Gel-mediated delivery of AAV1 vectors corrects ventilatory function in pompe mice with established disease

Cathryn S. Mah; Darin J. Falk; Sean A. Germain; Jeffry S. Kelley; Melissa A. Lewis; Denise A. Cloutier; Lara R. Deruisseau; Thomas J. Conlon; Kerry O. Cresawn; Thomas J. Fraites; Martha Campbell-Thompson; David D. Fuller; Barry J. Byrne

doi:10.1038/mt.2009.305

Gel-mediated delivery of AAV1 vectors corrects ventilatory function in pompe mice with established disease

Cathryn S. Mah, Darin J. Falk, Sean A. Germain, Jeffry S. Kelley, Melissa A. Lewis, Denise A. Cloutier, Lara R. Deruisseau, Thomas J. Conlon, Kerry O. Cresawn, Thomas J. Fraites, Martha Campbell-Thompson, David D. Fuller, Barry J. Byrne

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

66 Scopus citations

Abstract

Pompe disease is a muscular dystrophy that results in respiratory insufficiency. We characterized the outcomes of targeted delivery of recombinant adeno-associated virus serotype 1 (rAAV2/1) vector to diaphragms of Pompe mice with varying stages of disease progression. We observed significant improvement in diaphragm contractile strength in mice treated at 3 months of age that is sustained at least for 1 year and enhanced contractile strength in mice treated at 9 and 21 months of age, measured 3 months post-treatment. Ventilatory parameters including tidal volume/inspiratory time ratio, minute ventilation/expired CO 2 ratio, and peak inspiratory airflow were significantly improved in mice treated at 3 months and tested at 6 months. Despite early improvement, mice treated at 3 months and tested at 1 year had diminished normoxic ventilation, potentially due to attenuation of correction over time or progressive degeneration of nontargeted accessory tissues. However, for all rAAV2/1-treated mice (treated at 3, 9, and 21 months, assayed 3 months later; treated at 3 months, assayed at 1 year), minute ventilation and peak inspiratory flows were significantly improved during respiratory challenge. These results demonstrate that gel-mediated delivery of rAAV2/1 vectors can significantly augment ventilatory function at initial and late phases of disease in a model of muscular dystrophy.

Original language	English (US)
Pages (from-to)	502-510
Number of pages	9
Journal	Molecular Therapy
Volume	18
Issue number	3
DOIs	https://doi.org/10.1038/mt.2009.305
State	Published - Mar 2010
Externally published	Yes

ASJC Scopus subject areas

Molecular Medicine
Molecular Biology
Genetics
Pharmacology
Drug Discovery

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Mah, C. S., Falk, D. J., Germain, S. A., Kelley, J. S., Lewis, M. A., Cloutier, D. A., Deruisseau, L. R., Conlon, T. J., Cresawn, K. O., Fraites, T. J., Campbell-Thompson, M., Fuller, D. D., & Byrne, B. J. (2010). Gel-mediated delivery of AAV1 vectors corrects ventilatory function in pompe mice with established disease. Molecular Therapy, 18(3), 502-510. https://doi.org/10.1038/mt.2009.305

@article{4ba8e8d4dfb44dcc8369cd5771c650fe,

title = "Gel-mediated delivery of AAV1 vectors corrects ventilatory function in pompe mice with established disease",

abstract = "Pompe disease is a muscular dystrophy that results in respiratory insufficiency. We characterized the outcomes of targeted delivery of recombinant adeno-associated virus serotype 1 (rAAV2/1) vector to diaphragms of Pompe mice with varying stages of disease progression. We observed significant improvement in diaphragm contractile strength in mice treated at 3 months of age that is sustained at least for 1 year and enhanced contractile strength in mice treated at 9 and 21 months of age, measured 3 months post-treatment. Ventilatory parameters including tidal volume/inspiratory time ratio, minute ventilation/expired CO 2 ratio, and peak inspiratory airflow were significantly improved in mice treated at 3 months and tested at 6 months. Despite early improvement, mice treated at 3 months and tested at 1 year had diminished normoxic ventilation, potentially due to attenuation of correction over time or progressive degeneration of nontargeted accessory tissues. However, for all rAAV2/1-treated mice (treated at 3, 9, and 21 months, assayed 3 months later; treated at 3 months, assayed at 1 year), minute ventilation and peak inspiratory flows were significantly improved during respiratory challenge. These results demonstrate that gel-mediated delivery of rAAV2/1 vectors can significantly augment ventilatory function at initial and late phases of disease in a model of muscular dystrophy.",

author = "Mah, {Cathryn S.} and Falk, {Darin J.} and Germain, {Sean A.} and Kelley, {Jeffry S.} and Lewis, {Melissa A.} and Cloutier, {Denise A.} and Deruisseau, {Lara R.} and Conlon, {Thomas J.} and Cresawn, {Kerry O.} and Fraites, {Thomas J.} and Martha Campbell-Thompson and Fuller, {David D.} and Byrne, {Barry J.}",

note = "Funding Information: We gratefully acknowledge the University of Florida Powell Gene Therapy Center Vector Core Laboratory, which produced some of the rAAV vectors used in this study, the University of Florida Powell Gene Therapy NGVL Toxicology Core Center for nucleic acid analysis, and the University of Florida Molecular Pathology and Immunology Core for assistance in histologic analysis. This work was supported by grants from the National Institutes of Health (NHLBI P01 HL59412-06, NIDDK P01 DK58327-03, 1R01HD052682-01A1, NHLBI-1F32HL095282-01A1 (D.J.F.)) and the American Heart Association National Center (C.M.). B.J.B., The Johns Hopkins University, and the University of Florida could be entitled to patent royalties for inventions described in this article.",

year = "2010",

month = mar,

doi = "10.1038/mt.2009.305",

language = "English (US)",

volume = "18",

pages = "502--510",

journal = "Molecular Therapy",

issn = "1525-0016",

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T1 - Gel-mediated delivery of AAV1 vectors corrects ventilatory function in pompe mice with established disease

AU - Mah, Cathryn S.

AU - Falk, Darin J.

AU - Germain, Sean A.

AU - Kelley, Jeffry S.

AU - Lewis, Melissa A.

AU - Cloutier, Denise A.

AU - Deruisseau, Lara R.

AU - Conlon, Thomas J.

AU - Cresawn, Kerry O.

AU - Fraites, Thomas J.

AU - Campbell-Thompson, Martha

AU - Fuller, David D.

AU - Byrne, Barry J.

N1 - Funding Information: We gratefully acknowledge the University of Florida Powell Gene Therapy Center Vector Core Laboratory, which produced some of the rAAV vectors used in this study, the University of Florida Powell Gene Therapy NGVL Toxicology Core Center for nucleic acid analysis, and the University of Florida Molecular Pathology and Immunology Core for assistance in histologic analysis. This work was supported by grants from the National Institutes of Health (NHLBI P01 HL59412-06, NIDDK P01 DK58327-03, 1R01HD052682-01A1, NHLBI-1F32HL095282-01A1 (D.J.F.)) and the American Heart Association National Center (C.M.). B.J.B., The Johns Hopkins University, and the University of Florida could be entitled to patent royalties for inventions described in this article.

PY - 2010/3

Y1 - 2010/3

N2 - Pompe disease is a muscular dystrophy that results in respiratory insufficiency. We characterized the outcomes of targeted delivery of recombinant adeno-associated virus serotype 1 (rAAV2/1) vector to diaphragms of Pompe mice with varying stages of disease progression. We observed significant improvement in diaphragm contractile strength in mice treated at 3 months of age that is sustained at least for 1 year and enhanced contractile strength in mice treated at 9 and 21 months of age, measured 3 months post-treatment. Ventilatory parameters including tidal volume/inspiratory time ratio, minute ventilation/expired CO 2 ratio, and peak inspiratory airflow were significantly improved in mice treated at 3 months and tested at 6 months. Despite early improvement, mice treated at 3 months and tested at 1 year had diminished normoxic ventilation, potentially due to attenuation of correction over time or progressive degeneration of nontargeted accessory tissues. However, for all rAAV2/1-treated mice (treated at 3, 9, and 21 months, assayed 3 months later; treated at 3 months, assayed at 1 year), minute ventilation and peak inspiratory flows were significantly improved during respiratory challenge. These results demonstrate that gel-mediated delivery of rAAV2/1 vectors can significantly augment ventilatory function at initial and late phases of disease in a model of muscular dystrophy.

AB - Pompe disease is a muscular dystrophy that results in respiratory insufficiency. We characterized the outcomes of targeted delivery of recombinant adeno-associated virus serotype 1 (rAAV2/1) vector to diaphragms of Pompe mice with varying stages of disease progression. We observed significant improvement in diaphragm contractile strength in mice treated at 3 months of age that is sustained at least for 1 year and enhanced contractile strength in mice treated at 9 and 21 months of age, measured 3 months post-treatment. Ventilatory parameters including tidal volume/inspiratory time ratio, minute ventilation/expired CO 2 ratio, and peak inspiratory airflow were significantly improved in mice treated at 3 months and tested at 6 months. Despite early improvement, mice treated at 3 months and tested at 1 year had diminished normoxic ventilation, potentially due to attenuation of correction over time or progressive degeneration of nontargeted accessory tissues. However, for all rAAV2/1-treated mice (treated at 3, 9, and 21 months, assayed 3 months later; treated at 3 months, assayed at 1 year), minute ventilation and peak inspiratory flows were significantly improved during respiratory challenge. These results demonstrate that gel-mediated delivery of rAAV2/1 vectors can significantly augment ventilatory function at initial and late phases of disease in a model of muscular dystrophy.

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JO - Molecular Therapy

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ER -

Gel-mediated delivery of AAV1 vectors corrects ventilatory function in pompe mice with established disease

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