University of Pittsburgh researchers have designed unnatural chloride (Cl-) channel receptors that could act as therapeutic targets for existing novel drugs. Based on understanding of the glycine receptor (GlyR) transmembrane domain, two channel classes have been designed and engineered. Class I is pH-gated, and Class II has been designed to be activated by small molecules. Both classes have been designed to counter-balance depolarization of peripheral nerves upon activation and could be a novel therapeutic approach to pain relief.
Description
The GlyR 1 and 3 subunits are involved in mediating the pain relief effects of marijuana but not the psychoactive effects and could be novel targets for pain relief medication. These receptors form Cl- conducting channels. It was noted that while the human body has GlyR in the spinal cord and lower brain, there are no GlyR in the peripheral nervous system. Designing and engineering novel Cl- channels based on GlyR and selectively delivering these to the cells in the peripheral nervous system would provide a novel strategy to control pain.
Applications
- Chronic pain, including inflammatory pain or end-stage cancer pain
- Neuropathic pain
Advantages
Chronic pain is a major cause of suffering, impacting on the quality of life of millions with a substantial financial impact due to associated healthcare costs and loss of productivity. Pain-related pathways are complex making selective targeting of the root cause, particularly when peripheral neurons are involved, difficult. These complexities have led to systemic treatment of pain which can lead to tolerance, addiction, and side effects including delirium, gastrointestinal issues, and nausea.
This novel approach targets the cause of pain, the peripheral nerves. Using designed and engineering channel receptors not normally found in the human body, it is possible to deliver these directly to peripheral nerve cells using genetic therapy (i.e., a selective viral vector) to promote the expression of these novel channels. The channels can be engineered to open in response to pH changes inside or outside of the cell environment, or in response to therapeutic small molecules, resulting in targeted pain relief.
Invention Readiness
Several novel designer channels have been engineered. In vitro studies in oocytes using electrophysiology confirmed the ion channels were selective for Cl- permeability and negligible for cations. In vivo studies in rats demonstrated selective expression of the channels in peripheral nerve fibers and dorsal root ganglia. Administration of a small agonist molecule (not normally analgesic) for the Class II channel significantly improved pain scores in animals. Further testing using a viral vector to promote transgene expression of these novel channels led to selective expression in peripheral sensory neurons, not motor neurons. This selectivity should minimize the risk of effects on motor functions. Further work is required to optimize these engineered channels and their associated delivery platform (virus, nanoparticles etc.).
IP Status
https://patents.google.com/patent/US10246504B2
