BioCentury
ARTICLE | Distillery Therapeutics

Neurology

August 16, 2018 4:13 PM UTC

Mouse and rat studies suggest inhibiting PANX1 or its activator P2RX7 in spinal microglia, or an antibody-drug conjugate (ADC) targeting the microglia, could help treat joint pain. In spinal cord samples from a rat model of chemical-induced joint pain, spinal microglia levels of P2RX7 were higher than in samples from normal mice. In a mouse model of chemical-induced joint pain, spinal microglia-specific knockout of PANX1 decreased mechanical allodynia compared with normal PANX1 expression. In the rat model of chemical-induced joint pain, intrathecal injection of an ADC composed of an antibody targeting spinal lumbar microglia-expressed integrin β2 (MAC-1; CD18) linked to the ribosome-inactivating toxin saporin, a P2RX7 inhibitor tool compound or a PANX1 inhibitor tool peptide decreased mechanical allodynia compared with the free toxin, vehicle or scrambled peptide, respectively. Also in the model and in a rat model of osteoarthritis-induced joint pain, the PANX1 inhibitor probenecid decreased mechanical allodynia compared with vehicle. Next steps could include optimizing the potency of the ADC and identifying and testing additional PANX1 and P2RX7 inhibitors in the models.

The generic probenecid is marketed to treat gout...