Targeted gene therapy for ischemic stroke\

Abstract

Exogenous delivery of angiogenic and neuroprotective genes has been shown to enhance innate compensatory responses after ischemic injury. However, there are certain barriers in translating genebased therapy to the clinical setting. For example, systemic delivery of genes into the brain is prevented by the blood–brain barrier (BBB); intraventricular delivery results in nonspecifi c distribution and gene expression; and stereotactic injection of vectors into the ischemic penumbra requires an invasive procedure that can cause additional damage. This chapter describes an adeno-associated viral (AAV) vector with two primary attributes that have the potential to overcome these problems. First, the vector contains hypoxia response elements (HREs) that restrict therapeutic gene expression to ischemic tissue. Second, AAV serotype 9 (AAV9) effectively penetrates the BBB, enabling intravenous administration. This chapter also illustrates the methods of constructing AAV vectors with hypoxia-inducible gene expression, generating the mouse permanent distal middle cerebral artery occlusion (pMCAO) model, standard assays to analyze brain injury and gene transfer, and effective behavior tests for the pMCAO model.