Functional motor recovery from brain ischemic insult by carbon nanotube-mediated siRNA silencing
K.T. Al-Jamal, L. Gherardini, G. Bardi, A. Nunes, C. Guo, M.A. Herrero, A. Bianco, M. Prato, T. Pizzorusso, K. Kostarelos
The School of Pharmacy, UK
Keywords: siRNA, carbon nanotubes, stroke, behavioral assays
Abstract:Ischemic stroke accounts for 80% of all stroke insults and often leads to chronic functional limitations that adversely and long-lastly affect the ability of patients to movement. Physical and pharmacological rehabilitation strategies to reduce chronic impairment are often not sufficient to return to pre-lesion levels of performance of sensory and motor functions. In the past, gene therapy has been suggested to limit stroke derived anatomical and functional damage  and viral vector administration of genes into the affected area of the brain has been exploited. Carbon nanotubes have been recently proposed as novel nanomaterials that can offer significant advantages for the intracellular delivery of nucleic acids, such as siRNA. We have recently demonstrated in a proof-of-principle study  that amino-functionalized multi-walled carbon nanotubes (f-MWNT) can effectively deliver in vivo an siRNA sequence triggering cell apoptosis that results in human lung xenograft eradication and prolonged survival. Herein, we have investigated the use of the same functionalized carbon nanotubes material, to design a vector for non-viral delivery of small interference RNA (siRNA) directly into the brain (intracranial administration). This was based on the hypothesis that siRNA against neuronal Caspase-3 could rescue cells from stroke-induced apoptosis after injection of 60 picomoles of endothelin-1 (ET-1). ET-1 is a potent vasoconstrictor that when injected in the motor cortex (M1) induces stroke-like events that cause specific impairments of mobility performance. Using the skilled reaching test in rats, we demonstrate that gene silencing using CNT:siRNA vectors 24hr pre-endothelin administration reduces apoptosis in M1 and enhances motor skill recovery in rats after ischemic stroke.