Efficient gene delivery and selective transduction of astrocytes in the mammalian brain using viral vectors

Abstract

Astrocytes are now considered as key players in brain information processing because of their newly discovered roles in synapse formation and plasticity, energy metabolism and blood flow regulation. However, our understanding of astrocyte function is still fragmented compared to other brain cell types. A better appreciation of the biology of astrocytes requires the development of tools to generate animal models in which astrocyte-specific proteins and pathways can be manipulated. In addition, it is becoming increasingly evident that astrocytes are also important players in many neurological disorders. Targeted modulation of protein expression in astrocytes would be critical for the development of new therapeutic strategies. Gene transfer is valuable to target a subpopulation of cells and explore their function in experimental models. In particular, viral-mediated gene transfer provides a rapid, highly flexible and cost-effective, in vivo paradigm to study the impact of genes of interest during central nervous system development or in adult animals. We will review the different strategies that led to the recent development of efficient viral vectors that can be successfully used to selectively transduce astrocytes in the mammalian brain.

Gene transfer engineering for astrocyte-specific silencing in the CNS

“…4 Among them, lentiviral vectors (LVs) have a large cloning capacity, high transduction efficiency and can be engineered to restrict transgene expression to particular cell subtypes. 5,6 The pseudotyping of LV particles with the glycoprotein G of the vesicular stomatitis virus (VSV-G) results in efficient neuronal targeting with ubiquitous promoters, 7 whereas both neurons and astrocytes are transduced when LV is pseudotyped with the glycoprotein G of the Mokola virus (MOK-G). 8 Tissue-specific promoters may be used to restrict further transgene expression to a particular cell subpopulation.…”

Recombinant Adeno-Associated Virus Serotype 6 (rAAV6) Potently and Preferentially Transduces Rat Astrocytes In vitro and In vivo

“…With increased appreciation and evolving interest in normal and pathological roles for this class of glial cells, there is a growing demand for viral vectors effectively targeting astroglia (Merienne et al, 2013). Yet, the majority of past studies have focused on rAAV transduction of neuronal cells.…”

“…The reasons for variability in glial tropism of AAV serotypes are still poorly understood (see “Discussion” for further details). Some refinements in glial specificity have been made with incorporation of the astrocyte-specific promoters, such as gfa2 or gfaABC1D (Merienne et al, 2013; Weinberg et al, 2013). However, even with these improvements, astrocytic transduction rates appear to be moderate and new AAV vectors targeting astroglial cells would be a welcome addition to the field.…”

Pygmy MicroRNA: Surveillance Cops in Therapy Kingdom

“…As an example, delivered transgene with the binding site for miR-122 can be easily silenced in hepatocytes because it has specificity for liver tissues (133). This strategy has been widely used to restrict transgene expression through a lentiviral vector in astroglial cells (134,135) (134,136).…”