title: Biochemical and Physiological Improvement in a Mouse Model of Smith-Lemli-Opitz Syndrome (SLOS) Following Gene Transfer with AAV Vectors.
abstract: Smith-Lemli-Opitz syndrome (SLOS) is an inborn error of cholesterol synthesis resulting from a defect in 7-dehydrocholesterol reductase (DHCR7), the enzyme that produces cholesterol from its immediate precursor 7-dehydrocholesterol. Current therapy employing dietary cholesterol is inadequate. As SLOS is caused by a defect in a single gene, restoring enzyme functionality through gene therapy may be a direct approach for treating this debilitating disorder. In the present study, we first packaged a human DHCR7 construct into adeno-associated virus (AAV) vectors having either type-2 (AAV2) or type-8 (AAV2/8) capsid, and administered treatment to juvenile mice. While a positive response (assessed by increases in serum and liver cholesterol) was seen in both groups, the improvement was greater in the AAV2/8-DHCR7 treated mice. Newborn mice were then treated with AAV2/8-DHCR7 and these mice, compared to mice treated as juveniles, showed higher DHCR7 mRNA expression in liver and a greater improvement in serum and liver cholesterol levels. Systemic treatment did not affect brain cholesterol in any of the experimental groups. Both juvenile and newborn treatments with AAV2/8-DHCR7 resulted in increased rates of weight gain indicating that gene transfer had a positive physiological effect.
authors.affiliation: Children's Hospital Oakland Research Institute, 5700 Martin Luther King Jr. Way, Oakland, Ca 94609, USA.
authors.forename: Lee
authors.initials: L
authors.lastname: Ying
authors.affiliation: Children's Hospital Oakland Research Institute, 5700 Martin Luther King Jr. Way, Oakland, Ca 94609, USA.
authors.forename: Xavier
authors.initials: X
authors.lastname: Matabosch
authors.affiliation: Children's Hospital Oakland Research Institute, 5700 Martin Luther King Jr. Way, Oakland, Ca 94609, USA.
authors.forename: Montserrat
authors.initials: M
authors.lastname: Serra
authors.affiliation: Children's Hospital Oakland Research Institute, 5700 Martin Luther King Jr. Way, Oakland, Ca 94609, USA.
authors.forename: Berna
authors.initials: B
authors.lastname: Watson
authors.affiliation: Children's Hospital Oakland Research Institute, 5700 Martin Luther King Jr. Way, Oakland, Ca 94609, USA.
authors.forename: Cedric
authors.initials: C
authors.lastname: Shackleton
authors.affiliation: Children's Hospital Oakland Research Institute, 5700 Martin Luther King Jr. Way, Oakland, Ca 94609, USA.
authors.forename: Gordon
authors.initials: G
authors.lastname: Watson
keywords: 7-dehydrocholesterol reductase (DHCR7); AAV; Smith-Lemli-Opitz syndrome (SLOS); cholesterol synthesis; gene therapy