Lentiviral Hematopoietic Stem Cell Gene Therapy Corrects Murine Pompe Disease

被引:24
|
作者
Stok, Merel [1 ,2 ,3 ,9 ]
de Boer, Helen [1 ,4 ,10 ]
Huston, Marshall W. [1 ,5 ,11 ]
Jacobs, Edwin H. [5 ,6 ]
Roovers, Onno [1 ]
Visser, Trudi P. [1 ]
Jahr, Holger [7 ,12 ]
Duncker, Dirk J. [8 ]
van Deel, Elza D. [8 ,13 ]
Reuser, Arnold J. J. [3 ,4 ]
van Til, Niek P. [1 ,14 ,15 ]
Wagemaker, Gerard [1 ,16 ,17 ]
机构
[1] Erasmus Univ, Med Ctr, Dept Hematol, POB 37048, NL-3005 LA Rotterdam, Netherlands
[2] Erasmus Univ, Med Ctr, Dept Pediat, Rotterdam, Netherlands
[3] Erasmus Univ, Med Ctr, Ctr Lysosomal & Metab Dis, Rotterdam, Netherlands
[4] Erasmus Univ, Med Ctr, Dept Clin Genet, Mol Stem Cell Biol, Rotterdam, Netherlands
[5] Erasmus Univ, Med Ctr, Dept Mol Genet, Rotterdam, Netherlands
[6] Erasmus Univ, Med Ctr, Dept Clin Genet, Rotterdam, Netherlands
[7] Erasmus Univ, Med Ctr, Dept Orthopaed, Rotterdam, Netherlands
[8] Erasmus Univ, Med Ctr, Dept Cardiol, Div Expt Cardiol, Rotterdam, Netherlands
[9] ProPharma Grp, Leiden, Netherlands
[10] Merus NV, Utrecht, Netherlands
[11] Sangamo Therapeut, Richmond, CA USA
[12] Univ Hosp RWTH, Dept Orthopaed, Aachen, Germany
[13] Rotterdam Univ Appl Sci, Rotterdam, Netherlands
[14] Univ Med Ctr Utrecht, Ctr Translat Immunol, Cambridge, MA USA
[15] AvroBio, Cambridge, MA USA
[16] Hacettepe Med Univ, Stem Cell Res & Dev Ctr, Ankara, Turkey
[17] First Pavlov State Med Univ, Raisa Gorbacheva Mem Res Inst Pediat Oncol & Hema, St Petersburg, Russia
关键词
ENZYME REPLACEMENT THERAPY; ACID ALPHA-GLUCOSIDASE; CENTRAL-NERVOUS-SYSTEM; GLYCOGEN-STORAGE; NATURAL COURSE; ALGLUCOSIDASE ALPHA; ENERGY-METABOLISM; SCID PATIENTS; BONE-MARROW; VECTOR;
D O I
10.1016/j.omtm.2020.04.023
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
Pompe disease is an autosomal recessive lysosomal storage disorder characterized by progressive muscle weakness. The disease is caused by mutations in the acid a-glucosidase (GAA) gene. Despite the currently available enzyme replacement therapy (ERT), roughly half of the infants with Pompe disease die before the age of 3 years. Limitations of ERT are immune responses to the recombinant enzyme, incomplete correction of the disease phenotype, lifelong administration, and inability of the enzyme to cross the blood-brain barrier. We previously reported normalization of glycogen in heart tissue and partial correction of the skeletal muscle phenotype by ex vivo hematopoietic stem cell gene therapy. In the present study, using a codon-optimized GAA (GAAco), the enzyme levels resulted in close to normalization of glycogen in heart, muscles, and brain, and in complete normalization of motor function. A large proportion of microglia in the brain was shown to be GAA positive. All astrocytes contained the enzyme, which is in line with mannose-6-phosphate receptor expression and the key role in glycogen storage and glucose metabolism. The lentiviral vector insertion site analysis confirmed no preference for integration near proto-oncogenes. This correction of murine Pompe disease warrants further development toward a cure of the human condition.
引用
收藏
页码:1014 / 1025
页数:12
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