A research study has yielded pre-clinical evidence to support the feasibility of treating ischemic stroke using hypoxia-inducible heme oxygenase-1 (HO-1) gene expression system.
Stroke, one of the major causes of death and disability worldwide, is a devastating disease caused by a sudden halt of blood supply to the brain due to ischemia or hemorrhage and can lead to permanent brain damage. Currently, the main treatment for ischemic stroke is to revive the blood flow by using thrombolytic agents. New therapeutic options have been investigated and one promising approach is gene therapy with antiapoptotic and cytoprotective genes. Although HO-1 is a potential gene for the treatment of ischemic stroke, its non-specific expression limits its usage, thus requiring the development of strategies to restrict the expression of HO-1 gene to ischemic tissues.
In the current study published in Pharmaceutical Research, the team developed an HO-1 expression plasmid with the Epo enhancer-SV40 promoter, pEpo-SV-HO-1, as a therapeutic gene for ischemia-responsive gene therapy of ischemic stroke. Dexamethasone-conjugated polyamidoamine (PAMAM-Dexa) was used as a carrier for efficient gene delivery to brain. In vitro transfection assays were performed in the Neuro2A cells and in vivo efficacy of pEpo-SV-HO-1 was evaluated by the injection of PAMAM-Dexa/pEpo-SV-HO-1 complex into the brain of a transient middle cerebral artery occlusion (MCAO) rat model. Results showed that pEpo-SV-HO-1 reduced the level of apoptosis more efficiently than pSV-HO-1 (control) in Neuro2A cells under hypoxia. pEpo-SV-HO-1 increased HO-1 expression and reduced the number of apoptotic cells in the ischemic brain compared with the control group in vivo, resulting in efficient reduction of infarct volume by pEpo-SV-HO-1.
Thus, the study demonstrates the usefulness of PAMAM-Dexa in combination with pEpoSV-HO-1 as a potential site-specific gene therapy strategy for ischemic stroke.
Source: Delivery of Hypoxia-Inducible Heme Oxygenase-1 Gene for Site-Specific Gene Therapy in the Ischemic Stroke Animal Model. Choi M et al., Pharmaceutical Research, June 2016. DOI