Intrapleural administration of an AAVrh.10 vector coding for human α1-antitrypsin for the treatment of α1-antitrypsin deficiency

Maria J. Chiuchiolo, Stephen M. Kaminsky, Dolan Sondhi, Neil R. Hackett, Jonathan B. Rosenberg, Esther Z. Frenk, Yihharn Hwang, Benjamin G. Van De Graaf, Julie A. Hutt, Gensheng Wang, Janet Benson, Ronald Crystal

Research output: Contribution to journalArticle

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Abstract

Alpha-1 antitrypsin (α1AT) deficiency is a common autosomal recessive disorder characterized by a marked reduction in serum α1AT levels, lung and liver disease. α1AT is mainly produced and secreted by hepatocytes, with its primary function to protect the lung against the proteolytic activity of neutrophil elastase. Serum α1AT levels <11 μM are associated with progressive destruction of lung parenchyma and early-onset of panacinar emphysema in the age range 35-45. The current approved treatment for α1AT deficiency is a costly protein augmentation therapy requiring weekly intravenous infusion of purified α1AT from pooled human plasma. Gene therapy offers the advantage of a single vector administration, eliminating the burden of the repeated purified protein infusions, with the consequent reduced overall drug cost and improved compliance. We have developed a novel, highly efficient gene therapy approach for α1AT deficiency based on the administration of AAVrh.10hα1AT, an adeno-associated viral vector serotype rh.10 coding for normal M-type human α1AT via the intrapleural route. On the basis of prior murine studies, this approach provides sustained α1AT proximal to the lung with a highly efficient vector. In support of a clinical trial for this approach, we carried out a study to assess the safety of intrapleural administration of AAVrh.10hα1AT to 280 mice and 36 nonhuman primates. The data demonstrate that this approach is safe, with no toxicity issues. Importantly, there was persistent expression of the human α1AT mRNA in chest cavity cells for the duration of the study (6 months in mice and 1 year in nonhuman primates). Together, these data support the initiation of a clinical trial of intrapleural human AAVrh.10hα1AT for the treatment of α1AT deficiency.

Original languageEnglish
Pages (from-to)161-173
Number of pages13
JournalHuman Gene Therapy Clinical Development
Volume24
Issue number4
DOIs
Publication statusPublished - 1 Dec 2013
Externally publishedYes

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Genetic Therapy
Lung
Primates
Clinical Trials
alpha 1-Antitrypsin Deficiency
Pulmonary Emphysema
Leukocyte Elastase
Drug Costs
Therapeutics
Serum
Intravenous Infusions
Lung Diseases
Compliance
Liver Diseases
Hepatocytes
Proteins
Thorax
Safety
Messenger RNA
Autosomal Recessive alpha-1-Antitrypsin Deficiency

ASJC Scopus subject areas

  • Genetics(clinical)

Cite this

Intrapleural administration of an AAVrh.10 vector coding for human α1-antitrypsin for the treatment of α1-antitrypsin deficiency. / Chiuchiolo, Maria J.; Kaminsky, Stephen M.; Sondhi, Dolan; Hackett, Neil R.; Rosenberg, Jonathan B.; Frenk, Esther Z.; Hwang, Yihharn; Van De Graaf, Benjamin G.; Hutt, Julie A.; Wang, Gensheng; Benson, Janet; Crystal, Ronald.

In: Human Gene Therapy Clinical Development, Vol. 24, No. 4, 01.12.2013, p. 161-173.

Research output: Contribution to journalArticle

Chiuchiolo, MJ, Kaminsky, SM, Sondhi, D, Hackett, NR, Rosenberg, JB, Frenk, EZ, Hwang, Y, Van De Graaf, BG, Hutt, JA, Wang, G, Benson, J & Crystal, R 2013, 'Intrapleural administration of an AAVrh.10 vector coding for human α1-antitrypsin for the treatment of α1-antitrypsin deficiency', Human Gene Therapy Clinical Development, vol. 24, no. 4, pp. 161-173. https://doi.org/10.1089/humc.2013.168
Chiuchiolo, Maria J. ; Kaminsky, Stephen M. ; Sondhi, Dolan ; Hackett, Neil R. ; Rosenberg, Jonathan B. ; Frenk, Esther Z. ; Hwang, Yihharn ; Van De Graaf, Benjamin G. ; Hutt, Julie A. ; Wang, Gensheng ; Benson, Janet ; Crystal, Ronald. / Intrapleural administration of an AAVrh.10 vector coding for human α1-antitrypsin for the treatment of α1-antitrypsin deficiency. In: Human Gene Therapy Clinical Development. 2013 ; Vol. 24, No. 4. pp. 161-173.
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abstract = "Alpha-1 antitrypsin (α1AT) deficiency is a common autosomal recessive disorder characterized by a marked reduction in serum α1AT levels, lung and liver disease. α1AT is mainly produced and secreted by hepatocytes, with its primary function to protect the lung against the proteolytic activity of neutrophil elastase. Serum α1AT levels <11 μM are associated with progressive destruction of lung parenchyma and early-onset of panacinar emphysema in the age range 35-45. The current approved treatment for α1AT deficiency is a costly protein augmentation therapy requiring weekly intravenous infusion of purified α1AT from pooled human plasma. Gene therapy offers the advantage of a single vector administration, eliminating the burden of the repeated purified protein infusions, with the consequent reduced overall drug cost and improved compliance. We have developed a novel, highly efficient gene therapy approach for α1AT deficiency based on the administration of AAVrh.10hα1AT, an adeno-associated viral vector serotype rh.10 coding for normal M-type human α1AT via the intrapleural route. On the basis of prior murine studies, this approach provides sustained α1AT proximal to the lung with a highly efficient vector. In support of a clinical trial for this approach, we carried out a study to assess the safety of intrapleural administration of AAVrh.10hα1AT to 280 mice and 36 nonhuman primates. The data demonstrate that this approach is safe, with no toxicity issues. Importantly, there was persistent expression of the human α1AT mRNA in chest cavity cells for the duration of the study (6 months in mice and 1 year in nonhuman primates). Together, these data support the initiation of a clinical trial of intrapleural human AAVrh.10hα1AT for the treatment of α1AT deficiency.",
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