Intraventricular administration of recombinant adenovirus to neonatal twitcher mouse leads to clinicopathological improvements

Abstract

Twitcher mouse is a murine model of human globoid cell leukodystrophy (Krabbe disease), which is characterized by a genetic deficiency in galactocerebrosidase (GALC) activity. The nervous system is affected early and severely by demyelination in the white matter. So far, there is no effective treatment for Krabbe disease except bone marrow transplantation (BMT). However, BMT has inherent limitations such as unavailability of donors and graft-versus-host disease. In this study, we injected recombinant adenovirus encoding GALC into the lateral ventricle of twitcher mice at postnatal day 0 (PND 0) and the therapeutic effects were evaluated. Our results showed slight, but significant

Survival advantage of neonatal CNS gene transfer for late infantile neuronal ceroid lipofuscinosis

“…Finally, corrective gene therapies for neurodegenerative diseases are not restorative but rather halt disease progression, making delivery prior to disease onset an important objective. With these limitations in mind, three basic strategies have been employed to achieve therapeutic levels of gene expression throughout the brain: identifying gene transfer vectors that will diffuse through the CNS more effectively (Cearley and Wolfe2006;Deglon and Hantraye2005;Shevtsova et al, 2005;Sondhi et al, 2007), optimizing the method of delivery and volume and rate of infusion (Chen et al, 1999;Hackett et al, 2005;Hsich et al, 2002), and administration at an earlier time point, when the brain is smaller and immature (Bostick et al, 2007;Broekman et al, 2007;Daly et al, 1999;Griffey et al, 2006;Li and Daly2002;Passini et al, 2003;Passini and Wolfe2001;Rafi et al, 2005;Shen et al, 2001;Waddington et al, 2004). Studies from our laboratory and others have identified several serotypes of adeno-associated virus (AAV) vectors that are more effective than the first generation vectors used for CNS gene transfer (Broekman et al, 2006;Burger et al, 2005;Cearley and Wolfe2006;Harding et al, 2006;Sondhi et al, 2007;Taymans et al, 2007), the parameters for optimal administration of vectors to the CNS have been established (Chen et al, 1999;Hackett et al, 2005;Hsich et al, 2002) and several studies have shown that administration earlier in life results in an advantage over therapy in older animals (Bostick et al, 2007;Broekman et al, 2007;Daly et al, 1999;Griffey et al, 2006;Li and Daly2002;Passini et al, 2003;Passini and Wolfe2001...…”

Attenuation of ganglioside GM1 accumulation in the brain of GM1 gangliosidosis mice by neonatal intravenous gene transfer

“…However, only direct injections of the gene into the brain or into the ventricle have been shown to be effective on the central nervous system. [12][13][14] The blood-brain barrier blocks the enzyme protein-mediated correction or the gene transfer into the brain in any of these approaches. According to the previous literatures, neonatal treatments of ERT or BMT provide a more complete correction in many organs, even in the brain.…”

Gene therapy: prospects for glycolipid storage diseases

“…Yet another alternative is the direct injection of viral vectors into the brain with the aim of transducing a sufficient number of endogenous cells, which then serve as enzymeproducing platform cells (Consiglio et al 2001;Shen et al 2001). In glycolipid storage diseases, the effects of bone marrow transplantations with retrovirally modified stem cells, direct injections of viral vectors into the ventricular Phil.…”

“…Shen et al (2001) injected recombinant adenovirus encoding galactocerebrosidase into the lateral ventricle of twitcher mice. This treatment was performed in animals of various ages.…”