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Lentiviral gene therapy of murine hematopoietic stem cells ameliorates the Pompe disease phenotype.
Blood. 2010 Jul 01; 115(26):5329-37.Blood

Abstract

Pompe disease (acid alpha-glucosidase deficiency) is a lysosomal glycogen storage disorder characterized in its most severe early-onset form by rapidly progressive muscle weakness and mortality within the first year of life due to cardiac and respiratory failure. Enzyme replacement therapy prolongs the life of affected infants and supports the condition of older children and adults but entails lifelong treatment and can be counteracted by immune responses to the recombinant enzyme. We have explored the potential of lentiviral vector-mediated expression of human acid alpha-glucosidase in hematopoietic stem cells (HSCs) in a Pompe mouse model. After mild conditioning, transplantation of genetically engineered HSCs resulted in stable chimerism of approximately 35% hematopoietic cells that overexpress acid alpha-glucosidase and in major clearance of glycogen in heart, diaphragm, spleen, and liver. Cardiac remodeling was reversed, and respiratory function, skeletal muscle strength, and motor performance improved. Overexpression of acid alpha-glucosidase did not affect overall hematopoietic cell function and led to immune tolerance as shown by challenge with the human recombinant protein. On the basis of the prominent and sustained therapeutic efficacy without adverse events in mice we conclude that ex vivo HSC gene therapy is a treatment option worthwhile to pursue.

Authors+Show Affiliations

Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

20385789

Citation

van Til, Niek P., et al. "Lentiviral Gene Therapy of Murine Hematopoietic Stem Cells Ameliorates the Pompe Disease Phenotype." Blood, vol. 115, no. 26, 2010, pp. 5329-37.
van Til NP, Stok M, Aerts Kaya FS, et al. Lentiviral gene therapy of murine hematopoietic stem cells ameliorates the Pompe disease phenotype. Blood. 2010;115(26):5329-37.
van Til, N. P., Stok, M., Aerts Kaya, F. S., de Waard, M. C., Farahbakhshian, E., Visser, T. P., Kroos, M. A., Jacobs, E. H., Willart, M. A., van der Wegen, P., Scholte, B. J., Lambrecht, B. N., Duncker, D. J., van der Ploeg, A. T., Reuser, A. J., Verstegen, M. M., & Wagemaker, G. (2010). Lentiviral gene therapy of murine hematopoietic stem cells ameliorates the Pompe disease phenotype. Blood, 115(26), 5329-37. https://doi.org/10.1182/blood-2009-11-252874
van Til NP, et al. Lentiviral Gene Therapy of Murine Hematopoietic Stem Cells Ameliorates the Pompe Disease Phenotype. Blood. 2010 Jul 1;115(26):5329-37. PubMed PMID: 20385789.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Lentiviral gene therapy of murine hematopoietic stem cells ameliorates the Pompe disease phenotype. AU - van Til,Niek P, AU - Stok,Merel, AU - Aerts Kaya,Fatima S F, AU - de Waard,Monique C, AU - Farahbakhshian,Elnaz, AU - Visser,Trudi P, AU - Kroos,Marian A, AU - Jacobs,Edwin H, AU - Willart,Monique A, AU - van der Wegen,Pascal, AU - Scholte,Bob J, AU - Lambrecht,Bart N, AU - Duncker,Dirk J, AU - van der Ploeg,Ans T, AU - Reuser,Arnold J J, AU - Verstegen,Monique M, AU - Wagemaker,Gerard, Y1 - 2010/04/12/ PY - 2010/4/14/entrez PY - 2010/4/14/pubmed PY - 2010/8/3/medline SP - 5329 EP - 37 JF - Blood JO - Blood VL - 115 IS - 26 N2 - Pompe disease (acid alpha-glucosidase deficiency) is a lysosomal glycogen storage disorder characterized in its most severe early-onset form by rapidly progressive muscle weakness and mortality within the first year of life due to cardiac and respiratory failure. Enzyme replacement therapy prolongs the life of affected infants and supports the condition of older children and adults but entails lifelong treatment and can be counteracted by immune responses to the recombinant enzyme. We have explored the potential of lentiviral vector-mediated expression of human acid alpha-glucosidase in hematopoietic stem cells (HSCs) in a Pompe mouse model. After mild conditioning, transplantation of genetically engineered HSCs resulted in stable chimerism of approximately 35% hematopoietic cells that overexpress acid alpha-glucosidase and in major clearance of glycogen in heart, diaphragm, spleen, and liver. Cardiac remodeling was reversed, and respiratory function, skeletal muscle strength, and motor performance improved. Overexpression of acid alpha-glucosidase did not affect overall hematopoietic cell function and led to immune tolerance as shown by challenge with the human recombinant protein. On the basis of the prominent and sustained therapeutic efficacy without adverse events in mice we conclude that ex vivo HSC gene therapy is a treatment option worthwhile to pursue. SN - 1528-0020 UR - https://www.unboundmedicine.com/medline/citation/20385789/Lentiviral_gene_therapy_of_murine_hematopoietic_stem_cells_ameliorates_the_Pompe_disease_phenotype_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0006-4971(20)58381-X DB - PRIME DP - Unbound Medicine ER -