title: Long-term sex-biased correction of circulating propionic acidemia disease markers by adeno-associated virus vectors.
abstract: Propionic academia (PA) occurs because of mutations in the PCCA or PCCB genes encoding the two subunits of propionyl-CoA carboxylase, a pivotal enzyme in the breakdown of certain amino acids and odd-chain fatty acids. There is no cure for PA, but dietary protein restriction and liver transplantation can attenuate its symptoms. We show here that a single intravenous injection of adeno-associated virus 2/8 (AAV8) or AAVrh10 expressing PCCA into PA hypomorphic mice decreased systemic propionylcarnitine and methyl citrate for up to 1.5 years. However, long-term phenotypic correction was always better in male mice. AAV-mediated PCCA expression was similar in most tissues in males and females at early time points and differed only in the liver. Over 1.5 years, luciferase and PCCA expression remained elevated in cardiac tissue for both sexes. In contrast, transgene expression in the liver and skeletal muscles of female, but not male, mice waned—suggesting that these tissues were major sinks for systemic phenotypic correction. These data indicate that single systemic intravenous therapy by AAV vectors can mediate long-term phenotype correction for PA. However, tissue-specific loss of expression in females reduces efficacy when compared with males. Whether similar sex-biased AAV effects occur in human gene therapy remains to be determined.
authors: 1 Virology and Gene Therapy Graduate Program, Mayo Clinic , Rochester, MN 55905.
authors: Adam J
authors: AJ
authors: Guenzel
authors: Renata
authors: R
authors: Collard
authors: Jan P
authors: JP
authors: Kraus
authors: Dietrich
authors: D
authors: Matern
authors: Michael A
authors: MA
authors: Barry
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000097:blood*; D002331:Carnitine / Q000031:analogs & derivatives / Q000097:blood; D002951:Citrates / Q000097:blood; D000229:Dependovirus; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics*; D007275:Injections, Intravenous; D008099:Liver / Q000378:metabolism; D008156:Luciferases; D008297:Male; D043586:Methylmalonyl-CoA Decarboxylase / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018482:Muscle, Skeletal / Q000378:metabolism; D056693:Propionic Acidemia / Q000097:blood / Q000235:genetics* / Q000628:therapy*; D060888:Real-Time Polymerase Chain Reaction; D012727:Sex Characteristics
chemical_list: D015415:Biomarkers; D002951:Citrates; C003223:propionylcarnitine; C031605:2-methylcitric acid; D008156:Luciferases; D043586:Methylmalonyl-CoA Decarboxylase; D002331:Carnitine
references: Biochem J. 2006 Aug 15;398(1):107-12
references: 16686602
references: Pediatr Transplant. 2006 Nov;10(7):773-81
references: 17032422
references: J Inherit Metab Dis. 2012 Jan;35(1):51-63
references: 22033733
references: Science. 2013 Mar 1;339(6123):1084-8
references: 23328391
references: J Inherit Metab Dis. 2006 Apr-Jun;29(2-3):288-98
references: 16763890
references: Pediatr Res. 2008 Aug;64(2):213-7
references: 18414145
references: Mol Ther. 2009 Sep;17(9):1548-54
references: 19568224
references: Transplant Proc. 1997 Feb-Mar;29(1-2):444-5
references: 9123073
references: J Pediatr. 2000 Oct;137(4):572-4
references: 11035841
references: Hum Gene Ther. 2009 Feb;20(2):169-80
references: 19025475
references: Mol Genet Metab. 2001 Sep-Oct;74(1-2):238-47
references: 11592820
references: J Biol Chem. 2005 Jul 29;280(30):27719-27
references: 15890657
references: Pharmacol Biochem Behav. 2002 Oct;73(3):623-9
references: 12151037
references: J Inherit Metab Dis. 1995;18(4):448-61
references: 7494403
references: Hum Gene Ther. 2015 Mar;26(3):153-60
references: 25654275
references: Pediatr Res. 2009 Jul;66(1):91-5
references: 19342984
references: J Biol Chem. 2001 Sep 21;276(38):35995-9
references: 11461925
references: Gene Ther. 2001 Sep;8(17):1343-6
references: 11571571
references: J Clin Invest. 2015 Feb;125(2):870-80
references: 25607839
references: Mol Genet Metab. 2012 Jan;105(1):26-33
references: 21963082
references: J Virol. 2005 Mar;79(6):3606-14
references: 15731255
references: Hum Gene Ther. 2010 Oct;21(10):1259-71
references: 20497038
references: J Virol. 2005 Sep;79(17):11434-42
references: 16103194
references: Hum Gene Ther. 2011 Apr;22(4):477-81
references: 20950151
references: Mitochondrion. 2011 May;11(3):533-6
references: 21329767
references: Science. 2009 Apr 3;324(5923):98-102
references: 19342590
references: Clin Chem. 2008 Apr;54(4):657-64
references: 18281422
references: J Clin Invest. 1971 Jan;50(1):127-30
references: 5101292
references: Pediatr Res. 1975 Dec;9(12):905-8
references: 127973
references: Hum Gene Ther. 2009 Aug;20(8):908-17
references: 19419275
references: J Inherit Metab Dis. 2004;27(2):205-10
references: 15159651
references: Eur J Pediatr. 2000 Jan-Feb;159(1-2):54-8
references: 10653330
references: Pediatr Res. 1990 Apr;27(4 Pt 1):413-6
references: 2342832
references: Mol Genet Metab. 2003 Sep-Oct;80(1-2):181-8
references: 14567967
references: Pediatrics. 1974 Mar;53(3):391-5
references: 4815259
references: J Inherit Metab Dis. 2013 Jul;36(4):635-44
references: 23512157
references: Congest Heart Fail. 2001 Jul-Aug;7(4):218-219
references: 11828170
references: Mol Genet Metab. 2012 Jan;105(1):5-9
references: 21986446
references: Blood. 2003 Jul 15;102(2):480-8
references: 12637328
references: Science. 2007 Jul 27;317(5837):477
references: 17656716
references: Mol Ther. 2013 Jul;21(7):1316-23
references: 23648696
references: Pediatrics. 2010 Jul;126(1):e208-14
references: 20566609
references: Mol Genet Metab. 2005 Aug;85(4):286-90
references: 15939644
references: Orphanet J Rare Dis. 2014 Sep 02;9:130
references: 25205257
references: Clin Chem. 2010 Nov;56(11):1686-95
references: 20807894