Funded Projects

Opioids are widely used pain treatments, despite their relative ineffectiveness for chronic pain and their high potential for misuse and addiction. There is thus an urgent need for alternative, non-addictive pain treatments. Genetic and functional studies of human pain disorders and animal models of pain have validated Nav1.7, a voltage-gated sodium channel as an attractive target for new pain treatments. Currently available blockers of these channels can sometimes provide symptomatic relief for patients but have worrisome side effects affecting the brain and heart. This study aims to develop and validate an innovative site-directed RNA editing strategy that will offer the ability to create new versions of molecules to block Nav1.7, toward establishing a novel, non-addictive approach to treat chronic pain.

Cholecystokinin B receptor (CCKBR) is a molecule found in the brain that helps regulate anxiety and depression but also influences the development of tolerance to opioids. CCKBR levels are also increased in models of nerve injury-induced (neuropathic) pain. Therefore, targeting CCKBR may offer a new approach to treating neuropathic pain and the associated anxiety and depression. Researchers have developed mouse antibodies that can inactivate CCKBR. However, to be usable in humans without causing an immune response, these antibodies need to be modified to include more human sequences. This project will use a fragment of the CCKBR antibody, modify it with the addition of human antibody sequences, and then select the clones that bind most strongly and specifically to human CCKBR. These will then be tested in cell and animal models of neuropathic pain to identify the most promising candidates for further evaluation in humans.

Pain signals originate predominantly in a subset of peripheral sensory neurons that harbor a distinct subset of voltage-gated sodium (NaV) channels; however, current NaV channel blockers, such as local anesthetics, are non-selective and also block NaV channels vital for function of the heart, muscle, and central nervous system. Genetic studies have identified human NaV1.7, NaV1.8, and NaV1.9 channel subtypes as key players in pain signaling and as major contributors to action potential generation in peripheral neurons. ProTx-II is a highly potent and moderately selective peptide toxin that inhibits human NaV1.7 activation. This study will optimize ProTx-II selectivity, potency, and stability by exploiting the new structures of ProTx-II—human NaV1.7 channel complexes, advances in rational peptide optimization, and rigorous potency and efficacy screens to generate high-affinity, selective inhibitors of human NaV1.7, NaV1.8, and NaV1.9 channels that can define a new class of biologics to treat pain.

The development of non-addictive pain therapeutics can help counter opioid addiction and benefit patients, including those who suffer from neuropathic pain, in particular diabetic neuropathic pain (DNP). This project’s goal is to develop a safe, efficacious, and non-addictive small-molecule drug that activates Kv7 voltage-gated potassium channels to address overactive neuronal activity in DNP. Researchers will discover Kv7 activators that favor Kv7 isoforms altered in DNP and found in dorsal root ganglia, decrease off-target side effects observed with the use of earlier non-biased Kv7 activators, and optimize the absorption, distribution, metabolism, excretion, and toxicity profiles of these activators. This screening paradigm is intended to establish a clinic-ready, well-tolerated, and widely effective product to treat neuropathic pain.

Although opioid-based analgesics have been proven effective in reducing the intensity of pain for many neuropathic pain conditions, their clinical utility is grossly limited due to the substantial risks involved in such therapy, including nausea, constipation, physical dependence, tolerance, and respiratory depression. Cumulative evidence suggests that human Mas-related G protein-coupled receptor X1 (MRGPRX1) is a promising target for pain with limited side effects due to its restricted expression in nociceptors within the peripheral nervous system; however, direct activation of MRGPRX1 at peripheral terminals is expected to induce itch side effects, limiting the therapeutic utility of orthosteric MRGPRX1 agonists. This finding led to the exploration of positive allosteric modulators (PAMs) of MRGPRX1 to potentiate the effects of the endogenous agonists at the central terminals of sensory neurons without activating peripheral MRGPRX1. An intrathecal injection of a prototype MRGPRX1 PAM, ML382, effectively attenuated evoked, persistent, and spontaneous pain without causing itch side effects. The goal of this study is to develop a CNS-penetrant small-molecule MRGPRX1 PAM that can be given orally to treat neuropathic pain conditions.