Abstract
Natural brain repair after stroke is extremely limited, and current therapeutic options are even more scarce with no clinical break-through in sight. Despite restricted regeneration in the central nervous system, we have previously proved that human umbilical cord blood mono-nuclear cells (UCB-MC) transduced with adenoviral vectors carrying genes encoding vascular endothelial growth factor (VEGF), glial cell-derived neurotrophic factor (GDNF), and neural cell adhesion molecule (NCAM) successfully rescued neurons in amyotrophic lateral sclerosis and spinal cord injury. This proof-of-principle project was aimed at evaluating the beneficial effects of the same triple-gene approach in stroke. Rats subjected to distal occlusion of the middle cerebral artery were treated intrathecally with a combination of these genes either directly or using our cell-based (UCB-MC) approach. Various techniques and markers were employed to evaluate brain injury and subsequent recovery after treatment. Brain repair was most prominent when therapeutic genes were delivered via adenoviral vector- or UCB-MC-mediated approach. Remodeling of brain cortex in the stroke area was confirmed by reduction of infarct volume and attenuated neural cell death, depletion of astrocytes and microglial cells, and increase in the number of oligodendroglial cells and synaptic proteins expression. These results imply that intrathecal injection of genetically engineered UCB-MC over-expressing therapeutic molecules (VEGF, GDNF, and NCAM) following cerebral blood vessel occlusion might represent a novel avenue for future research into treating stroke.
Highlights
A lack of available and effective treatments for ischemic injury results in the high mortality and disability of patients with stroke throughout the world
The volume of the brain cortex infarct was significantly less in adenovirus serotype 5 (Ad)-vascular endothelial growth factor (VEGF)-glial cell-derived neurotrophic factor (GDNF)-neural cell adhesion molecule (NCAM) (0.007 [0.001; 0.012]) and umbilical cord blood mono-nuclear cells (UCBMC)+Ad-VEGF-GDNF-NCAM (0.021 [0.010; 0.025]) groups, when compared with control saline (0.168 [0.148; 0.171]) and Ad-GFP (0.091 [0.080; 0.098]) groups
The level of the Hsp70 immunoexpression in gene-treated Ad-VEGF-GDNF-NCAM (34.7 [30.7; 39.1]) and umbilical cord blood mono-nuclear cells (UCB-MC)+Ad-VEGF-GDNF-NCAM (33.1 [30.0; 35.8]) groups was significantly downregulated when compared with saline control group
Summary
A lack of available and effective treatments for ischemic injury results in the high mortality and disability of patients with stroke throughout the world. Gene Therapy for Stroke for central nervous system (CNS) disorders have been reported for treatment of Alzheimer’s (Rafii et al, 2014) and Parkinson’s (Warren Olanow et al, 2015) diseases. These clinical investigations failed to show therapeutic efficacy proved the safety of the intracranial injection suggesting a potential route of recombinant viral vectors carrying therapeutic genes after stroke. There have been clinical trials employing autologous or allogeneic types of cells for patients with stroke (Jeong et al, 2014). To treat X-linked adreno-leuko-dystrophy (a fatal neurodegenerative disease caused by mutations of the ABCD1 gene encoding an adenosine triphosphate-binding cassette transporter localized in the membrane of peroxisomes in oligodendrocytes and microglia), the autologous CD34 positive cells infected with lentiviral vector encoding wild-type ABCD1 were reinfused to stop progressive cerebral demyelination in patients (Cartier et al, 2009)
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