Rho as a target to promote repair: translation to clinical studies with cethrin.
Spinal cord injury (SCI) often results in permanent paralysis because there is little spontaneous repair. Neuronal injury in the central nervous system (CNS) causes breakage of axonal connections, release of myelin, inflammation and cell death at the lesion site. Many factors contribute to the failure of spontaneous repair after SCI, including the presence of growth inhibitory proteins in myelin, the inflammatory environment of the injured CNS, and the resulting signaling cascades that result in over-activation of Rho, a signaling switch in neurons and axons. In this review, we provide a general overview of growth inhibition in the CNS, and show evidence that most growth inhibitory proteins signal through a common intracellular pathway. Rho is a convergent signal for growth inhibition, and also for signaling some of the secondary consequences of inflammation after SCI. We review the preclinical evidence that targeting Rho is an effective way to stimulate axon regeneration and functional recovery in preclinical animal models. In the last part of the review, we describe the creation of Cethrin, a new investigational drug, and summarize the results of the Phase I/IIa clinical study to examine the safety, tolerability and efficacy of Cethrin in patients with acute SCI. We conclude with some insight for future clinical studies.
BioAxone BioSciences Inc., 207 NE Third Street, Suite 207, Dania Beach, FL 33004, USA. lmck@bioaxonbio.com
Lisa
L
McKerracher
Pierre
P
Guertin
D036002:ADP Ribose Transferases / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000818:Animals; D001369:Axons / Q000187:drug effects / Q000473:pathology; D001905:Botulinum Toxins / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D002986:Clinical Trials as Topic; D004353:Drug Evaluation, Preclinical; D006801:Humans; D009043:Motor Activity / Q000187:drug effects; D009416:Nerve Regeneration / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D013119:Spinal Cord Injuries / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors*
D018696:Neuroprotective Agents; D036002:ADP Ribose Transferases; C063007:exoenzyme C3, Clostridium botulinum; D054460:rho-Associated Kinases; D001905:Botulinum Toxins