Center for Restoration of Nervous System Function

Va Connecticut Healthcare System, West Haven CT

Investigators

Linked publications & trials

Abstract

Chronic pain and spasticity are major unmet needs within the VA. Since our discovery of Nav1.7 as a “master switch” for pain in humans, the biopharma industry has invested more than $1 billion in development of Nav1.7 blockers. That work is continuing with the development of 2nd-generation blockers that build on our initial efforts (Cao et al., 2016) and the targeting of Nav1.8 which functions in concert with Nav1.7. We are committed to more effective, non-addictive treatments for pain and spasticity in Veterans and are taking a “multiple shots on goal approach” through the following novel efforts. Research Program I: Pain Pharmacogenomics. A. Pain Resilience—Why do some people experience severe pain after injury, while others feel little or no pain? We have begun to use our innovative platform of patient-specific stem cells to identify genes that confer resilience to pain. Thus far we have identified Kv7.2 and Kv7.3 channels as strong modulators of pain and are analyzing KCNK18. These are potentially druggable targets. Going forward we will analyze the effect of pharmacological agents on these protective channels as a prelude to clinical studies. B. Limb Amputation & Phantom Limb Pain in Veterans—Building upon our success in identifying genetic risk factors in patients with painful neuropathy, trigeminal neuralgia and ocular pain, we now plan to identify genetic risk factors in Veterans with limb amputation and phantom limb pain (Hannon Act Sect. 305) as a prelude to larger-scale studies in Veterans that capitalize on the MVP database. Research Program II: Accelerating Toward Improved Pain Pharmacotherapy. A. Chemotherapy- Induced Pain—We have demonstrated that chemotherapy affects sensory neurons in a drug-dependent manner and are building a unique collection of animal models to advance this research, which has important implications for Veterans with CIPN. We are also evaluating cannabinoids as a therapy for CIPN. B. Osteoarthritis—We are advancing an entirely new approach to treatment of osteoarthritis (OA), an unmet need in Veterans, having demonstrated that Nav1.7 is upregulated within human OA chondrocytes and contributes to disease progression. We are now elucidating the actions of Nav1.7 in OA and assessing Nav blockers in animal models and human tissue to attenuate pain and slow disease progression in OA. C. Novel Discovery Platforms—We are developing innovative stem cell technology platforms, powerful methods to visualize transport of single ion channels, and high-throughput assays for drug screening. Research Program III: New Treatments for Spasticity. We have uncovered ventral horn dendritic spine dysgenesis as a strong contributor to spasticity following SCI, validated Rac1-Pak1 pathway as a novel target, and are evaluating the repurposing of FDA-approved Romidepsin to inform human clinical trials (provisional patent filed through VA TTS). We are developing powerful new methods—intravital visualization of dendritic spines via spinal cord window implants, high-resolution two-photon microscopy, and virtual reality integration, to utilize spine dysgenesis as a biomarker as we progress our animal studies toward human clinical trials. Research Program IV: Targeting Nav1.7 through RNA Editing. Advancing in a multi-pronged approach to feed the translational pipeline to novel, effective non-addictive treatments for pain, we are developing RNA editing as a novel approach to target Nav1.7, which remains one of the best validated targets for chronic pain. Research Program V: Targeting Nav1.8 with Repurposed Drugs. Advancing in a multi-pronged approach to feed the translational pipeline to novel, effective non-addictive treatments for pain, we are evaluating the repurposing of two drugs, Dexpramipexole (DEX) and Ambroxol. Ambroxol is known to block Nav1.8, which works with Nav1.7 to control the firing of pain-signaling neurons. We have shown that DEX blocks Nav1.8 and reduces pain in several animal models. We will now assess DEX and Ambroxol in a head-to-head comparison as a prelude to a clinical study using one or the other for the treatment of chronic pain.