Newly published research in the journal Cell reported that neuronal knockdown of the CCR5 gene, implicated in learning/memory and uniquely expressed in cortical neurons after stroke, leads to early recovery of motor control. The groundbreaking study also demonstrated that administration of CCR5 antagonist devised for HIV produces similar effects on motor recovery post stroke and cognitive recovery post TBI. Critically, in a large clinical cohort of stroke patients (Tel Aviv Brain Acute Stroke Cohort; TABASCO), carriers of a naturally occurring loss-of-function mutation in CCR5 (CCR5-D32) showed better recovery of neurological impairments and cognitive function months after the stroke. The UCLA and Tel Aviv Medical Center researchers conclude that CCR5 is a translational target for neural repair in stroke and TBI as well as the first ever gene associated with enhanced recovery in human stroke.
Patients in the TABASCO cohort are followed up post-stroke to evaluate long-term recovery. NeuroTrax computerized cognitive testing is administered at baseline, 6, 12, and 24 months. For the Cell study, 446 patients with NeuroTrax scores available were screened for the CCR5-D32 mutation; 68 were found to be carriers. There were no differences in baseline cognitive performance between carriers and non-carriers. However, at 1 year, CCR5-D32 carriers showed improvement in memory, verbal function, attention, and overall cognitive performance relative to non-carriers, even after adjustment for age, gender and education. There was converging evidence of CCR5-D32 carrier improvement on the MoCA, as well as improvement on functional and neurological scales.
Stroke and TBI cause loss of connections in adjacent and interacting brain regions. A mechanism of action for CCR5 knockdown in recovery from brain injury may be in preventing the loss of synaptic connections in adjacent cortex or promoting the formation of new connections after brain injury. Specifically, CCR5 knockdown induces recovery through two intracellular cascades, CREB and dual leucine zipper kinase (DLK), both of which mediate injury signals, dendritic spine morphogenesis, and axonal regeneration in other systems. Led by Prof. S. Thomas Carmichael of UCLA and Dr. Einor Ben Assayag of Tel Aviv Medical Center, the authors state that their data point to the CCR5 receptor system as a valid target for future clinical trials of a stroke and TBI recovery approach.
Joy, M.T., Ben Assayag, E., Shabashov-Stone, D., Liraz-Zaltsman, S., Mazzitelli, J., Arenas, M., Abduljawad, N., Kliper, E., Korczyn, A.D., Thareja, N.S., Kesner, E.L., Zhou, M., Huang, S., Silva, T.K., Katz, N., Bornstein, N.M., Silva, A.J., Shohami, E., and Carmichael, S.T. (2019). CCR5 is a therapeutic target for recovery after stroke and traumatic brain injury. Cell, 176, 1143–1157. PMID: 30794775