Administration of intramuscular AAV-BDNF and intranasal AAV-TrkB promotes neurological recovery via enhancing corticospinal synaptic connections in stroke rats

Gene therapy of adeno‐associated virus (AAV) vectors in preclinical models of ischemic stroke

“…75 Additionally, combinational therapy involving intramuscular AAV-BDNF and intranasal AAV-TrkB administered 1 day after surgery promoted motor function recovery, axon reorganization, and synaptic plasticity in the spinal cord denervated gray matter in pMCAO rats for 8 weeks. 76 Injecting AAV into the contralateral somatosensory motor cortex in mice 3 days post-unilateral PT stroke succeeded in co-expressing two soluble proteins, IGF1 and osteopontin (OPN), which promoted CST sprouting in the spinal cord and subcortical regions and restored behavioral function. 77 Histone deacetylase 2 (HDAC2) is a negative regulator of neural plasticity, and virus-mediated HDAC2 downregulation promoted axon sprouting and enhanced the expression of neurotrophic factors (NGF and BDNF) and neural plasticity-related proteins (PSD95 and synapsin), enhancing neural plasticity.…”

“…[110][111][112] In stroke research, ubiquitous promoters such as the non-specific cytomegalovirus (CMV) or chickenβ-actin hybrid (CAG) are expressed in most CNS cells, primarily neurons and some scattered astrocytes. 79,103,113 Various promoters can drive specific transgene expressions, such as the hSyn promoter driving neuron-specific gene expression, 53,75,76,106,114 the GFAP promoter driving astrocyte-specific expression, 44,66,73,88 the F4/80 promoter driving microglia-specific expression, 44,66,73 the CaMK2a promoter driving glutamatergic neuronal expression, 80 and the Olig2 promoter driving oligodendrocyte-specific expression. 115 Additionally, regulatory elements such as the Tie1 promoter can drive brain endothelial cell-specific expression 57,116 and the HIF-1α…”

“…64 Similarly, after nasal administration, exogenous BDNF or TrkB can be delivered to the CNS through the nasal-brain pathway for expression. 76,82 These strategies can be administered within 0-3 h after brain ischemia occurs, 54,58,74 such as intravenous injection of IL-10 gene-transferred MSCs at 0 or 3 h after reperfusion in rats, which extended the treatment time window of MSC transplantation from 0 to 3 h. 58 Delayed administration, ranging from 1 day to 1 month after ischemia, is more commonly used to promote functional recovery in the subacute and chronic stroke phase, [75][76][77] thus laying the foundation for clinical translation.…”

“…The tPA was not used as a fibrinolytic agent but as a neural recovery agent stimulating axon remodeling 75 . Additionally, combinational therapy involving intramuscular AAV‐BDNF and intranasal AAV‐TrkB administered 1 day after surgery promoted motor function recovery, axon reorganization, and synaptic plasticity in the spinal cord denervated gray matter in pMCAO rats for 8 weeks 76 . Injecting AAV into the contralateral somatosensory motor cortex in mice 3 days post‐unilateral PT stroke succeeded in co‐expressing two soluble proteins, IGF1 and osteopontin (OPN), which promoted CST sprouting in the spinal cord and subcortical regions and restored behavioral function 77 .…”

“…When injected into PV‐Cre mice's spinal cord, AAV‐retro or AAV6 was reported to preferentially label DRG neurons, 108 but the retrograde targeting ability of AAV6 was much lower than that of rAAV‐retro 31 . In addition, muscle injection of AAV‐retro can effectively transduce lower motor neurons in the spinal cord and brainstem, providing a simple and practical method for stroke gene delivery 76,109 …”