Therapeutic Response in Feline Sandhoff Disease Despite Immunity to Intracranial Gene Therapy

被引：65

作者：

Bradbury, Allison M. ^{[1
,2
]}

Cochran, J. Nicholas ^{[1
]}

McCurdy, Victoria J. ^{[1
,2
]}

Johnson, Aime K. ^{[3
]}

Brunson, Brandon L. ^{[2
]}

Gray-Edwards, Heather ^{[1
]}

Leroy, Stanley G. ^{[4
,5
]}

Hwang, Misako ^{[1
]}

Randle, Ashley N. ^{[1
]}

Jackson, Laura S. ^{[1
]}

Morrison, Nancy E. ^{[1
]}

Baek, Rena C. ^{[6
]}

Seyfried, Thomas N. ^{[6
]}

Cheng, Seng H. ^{[7
]}

Cox, Nancy R. ^{[1
]}

Baker, Henry J. ^{[1
]}

Cachon-Gonzalez, M. Begona ^{[9
]}

Cox, Timothy M. ^{[8
,9
]}

Sena-Esteves, Miguel ^{[4
,5
]}

Martin, Douglas R. ^{[1
,2
]}

机构：

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

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

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

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

[5] Univ Massachusetts, Sch Med, Gene Therapy Ctr, Worcester, MA USA

[6] Boston Coll, Dept Biol, Chestnut Hill, MA 02167 USA

[7] Genzyme Corp, Framingham, MA 01701 USA

[8] Auburn Univ, Coll Vet Med, Dept Pathobiol, Auburn, AL 36849 USA

[9] Univ Cambridge, Addenbrookes Hosp, Dept Med, Cambridge CB2 2QQ, England

来源：

MOLECULAR THERAPY | 2013年 / 21卷 / 07期

基金：

美国国家卫生研究院;

关键词：

BETA-HEXOSAMINIDASE DEFICIENCY; THIN-LAYER-CHROMATOGRAPHY; LYSOSOMAL STORAGE DISEASE; TAY-SACHS-DISEASE; GM2; GANGLIOSIDOSIS; BRAIN GANGLIOSIDE; MOUSE-BRAIN; MODEL MICE; SURVIVAL; DELIVERY;

D O I：

10.1038/mt.2013.86

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：

Salutary responses to adeno-associated viral (AAV) gene therapy have been reported in the mouse model of Sandhoff disease (SD), a neurodegenerative lysosomal storage disease caused by deficiency of beta-N-acetylhexosaminidase (Hex). While untreated mice reach the humane endpoint by 4.1 months of age, mice treated by a single intracranial injection of vectors expressing human hexosaminidase may live a normal life span of 2 years. When treated with the same therapeutic vectors used in mice, two cats with SD lived to 7.0 and 8.2 months of age, compared with an untreated life span of 4.5 +/- 0.5 months (n = 11). Because a pronounced humoral immune response to both the AAV1 vectors and human hexosaminidase was documented, feline cDNAs for the hexosaminidase alpha- and beta-subunits were cloned into AAVrh8 vectors. Cats treated with vectors expressing feline hexosaminidase produced enzymatic activity >75-fold normal at the brain injection site with little evidence of an immune infiltrate. Affected cats treated with feline-specific vectors by bilateral injection of the thalamus lived to 10.4 +/- 3.7 months of age (n = 3), or 2.3 times as long as untreated cats. These studies support the therapeutic potential of AAV vectors for SD and underscore the importance of species-specific cDNAs for translational research.

引用

页码：1306 / 1315

页数：10

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