In Vivo Selection Yields AAV-B1 Capsid for Central Nervous System and Muscle Gene Therapy

被引：97

作者：

Choudhury, Sourav R. ^{[1
,2
]}

Fitzpatrick, Zachary ^{[3
,4
]}

Harris, Anne F. ^{[1
,2
]}

Maitland, Stacy A. ^{[1
,2
]}

Ferreira, Jennifer S. ^{[1
,2
]}

Zhang, Yuanfan ^{[5
,6
,7
]}

Ma, Shan ^{[2
,8
]}

Sharma, Rohit B. ^{[9
]}

Gray-Edwards, Heather L. ^{[10
]}

Johnson, Jacob A. ^{[11
]}

Johnson, Aime K. ^{[11
]}

Alonso, Laura C. ^{[9
]}

Punzo, Claudio ^{[2
,8
]}

Wagner, Kathryn R. ^{[5
,6
,7
]}

Maguire, Casey A. ^{[3
,4
]}

Kotin, Robert M. ^{[2
,12
]}

Martin, Douglas R. ^{[10
,13
]}

Sena-Esteves, Miguel ^{[1
,2
]}

机构：

[1] Univ Massachusetts, Sch Med, Dept Neurol, Worcester, MA USA

[2] Univ Massachusetts, Sch Med, Gene Therapy Ctr, 368 Plantat St,ASC6-2055, Worcester, MA 01605 USA

[3] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA

[4] Harvard Med Sch, Program Neurosci, Boston, MA USA

[5] Johns Hopkins Sch Med, Kennedy Krieger Inst, Hugo W Moser Res Inst, Baltimore, MD USA

[6] Johns Hopkins Sch Med, Dept Neurol, Baltimore, MD USA

[7] Johns Hopkins Sch Med, Dept Neurosci, Baltimore, MD USA

[8] Univ Massachusetts, Sch Med, Dept Ophthalmol, Worcester, MA USA

[9] Univ Massachusetts, Sch Med, Diabet Ctr Excellence, Worcester, MA USA

[10] Auburn Univ, Coll Vet Med, Scott Ritchey Res Ctr, Auburn, AL 36849 USA

[11] Auburn Univ, Coll Vet Med, Dept Clin Sci, Auburn, AL 36849 USA

[12] Voyager Therapeut, Cambridge, MA USA

[13] Auburn Univ, Coll Vet Med, Dept Anat Physiol & Pharmacol, Auburn, AL 36849 USA

来源：

MOLECULAR THERAPY | 2016年 / 24卷 / 07期

关键词：

BLOOD-BRAIN-BARRIER; ADENOASSOCIATED VIRAL VECTOR; DIRECTED EVOLUTION; ADULT MICE; PERIPHERAL-TISSUES; NONHUMAN-PRIMATES; HEMOPHILIA-B; VIRUS VECTOR; PHASE-I; DELIVERY;

D O I：

10.1038/mt.2016.84

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：

Adeno-associated viral (AAV) vectors have shown promise as a platform for gene therapy of neurological disorders. Achieving global gene delivery to the central nervous system (CNS) is key for development of effective therapies for many of these diseases. Here we report the isolation of a novel CNS tropic AAV capsid, AAV-B1, after a single round of in vivo selection from an AAV capsid library. Systemic injection of AAV-B1 vector in adult mice and cat resulted in widespread gene transfer throughout the CNS with transduction of multiple neuronal subpopulations. In addition, AAV-B1 transduces muscle, beta-cells, pulmonary alveoli, and retinal vasculature at high efficiency. This vector is more efficient than AAV9 for gene delivery to mouse brain, spinal cord, muscle, pancreas, and lung. Together with reduced sensitivity to neutralization by antibodies in pooled human sera, the broad transduction profile of AAV-B1 represents an important improvement over AAV9 for CNS gene therapy.

引用

页码：1247 / 1257

页数：11

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