Long-term amelioration of feline mucopolysaccharidosis VI after AAV-mediated liver gene transfer

Gabriella Cotugno; Patrizia Annunziata; Alessandra Tessitore; Thomas O'Malley; Anita Capalbo; Armida Faella; Rosa Bartolomeo; Patricia O'Donnell; Ping Wang; Fabio Russo; Meg M. Sleeper; Van W. Knox; Steven Fernandez; Leah Levanduski; John Hopwood; Elvira De Leonibus; Mark Haskins; Alberto Auricchio

doi:10.1038/mt.2010.257

Long-term amelioration of feline mucopolysaccharidosis VI after AAV-mediated liver gene transfer

Gabriella Cotugno, Patrizia Annunziata, Alessandra Tessitore, Thomas O'Malley, Anita Capalbo, Armida Faella, Rosa Bartolomeo, Patricia O'Donnell, Ping Wang, Fabio Russo, Meg M. Sleeper, Van W. Knox, Steven Fernandez, Leah Levanduski, John Hopwood, Elvira De Leonibus, Mark Haskins, Alberto Auricchio

Lysosomal Diseases Research Unit

Research output: Contribution to journal › Article › peer-review

56 Citations (Scopus)

Abstract

Mucopolysaccharidosis VI (MPS VI) is caused by deficient arylsulfatase B (ARSB) activity resulting in lysosomal storage of glycosaminoglycans (GAGs). MPS VI is characterized by dysostosis multiplex, organomegaly, corneal clouding, and heart valve thickening. Gene transfer to a factory organ like liver may provide a lifetime source of secreted ARSB. We show that intravascular administration of adeno-associated viral vectors (AAV) 2/8-TBG-felineARSB in MPS VI cats resulted in ARSB expression up to 1 year, the last time point of the study. In newborn cats, normal circulating ARSB activity was achieved following delivery of high vector doses (6 × 10¹³ genome copies (gc)/kg) whereas delivery of AAV2/8 vector doses as low as 2 × 10¹² gc/kg resulted in higher than normal serum ARSB levels in juvenile MPS VI cats. In MPS VI cats showing high serum ARSB levels, independent of the age at treatment, we observed: (i) clearance of GAG storage, (ii) improvement of long bone length, (iii) reduction of heart valve thickness, and (iv) improvement in spontaneous mobility. Thus, AAV2/ 8-mediated liver gene transfer represents a promising therapeutic strategy for MPS VI patients.

Original language	English
Pages (from-to)	461-469
Number of pages	9
Journal	Molecular Therapy
Volume	19
Issue number	3
DOIs	https://doi.org/10.1038/mt.2010.257
Publication status	Published or Issued - Mar 2011

ASJC Scopus subject areas

Molecular Medicine
Molecular Biology
Genetics
Pharmacology
Drug Discovery

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Cotugno, G., Annunziata, P., Tessitore, A., O'Malley, T., Capalbo, A., Faella, A., Bartolomeo, R., O'Donnell, P., Wang, P., Russo, F., Sleeper, M. M., Knox, V. W., Fernandez, S., Levanduski, L., Hopwood, J., De Leonibus, E., Haskins, M., & Auricchio, A. (2011). Long-term amelioration of feline mucopolysaccharidosis VI after AAV-mediated liver gene transfer. Molecular Therapy, 19(3), 461-469. https://doi.org/10.1038/mt.2010.257

@article{8ee63ac17ff641f8ad258b263bf60ae7,

title = "Long-term amelioration of feline mucopolysaccharidosis VI after AAV-mediated liver gene transfer",

abstract = "Mucopolysaccharidosis VI (MPS VI) is caused by deficient arylsulfatase B (ARSB) activity resulting in lysosomal storage of glycosaminoglycans (GAGs). MPS VI is characterized by dysostosis multiplex, organomegaly, corneal clouding, and heart valve thickening. Gene transfer to a factory organ like liver may provide a lifetime source of secreted ARSB. We show that intravascular administration of adeno-associated viral vectors (AAV) 2/8-TBG-felineARSB in MPS VI cats resulted in ARSB expression up to 1 year, the last time point of the study. In newborn cats, normal circulating ARSB activity was achieved following delivery of high vector doses (6 × 1013 genome copies (gc)/kg) whereas delivery of AAV2/8 vector doses as low as 2 × 1012 gc/kg resulted in higher than normal serum ARSB levels in juvenile MPS VI cats. In MPS VI cats showing high serum ARSB levels, independent of the age at treatment, we observed: (i) clearance of GAG storage, (ii) improvement of long bone length, (iii) reduction of heart valve thickness, and (iv) improvement in spontaneous mobility. Thus, AAV2/ 8-mediated liver gene transfer represents a promising therapeutic strategy for MPS VI patients.",

author = "Gabriella Cotugno and Patrizia Annunziata and Alessandra Tessitore and Thomas O'Malley and Anita Capalbo and Armida Faella and Rosa Bartolomeo and Patricia O'Donnell and Ping Wang and Fabio Russo and Sleeper, {Meg M.} and Knox, {Van W.} and Steven Fernandez and Leah Levanduski and John Hopwood and {De Leonibus}, Elvira and Mark Haskins and Alberto Auricchio",

note = "Funding Information: The TIGEM AAV Vector Core produced the vectors used in this study. This work was supported by the European Union, 7th Frame Program “Euclyd—a European Consortium for Lysosomal Storage Diseases” grant 201678, and NIH grants DK25759 and RR02512. This work was done in Naples, Italy and in Philadelphia, PA, USA. The authors declared no conflict of interest.",

year = "2011",

month = mar,

doi = "10.1038/mt.2010.257",

language = "English",

volume = "19",

pages = "461--469",

journal = "Molecular Therapy",

issn = "1525-0016",

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Cotugno, G, Annunziata, P, Tessitore, A, O'Malley, T, Capalbo, A, Faella, A, Bartolomeo, R, O'Donnell, P, Wang, P, Russo, F, Sleeper, MM, Knox, VW, Fernandez, S, Levanduski, L, Hopwood, J, De Leonibus, E, Haskins, M & Auricchio, A 2011, 'Long-term amelioration of feline mucopolysaccharidosis VI after AAV-mediated liver gene transfer', Molecular Therapy, vol. 19, no. 3, pp. 461-469. https://doi.org/10.1038/mt.2010.257

TY - JOUR

T1 - Long-term amelioration of feline mucopolysaccharidosis VI after AAV-mediated liver gene transfer

AU - Cotugno, Gabriella

AU - Annunziata, Patrizia

AU - Tessitore, Alessandra

AU - O'Malley, Thomas

AU - Capalbo, Anita

AU - Faella, Armida

AU - Bartolomeo, Rosa

AU - O'Donnell, Patricia

AU - Wang, Ping

AU - Russo, Fabio

AU - Sleeper, Meg M.

AU - Knox, Van W.

AU - Fernandez, Steven

AU - Levanduski, Leah

AU - Hopwood, John

AU - De Leonibus, Elvira

AU - Haskins, Mark

AU - Auricchio, Alberto

N1 - Funding Information: The TIGEM AAV Vector Core produced the vectors used in this study. This work was supported by the European Union, 7th Frame Program “Euclyd—a European Consortium for Lysosomal Storage Diseases” grant 201678, and NIH grants DK25759 and RR02512. This work was done in Naples, Italy and in Philadelphia, PA, USA. The authors declared no conflict of interest.

PY - 2011/3

Y1 - 2011/3

N2 - Mucopolysaccharidosis VI (MPS VI) is caused by deficient arylsulfatase B (ARSB) activity resulting in lysosomal storage of glycosaminoglycans (GAGs). MPS VI is characterized by dysostosis multiplex, organomegaly, corneal clouding, and heart valve thickening. Gene transfer to a factory organ like liver may provide a lifetime source of secreted ARSB. We show that intravascular administration of adeno-associated viral vectors (AAV) 2/8-TBG-felineARSB in MPS VI cats resulted in ARSB expression up to 1 year, the last time point of the study. In newborn cats, normal circulating ARSB activity was achieved following delivery of high vector doses (6 × 1013 genome copies (gc)/kg) whereas delivery of AAV2/8 vector doses as low as 2 × 1012 gc/kg resulted in higher than normal serum ARSB levels in juvenile MPS VI cats. In MPS VI cats showing high serum ARSB levels, independent of the age at treatment, we observed: (i) clearance of GAG storage, (ii) improvement of long bone length, (iii) reduction of heart valve thickness, and (iv) improvement in spontaneous mobility. Thus, AAV2/ 8-mediated liver gene transfer represents a promising therapeutic strategy for MPS VI patients.

AB - Mucopolysaccharidosis VI (MPS VI) is caused by deficient arylsulfatase B (ARSB) activity resulting in lysosomal storage of glycosaminoglycans (GAGs). MPS VI is characterized by dysostosis multiplex, organomegaly, corneal clouding, and heart valve thickening. Gene transfer to a factory organ like liver may provide a lifetime source of secreted ARSB. We show that intravascular administration of adeno-associated viral vectors (AAV) 2/8-TBG-felineARSB in MPS VI cats resulted in ARSB expression up to 1 year, the last time point of the study. In newborn cats, normal circulating ARSB activity was achieved following delivery of high vector doses (6 × 1013 genome copies (gc)/kg) whereas delivery of AAV2/8 vector doses as low as 2 × 1012 gc/kg resulted in higher than normal serum ARSB levels in juvenile MPS VI cats. In MPS VI cats showing high serum ARSB levels, independent of the age at treatment, we observed: (i) clearance of GAG storage, (ii) improvement of long bone length, (iii) reduction of heart valve thickness, and (iv) improvement in spontaneous mobility. Thus, AAV2/ 8-mediated liver gene transfer represents a promising therapeutic strategy for MPS VI patients.

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U2 - 10.1038/mt.2010.257

DO - 10.1038/mt.2010.257

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VL - 19

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JO - Molecular Therapy

JF - Molecular Therapy

SN - 1525-0016

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ER -

Long-term amelioration of feline mucopolysaccharidosis VI after AAV-mediated liver gene transfer

Abstract

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