Widespread gene transduction to the central nervous system by adenovirus in utero: implication for prenatal gene therapy to brain involvement of lysosomal storage disease

Abstract

Brain-directed in utero gene therapy through an intra-ventricular route would be an effective strategy to treat some lysosomal storage diseases with early and severe CNS alterations.

Lentiviruses allow widespread and conditional manipulation of gene expression in the developing mouse brain

“…These two limitations constitute a disadvantage, particularly during embryonic development, when a substantial proportion of cells are characterized by a high proliferative activity. In fact, the genome of non-integrating adenoviruses, similarly to electroporated plasmids, is diluted by consecutive cell cycles, and although the ectopic protein may persist over a long period of time in postmitotic cells [1 year in the case of β-galactosidase (Shen et al, 2004)], the ectopic transgene will soon disappear in dividing cells, thus limiting the use of Cre-mediated recombination. However, the rather low infectivity of integrating retroviruses seems unlikely to be sufficient to induce major morphological changes at the level of whole organs.…”

“…However, infectivity with retroviruses was revealed to be modest relative to other viral vectors, and this is probably the reason why their first use in the developing mammalian brain has been exploited for clonal analysis (Luskin et al, 1988;Price and Thurlow, 1988;Walsh and Cepko, 1988). By contrast, adenoviruses were reported to achieve higher infectivity, probably because they can be produced at very high titre and can transduce both dividing and nondividing cells (Leingärtner et al, 2003;Rahim et al, 2012;Shen et al, 2004). However, similarly to electroporation, manipulation of gene expression by adenoviruses is transient owing to lack of integration, leading to dilution as a result of cell divisions, which is particularly troublesome when targeting cells with high proliferative activity.…”

The developmental stage determines the distribution and duration of gene expression after early intra-amniotic gene transfer using lentiviral vectors

“…These include intratracheal, 1-3 intravascular, 4,5 intraventricular, 6,7 intracardiac, 8 intraperitoneal, 5,[9][10][11][12] intraplacental, 13 intramuscular [14][15][16][17][18] and intra-amniotic injection. 1,5,[19][20][21][22] Intra-amniotic gene transfer (IAGT) has been used to target organs exposed to amniotic fluid, that is, the skin, amniotic membranes and the respiratory and digestive systems.…”

In utero gene transfer to the mouse nervous system

“…Shen and colleagues performed a series of studies investigating adenovirus vectors for gene transfer to the rat CNS, first by intra-amniotic injection at mid-gestation (12 dpc, where dpc is days postcoitus; gestation in mice and rats is approx. 20 days) [13] and then, more targeted, by injection into the lateral ventricle at late gestation (14 and 17 dpc) [14]. The late gestation injection, in particular, led to long-term expression for up to 10 months after injection, albeit at diminishing levels.…”