title: Increasing cholesterol synthesis in 7-dehydrosterol reductase (DHCR7) deficient mouse models through gene transfer.
abstract: Smith-Lemli-Opitz syndrome (SLOS) is caused by deficiency in the terminal step of cholesterol biosynthesis: the conversion of 7-dehydrocholesterol (7DHC) to cholesterol (C), catalyzed by 7-dehydrocholesterol reductase (DHCR7). This disorder exhibits several phenotypic traits including dysmorphia and mental retardation with a broad range of severity. There are few proven treatment options. That most commonly used is a high cholesterol diet that seems to enhance the quality of life and improve behavioral characteristics of patients, although these positive effects are controversial. The goal of our study was to investigate the possibility of restoring DHCR7 activity by gene transfer. We constructed an adeno-associated virus (AAV) vector containing the DHCR7 gene. After we infused this vector into affected mice, the introduced DHCR7 gene could be identified in liver, mRNA was expressed and a functional enzyme was produced. Evidence of functionality came from the ability to partially normalize the serum ratio of 7DHC/C in treated animals, apparently by increasing cholesterol production with concomitant decrease in 7DHC precursor. By 5 weeks after treatment the mean ratio (for 7 animals) had fallen to 0.05 while the ratio for untreated littermate controls had risen to 0.14. This provides proof of principle that gene transfer can ameliorate the genetic defect causing SLOS and provides a new experimental tool for studying the pathogenesis of this disease. If effective in humans, it might also offer a possible alternative to exogenous cholesterol therapy. However, it would not offer a complete cure for the disorder as many of the negative implications of defective synthesis are already established during prenatal development.
authors.affiliation: Children's Hospital Oakland Research Institute, 5700 Martin Luther King Jr Way, Oakland, CA 94609, United States.
authors.forename: Xavier
authors.initials: X
authors.lastname: Matabosch
authors.forename: Lee
authors.initials: L
authors.lastname: Ying
authors.forename: Montserrat
authors.initials: M
authors.lastname: Serra
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Wassif
authors.forename: Forbes D
authors.initials: FD
authors.lastname: Porter
authors.forename: Cedric
authors.initials: C
authors.lastname: Shackleton
authors.forename: Gordon
authors.initials: G
authors.lastname: Watson
mesh_terms: D000818:Animals; D002784:Cholesterol / Q000096:biosynthesis*; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000627:therapeutic use; D051379:Mice; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000172:deficiency* / Q000235:genetics*; D019082:Smith-Lemli-Opitz Syndrome / Q000201:enzymology / Q000628:therapy
chemical_list: D002784:Cholesterol; D044925:Oxidoreductases Acting on CH-CH Group Donors; C019995:7-dehydrocholesterol reductase
references.citation: Am J Med Genet. 2001 Jul 22;102(1):18-20
references.pmid: 11471166
references.citation: Proc Natl Acad Sci U S A. 1991 Mar 15;88(6):2065-9
references.pmid: 1848692
references.citation: Am J Med Genet. 2000 Jan 31;90(3):260
references.pmid: 10678669
references.citation: Prenat Diagn. 2001 Mar;21(3):207-12
references.pmid: 11260610
references.citation: Mol Genet Metab. 2005 Feb;84(2):112-26
references.pmid: 15670717
references.citation: J Virol. 2004 Mar;78(6):3110-22
references.pmid: 14990730
references.citation: Curr Opin Lipidol. 2001 Apr;12(2):105-12
references.pmid: 11264981
references.citation: Curr Opin Pediatr. 1999 Aug;11(4):353-62
references.pmid: 10439210
references.citation: Prenat Diagn. 2006 Sep;26(9):842-9
references.pmid: 16832833
references.citation: Steroids. 2007 Oct;72(11-12):802-8
references.pmid: 17714750
references.citation: Gene Ther. 1999 Jun;6(6):973-85
references.pmid: 10455399
references.citation: J Med Genet. 1998 Jul;35(7):558-65
references.pmid: 9678700
references.citation: Curr Opin Pediatr. 2003 Dec;15(6):607-13
references.pmid: 14631207
references.citation: Mol Ther. 2002 May;5(5 Pt 1):617-26
references.pmid: 11991753
references.citation: Hum Mol Genet. 2001 Mar 15;10(6):555-64
references.pmid: 11230174
references.citation: Gene Ther. 1998 Jul;5(7):938-45
references.pmid: 9813665
references.citation: Am J Med Genet. 2001 Jan 15;98(2):191-200
references.pmid: 11223857
references.citation: Mol Genet Metab. 2001 Jan;72(1):67-71
references.pmid: 11161831
references.citation: Am J Med Genet. 1999 Feb 19;82(5):376-81
references.pmid: 10069707
references.citation: Am J Med Genet A. 2007 Sep 15;143A(18):2129-36
references.pmid: 17702049
references.citation: Eur J Pediatr. 2010 Jan;169(1):121-3
references.pmid: 19365639
references.citation: Pediatr Res. 2009 Jun;65(6):681-5
references.pmid: 19430384
references.citation: Am J Med Genet. 1980;5(2):137-43
references.pmid: 7395908
references.citation: Hum Mol Genet. 2006 Mar 15;15(6):839-51
references.pmid: 16446309
references.citation: Am J Med Genet. 1995 Apr 10;56(3):281-5
references.pmid: 7778590
references.citation: Gene Ther. 2006 Jun;13(11):917-25
references.pmid: 16482204
references.citation: Eur J Med Genet. 2006 Nov-Dec;49(6):499-504
references.pmid: 16497572
references.citation: Clin Chim Acta. 1995 Apr 30;236(1):45-58
references.pmid: 7664465
references.citation: Annu Rev Genomics Hum Genet. 2001;2:299-341
references.pmid: 11701653
references.citation: Proc Natl Acad Sci U S A. 1998 Jul 7;95(14):8181-6
references.pmid: 9653161
references.citation: Am J Med Genet. 1997 Jan 31;68(3):311-4
references.pmid: 9024565
references.citation: Clin Chem. 2008 Aug;54(8):1317-24
references.pmid: 18556335
references.citation: Am J Med Genet. 1997 Jan 31;68(3):305-10
references.pmid: 9024564
references.citation: Am J Med Genet A. 2010 Jan;152A(1):91-5
references.pmid: 20014133
references.citation: Gene Ther. 1998 Dec;5(12):1642-9
references.pmid: 10023443
references.citation: Gene Ther. 2001 Sep;8(17):1291-8
references.pmid: 11571565
references.citation: Am J Med Genet. 2001 Sep 1;102(4):383-6
references.pmid: 11503168
references.citation: J Pediatr. 2004 Jun;144(6):783-91
references.pmid: 15192627
references.citation: Am J Med Genet A. 2006 Oct 1;140(19):2057-62
references.pmid: 16906538
references.citation: J Med Genet. 2000 May;37(5):321-35
references.pmid: 10807690
references.citation: J Inherit Metab Dis. 2007 Jun;30(3):375-87
references.pmid: 17497248