Widespread, Specific, and Efficient Transgene Expression in Oligodendrocytes After Intracerebral and Intracerebroventricular Delivery of Viral Vectors in Rodent Brain

Several neurodegenerative disorders are characterized by oligodendroglial pathology and myelin loss. Oligodendrogliopathies are a group of rare diseases for which there currently is no therapy. Gene delivery through viral vectors to oligodendrocytes is a potential strategy to deliver therapeutic molecules to oligodendrocytes for disease modification. However, targeting oligodendroglial cells in vivo is challenging due to their widespread distribution in white and gray matter. In this study, we aimed to address several of these difficulties by designing and testing different oligodendroglial targeting vectors in rat and mouse brain, utilizing different promoters, serotypes, and delivery routes. We found that different oligodendroglial promoters (myelin basic protein [MBP], cytomegalovirus-enhanced MBP, and myelin-associated glycoprotein [MAG]) vary considerably in their ability to drive oligodendroglial transgene expression and different viral vector serotypes (rAAV2/7, rAAV2/8, and rAAV2/9) exhibit varying efficacies in transducing oligodendrocytes. Different administration routes through intracerebral or intraventricular injection allow widespread targeting of mature oligodendrocytes. Delivery of rAAV2/9-MAG-GFP into the cerebrospinal fluid results in GFP expression along the entire rostrocaudal axis of the spinal cord. Collectively, these results show that oligodendrocytes can be targeted with high specificity and widespread expression, which will be useful for gene therapeutic interventions or disease modeling purposes.