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.
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机构:
Univ N Carolina, UNC Gene Therapy Ctr, Chapel Hill, NC 27515 USAUniv N Carolina, UNC Gene Therapy Ctr, Chapel Hill, NC 27515 USA
Gray, Steven J.
[1
]
Blake, Bonita L.
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机构:
Univ N Carolina, Dept Psychiat, Chapel Hill, NC USA
Univ N Carolina, Dept Pharmacol, Chapel Hill, NC USAUniv N Carolina, UNC Gene Therapy Ctr, Chapel Hill, NC 27515 USA
Blake, Bonita L.
[2
,3
]
Criswell, Hugh E.
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机构:
Univ N Carolina, Dept Psychiat, Chapel Hill, NC USA
Univ N Carolina, Bowles Ctr Alcohol Studies, Chapel Hill, NC USAUniv N Carolina, UNC Gene Therapy Ctr, Chapel Hill, NC 27515 USA
Criswell, Hugh E.
[2
,4
]
Nicolson, Sarah C.
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机构:
Univ N Carolina, UNC Gene Therapy Ctr, Chapel Hill, NC 27515 USA
Univ N Carolina, Dept Pharmacol, Chapel Hill, NC USAUniv N Carolina, UNC Gene Therapy Ctr, Chapel Hill, NC 27515 USA
Nicolson, Sarah C.
[1
,3
]
Samulski, R. Jude
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机构:
Univ N Carolina, UNC Gene Therapy Ctr, Chapel Hill, NC 27515 USA
Univ N Carolina, Dept Pharmacol, Chapel Hill, NC USAUniv N Carolina, UNC Gene Therapy Ctr, Chapel Hill, NC 27515 USA
Samulski, R. Jude
[1
,3
]
McCown, Thomas J.
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机构:
Univ N Carolina, UNC Gene Therapy Ctr, Chapel Hill, NC 27515 USA
Univ N Carolina, Dept Psychiat, Chapel Hill, NC USA
Univ N Carolina, Bowles Ctr Alcohol Studies, Chapel Hill, NC USAUniv N Carolina, UNC Gene Therapy Ctr, Chapel Hill, NC 27515 USA
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
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.
机构:
Univ N Carolina, Bowles Ctr Alcohol Studies, Chapel Hill, NC 27599 USA
Univ N Carolina, Dept Psychiat, Chapel Hill, NC 27599 USAUniv N Carolina, Bowles Ctr Alcohol Studies, Chapel Hill, NC 27599 USA
Criswell, Hugh E.
;
Ming, Zhen
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机构:
Univ N Carolina, Bowles Ctr Alcohol Studies, Chapel Hill, NC 27599 USAUniv N Carolina, Bowles Ctr Alcohol Studies, Chapel Hill, NC 27599 USA
Ming, Zhen
;
Kelm, M. Katherine
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机构:
Univ N Carolina, Bowles Ctr Alcohol Studies, Chapel Hill, NC 27599 USA
Univ N Carolina, Dept Pharmacol, Chapel Hill, NC 27599 USAUniv N Carolina, Bowles Ctr Alcohol Studies, Chapel Hill, NC 27599 USA
Kelm, M. Katherine
;
Breese, George R.
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h-index: 0
机构:
Univ N Carolina, Bowles Ctr Alcohol Studies, Chapel Hill, NC 27599 USA
Univ N Carolina, Dept Psychiat, Chapel Hill, NC 27599 USA
Univ N Carolina, Dept Pharmacol, Chapel Hill, NC 27599 USAUniv N Carolina, Bowles Ctr Alcohol Studies, Chapel Hill, NC 27599 USA
机构:
Univ N Carolina, Bowles Ctr Alcohol Studies, Chapel Hill, NC 27599 USA
Univ N Carolina, Dept Psychiat, Chapel Hill, NC 27599 USAUniv N Carolina, Bowles Ctr Alcohol Studies, Chapel Hill, NC 27599 USA
Criswell, Hugh E.
;
Ming, Zhen
论文数: 0引用数: 0
h-index: 0
机构:
Univ N Carolina, Bowles Ctr Alcohol Studies, Chapel Hill, NC 27599 USAUniv N Carolina, Bowles Ctr Alcohol Studies, Chapel Hill, NC 27599 USA
Ming, Zhen
;
Kelm, M. Katherine
论文数: 0引用数: 0
h-index: 0
机构:
Univ N Carolina, Bowles Ctr Alcohol Studies, Chapel Hill, NC 27599 USA
Univ N Carolina, Dept Pharmacol, Chapel Hill, NC 27599 USAUniv N Carolina, Bowles Ctr Alcohol Studies, Chapel Hill, NC 27599 USA
Kelm, M. Katherine
;
Breese, George R.
论文数: 0引用数: 0
h-index: 0
机构:
Univ N Carolina, Bowles Ctr Alcohol Studies, Chapel Hill, NC 27599 USA
Univ N Carolina, Dept Psychiat, Chapel Hill, NC 27599 USA
Univ N Carolina, Dept Pharmacol, Chapel Hill, NC 27599 USAUniv N Carolina, Bowles Ctr Alcohol Studies, Chapel Hill, NC 27599 USA