Long-term systemic therapy of Fabry disease in a knockout mouse by adeno-associated virus-mediated muscle-directed gene transfer

Abstract

Fabry disease is a systemic disease caused by genetic deficiency of a lysosomal enzyme, ␣-galactosidase A (␣-gal A), and is thought to be an important target for enzyme replacement therapy. We studied the feasibility of gene-mediated enzyme replacement for Fabry disease. The adeno-associated virus (AAV) vector containing the ␣-gal A gene was injected into the right quadriceps muscles of Fabry knockout mice. A time course study showed that ␣-gal A activity in plasma was increased to Ϸ25% of normal mice and that this elevated activity persisted for up to at least 30 weeks without development of anti-␣-gal A antibodies. The ␣-gal A activity in various organs of treated Fabry mice remained 5-20% of those observed in normal mice. Accumulated globotriaosylceramide in these organs was completely cleared by 25 weeks after vector injection. Reduction of globotriaosylceramide levels was also confirmed by immunohistochemical and electronmicroscopic analyses. Echocardiographic examination of treated mice demonstrated structural improvement of cardiac hypertrophy 25 weeks after the treatment. AAV vector-mediated muscle-directed gene transfer provides an efficient and practical therapeutic approach for Fabry disease.

Efficient correction of Fabry mice and patient cells mediated by lentiviral transduction of hematopoietic stem/progenitor cells

“…It is noteworthy that this level of organ a-gal A activity was higher (to our knowledge) than that of any other Fabry disease gene therapy experiments to date in all organs. 13,14,19,23,[31][32][33] This finding indicated efficient in vivo metabolic cooperativity of enzyme-deficient, affected cells from transduced and enzyme-overproducing cells (Table 1). These data also suggest that correction of only relatively a small number of key cells, such as repopulating HSPCs, may be sufficient to cure Fabry disease.…”

Adeno-associated virus-mediated knockdown of melanocortin-4 receptor in the paraventricular nucleus of the hypothalamus promotes high-fat diet-induced hyperphagia and obesity

“…In this study, we demonstrate that selective MC4R knockdown in PVN neurons of the adult wild-type rat results in no changes in food intake and body weight when animals are fed with a regular diet within 2 weeks, but causes increased feeding and excessive weight gain in response to a high-fat diet. It is unlikely that the unaltered feeding and body weight in response to the regular diet is due to insufficient gene suppression because AAV-mediated gene expression occurs within 3 days (Flotte et al 1993, Takahashi et al 2002 and AAV-mediated effective gene silencing has been reported at days 6-10 after injection of AAV-shRNA (Hommel et al 2003, Wang et al 2006, Paskowitz et al 2007). Thus, our results suggest that the disruption of MC4R in PVN neurons increases the sensitivity to diet-induced hyperphagia and obesity.…”

Engagement of the B-cell antigen receptor (BCR) allows efficient transduction of ZAP-70-positive primary B-CLL cells by recombinant adeno-associated virus (rAAV) vectors

“…19 HSPGs are critical regulators of growth and differentiation of epithelial and connective tissues for which AAV has a specific tropism. [20][21][22][23][24] Moreover, HSPGs function as coreceptors promoting cytokine signaling in normal B cells in the context of antigen-specific B-cell differentiation. Besides activation of the BCR, CD40 was shown to control the expression of HSPGs on tonsillar B cells.…”