ASO in sensory neurons derived from EM/SFN patients with neuropathic pain conditions. We will also evaluate long term in vivo tolerability and investigate translational biomarker approaches. Based on these studies, we aim to select one optimized ASO lead candidate with an acceptable tolerability profile and in vivo NHP PK/PD data profile by the end of the UG3 phase. In the UH3 phase, we will conduct dose-range finding toxicology studies, establish clinical biomarkers, perform large-scale manufacturing of the ASO candidate for IND-enabling studies, and initiate a Phase I clinical trial in young adult EM patients. The UH3 phase will conclude with the identification of an ASO candidate with an acceptable toxicology and preclinical profile that is advanced through IND-submission to enable the initiation of Phase I clinical trial. Our ultimate goal is to deliver a much-needed, non-opioid therapy to patients suffering from severe, chronic pain.