Gene Transfer to the CNS Using Recombinant Adeno‐Associated Virus

Abstract

Recombinant adeno‐associated virus (rAAV) vectors are great tools for gene transfer due to their ability to mediate long‐term gene expression. rAAVs have been used successfully as gene transfer vehicles in multiple animal models of CNS disorders, and several clinical trials are currently underway. rAAV vectors have been used at various stages of development with no apparent toxicity. There are multiple ways of delivering AAV vectors to the mouse CNS, depending on the stage of development. In neonates, intravascular injections into the facial vein are often used. In adults, direct injections into target regions of the brain are achieved with great spatiotemporal control through stereotaxic surgeries. Recently, discoveries of new AAV vectors with the ability to cross the blood brain barrier have made it possible to target the adult CNS by intravascular injections. Curr. Protoc. Microbiol. 29:14D.5.1‐14D.5.18. © 2013 by John Wiley & Sons, Inc.

Global CNS Transduction of Adult Mice by Intravenously Delivered rAAVrh.8 and rAAVrh.10 and Nonhuman Primates by rAAVrh.10

“…[4][5][6][7][8][9] A significant barrier of CNS gene delivery is the blood-brain barrier (BBB), which prevents large or hydrophilic molecules such as dopamine, chemotherapeutics, and viruses from passively entering the brain. 10,11 On the other hand, recombinant adeno-associated viruses (rAAVs) hold promise for efficient, stable, and safe gene delivery to a wide range of tissues including the CNS, 4,8,[12][13][14][15] but methods of delivery for rAAV-mediated gene transfer remain an intricate and demanding aspect of vectorbased CNS gene therapy. Direct stereotactic injections of rAAVs are ideal for diseases with local CNS pathology but cannot transduce the CNS broadly.…”

Fluorescent Biosensors for Neurotransmission and Neuromodulation: Engineering and Applications

“…AAV injection can be performed intravenously via either tail injection or using stereotactic injection, which requires surgery. Tail injection allows to achieve even AAV distribution in the rodent brain whereas stereotactic injection leads to expression of the neurotransmitter only at the injection place (Figure 4A; Boulaire et al, 2009; Stoica et al, 2013). In the case of tail injection a tissue-specific promoter is important to limit biosensor expression to certain tissue or subset of cells.…”

Alternative Anesthesia of Neonatal Mice for Global rAAV Delivery in the Brain With Non-detectable Behavioral Interference in Adults

“…For a global expression of transduced genes in the mouse brain, a neonatal rAAV delivery method was introduced and used successfully (Passini and Wolfe, 2001 ; Pilpel et al, 2009 ; Chakrabarty et al, 2013 ; Kim et al, 2013 , 2014 ; McLean et al, 2014 ; Ayers et al, 2015 ; He et al, 2018 ). As alternatives to this global, neonatal rAAV gene transduction, in utero electroporation (Saito, 2006 ; Huang and Carcagno, 2018 ), or systemic injection of rAAV into the tail vein of adult or adolescent mice (Foust et al, 2009 ; Stoica et al, 2013 ; Körbelin et al, 2016 ; Thomsen et al, 2017 ) achieved similar expression of transfected or transduced genes in the mouse brain. However, high expression of the transfected gene is of relatively short duration after in utero electroporation and is more restricted to the area that received the DNA injection.…”