Directed Evolution of a Novel Adeno-associated Virus (AAV) Vector That Crosses the Seizure-compromised Blood-Brain Barrier (BBB)

被引:139
作者
Gray, Steven J. [1 ]
Blake, Bonita L. [2 ,3 ]
Criswell, Hugh E. [2 ,4 ]
Nicolson, Sarah C. [1 ,3 ]
Samulski, R. Jude [1 ,3 ]
McCown, Thomas J. [1 ,2 ,4 ]
机构
[1] Univ N Carolina, UNC Gene Therapy Ctr, Chapel Hill, NC 27515 USA
[2] Univ N Carolina, Dept Psychiat, Chapel Hill, NC USA
[3] Univ N Carolina, Dept Pharmacol, Chapel Hill, NC USA
[4] Univ N Carolina, Bowles Ctr Alcohol Studies, Chapel Hill, NC USA
关键词
IN-VIVO; DISEASE PROGRESSION; GENE-TRANSFER; FACTOR-IX; EXPRESSION; DELIVERY; TRANSDUCTION; HEMOPHILIA; TROPISM; LIVER;
D O I
10.1038/mt.2009.292
中图分类号
Q81 [生物工程学(生物技术)]; Q93 [微生物学];
学科分类号
071005 ; 0836 ; 090102 ; 100705 ;
摘要
DNA shuffling and directed evolution were employed to develop a novel adeno-associated virus (AAV) vector capable of crossing the seizure-compromised blood-brain barrier (BBB) and transducing cells in the brain. Capsid DNA from AAV serotypes 1-6, 8, and 9 were shuffled and recombined to create a library of chimeric AAVs. One day after kainic acid-induced limbic seizure activity in rats, the virus library was infused intravenously (i.v.), and 3 days later, neuron-rich cells were mechanically dissociated from seizure-sensitive brain sites, collected and viral DNA extracted. After three cycles of selection, green fluorescent protein (GFP)-packaged clones were administered directly into brain or i.v. 1 day after kainic acid-induced seizures. Several clones that were effective after intracranial administration did not transduce brain cells after the i.v. administration. However, two clones (32 and 83) transduced the cells after direct brain infusion and after i.v. administration transduced the cells that were localized to the piriform cortex and ventral hippocampus, areas exhibiting a seizure-compromised BBB. No transduction occurred in areas devoid of BBB compromise. Only one parental serotype (AAV8) exhibited a similar expression profile, but the biodistribution of 32 and 83 diverged dramatically from this parental serotype. Thus, novel AAV vectors have been created that can selectively cross the seizure-compromised BBB and transduce cells.
引用
收藏
页码:570 / 578
页数:9
相关论文
共 29 条
[1]   Astrocyte-endothelial interactions at the blood-brain barrier [J].
Abbott, NJ ;
Rönnbäck, L ;
Hansson, E .
NATURE REVIEWS NEUROSCIENCE, 2006, 7 (01) :41-53
[2]   Brain regional differences in the effect of ethanol on GABA release from presynaptic terminals [J].
Criswell, Hugh E. ;
Ming, Zhen ;
Kelm, M. Katherine ;
Breese, George R. .
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, 2008, 326 (02) :596-603
[3]   Intravenous Administration of Self-complementary AAV9 Enables Transgene Delivery to Adult Motor Neurons [J].
Duque, Sandra ;
Joussemet, Beatrice ;
Riviere, Christel ;
Marais, Thibaut ;
Dubreil, Laurence ;
Douar, Anne-Marie ;
Fyfe, John ;
Moullier, Philippe ;
Colle, Marie-Anne ;
Barkats, Martine .
MOLECULAR THERAPY, 2009, 17 (07) :1187-1196
[4]  
Foti SB, 2009, NEUROMETHODS, V40, P235, DOI 10.1007/978-1-60327-263-6_13
[5]   Intravascular AAV9 preferentially targets neonatal neurons and adult astrocytes [J].
Foust, Kevin D. ;
Nurre, Emily ;
Montgomery, Chrystal L. ;
Hernandez, Anna ;
Chan, Curtis M. ;
Kaspar, Brian K. .
NATURE BIOTECHNOLOGY, 2009, 27 (01) :59-65
[6]   Adeno-Associated Virus-Mediated Gene Transfer to Nonhuman Primate Liver Can Elicit Destructive Transgene-Specific T Cell Responses [J].
Gao, Guangping ;
Wang, Qiang ;
Calcedo, Roberto ;
Mays, Lauren ;
Bell, Peter ;
Wang, Lili ;
Vandenberghe, Luk H. ;
Grant, Rebecca ;
Sanmiguel, Julio ;
Furth, Emma E. ;
Wilson, James M. .
HUMAN GENE THERAPY, 2009, 20 (09) :930-942
[7]   Production and characterization of adeno-associated viral vectors [J].
Grieger, Joshua C. ;
Choi, Vivian W. ;
Samulski, R. Jude .
NATURE PROTOCOLS, 2006, 1 (03) :1412-1428
[8]   In vitro and in vivo gene therapy vector evolution via multispecies interbreeding and retargeting of adeno-associated viruses [J].
Grimm, Dirk ;
Lee, Joyce S. ;
Wang, Lora ;
Desai, Tushar ;
Akache, Bassel ;
Storm, Theresa A. ;
Kay, Mark A. .
JOURNAL OF VIROLOGY, 2008, 82 (12) :5887-5911
[9]   Attenuation of seizures and neuronal death by adeno-associated virus vector galanin expression and secretion [J].
Haberman, RP ;
Samulski, RJ ;
McCown, TJ .
NATURE MEDICINE, 2003, 9 (08) :1076-1080
[10]   Brain diffusion after single seizures [J].
Hufnagel, A ;
Weber, J ;
Marks, S ;
Ludwig, T ;
De Greiff, A ;
Leonhardt, G ;
Widmann, G ;
Stolke, T ;
Forsting, M .
EPILEPSIA, 2003, 44 (01) :54-63