Effective gene therapy in an authentic model of Tay-Sachs-related diseases

被引：108

作者：

Cachon-Gonzalez, M. Begona

Wang, Susan Z.

Lynch, Andrew

Ziegler, Robin

Cheng, Seng H.

Cox, Timothy M.

机构：

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

[2] Ctr Appl Med Stat, Dept Publ Hlth & Primary Care, Cambridge CB2 2SR, England

[3] Genzyme Corp, Framingham, MA 01701 USA

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2006年 / 103卷 / 27期

基金：

英国惠康基金;

关键词：

adeno-associated virus; GM2; gangliosidosis; neurodegeneration;

D O I：

10.1073/pnas.0603765103

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Tay-Sachs disease is a prototypic neurodegenerative disease. Lysosomal storage of GM2 ganglioside in Tay-Sachs and the related disorder, Sandhoff disease, is caused by deficiency of beta-hexosaminidase A, a heterodimeric protein. Tay-Sachs-related diseases (GM2 gangliosidoses) are incurable, but gene therapy has the potential for widespread correction of the underlying lysosomal defect by means of the secretion-recapture cellular pathway for enzymatic complementation. Sandhoff mice, lacking the beta-subunit of hexosaminidase, manifest many signs of classical human Tay-Sachs disease and, with an acute course, die before 20 weeks of age. We treated Sandhoff mice by stereotaxic intracranial inoculation of recombinant adeno-associated viral vectors encoding the complementing human beta-hexosaminidase a and beta subunit genes and elements, including an HIV tat sequence, to enhance protein expression and distribution. Animals survived for > 1 year with sustained, widespread, and abundant enzyme delivery in the nervous system. Onset of the disease was delayed with preservation of motor function; inflammation and GM2 ganglioside storage in the brain and spinal cord was reduced. Gene delivery of beta-hexosaminidase A by using adeno-associated viral vectors has realistic potential for treating the human Tay-Sachs-related diseases.

引用

页码：10373 / 10378

页数：6

共 33 条

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