Nanomule Peptide-siRNA Conjugate that Traverses the Intact Blood Brain Barrier and Attenuates Stroke

Abstract

The blood-brain barrier (BBB), hinders the distribution of therapeutics, intended for treatment of diseases of the brain. A twelve-amino acid peptide, termed MTfp, was derived from MTf, and retains the ability to cross the BBB intact and ferry cargo into intacellular organelles within neurons, glia and microglia in the brain. A novel MTfp-siRNA peptide-oligonucleotide conjugate (POC), directed against NOX4, a gene known to potentiate ischemic stroke, was chemically synthesized. The MTfp-NOX4 siRNA POC traversed the BBB, resulting in the knockdown of NOX4 expression in the brain. Following induction of ischemic stroke, animals treated with the POC exhibited significantly smaller infarcts; accompanied by significant protection against neurological deterioration and improved recovery. The data demonstrates that the MTfp portion, of this novel POC, can facilitate BBB transcytosis; where the siRNA moiety can elicit effective therapeutic knockdown of a gene associated with a disease of the central nervous system (CNS). This is a general platform to transport therapeutics to the CNS and thereby, offers new avenues for potential treatments of neuropathologies that are currently refractory to existing therapies.