Liver-directed SERPINA1 gene therapy attenuates progression of spontaneous and tobacco smoke-induced emphysema in α1-antitrypsin null mice

Abstract

α1-antitrypsin deficiency is a rare genetic condition that can cause liver and/or lung disease. There is currently no cure for this disorder, although repeated infusions of plasma-purified protein may slow down emphysema progression. Gene therapy in which a single recombinant adeno-associated viral vector (rAAV) administration would lead to sustained protein expression could therefore similarly affect disease progression, and provide the added benefits of reducing treatment burden and thereby improving the patient’s quality of life. The study presented here tests whether treating the Serpina1a-e knockout mouse model of α1-antitrypsin-deficiency lung disease with gene therapy would have an impact on the disease course, either on spontaneous disease caused by aging or on accelerated disease caused by exposure to cigarette smoke. Liver-directed gene therapy led to dose-dependent levels of biologically active human α1-antitrypsin protein. Furthermore, decreased lung compliance and increased elastic recoil indicate that treated mice had largely preserved lung tissue elasticity and alveolar wall integrity compared with untreated mice. rAAV-mediated gene augmentation is therefore able to compensate for the loss of function and restore a beneficial lung protease-antiprotease balance. This work constitutes a preclinical study report of a disease-modifying treatment in the Serpina1a-e knockout mouse model using a liver-specific rAAV serotype 8 capsid. α1-antitrypsin deficiency is a rare genetic condition that can cause liver and/or lung disease. There is currently no cure for this disorder, although repeated infusions of plasma-purified protein may slow down emphysema progression. Gene therapy in which a single recombinant adeno-associated viral vector (rAAV) administration would lead to sustained protein expression could therefore similarly affect disease progression, and provide the added benefits of reducing treatment burden and thereby improving the patient’s quality of life. The study presented here tests whether treating the Serpina1a-e knockout mouse model of α1-antitrypsin-deficiency lung disease with gene therapy would have an impact on the disease course, either on spontaneous disease caused by aging or on accelerated disease caused by exposure to cigarette smoke. Liver-directed gene therapy led to dose-dependent levels of biologically active human α1-antitrypsin protein. Furthermore, decreased lung compliance and increased elastic recoil indicate that treated mice had largely preserved lung tissue elasticity and alveolar wall integrity compared with untreated mice. rAAV-mediated gene augmentation is therefore able to compensate for the loss of function and restore a beneficial lung protease-antiprotease balance. This work constitutes a preclinical study report of a disease-modifying treatment in the Serpina1a-e knockout mouse model using a liver-specific rAAV serotype 8 capsid. IntroductionEmphysema is a major life-limiting chronic obstructive pulmonary disease (COPD) condition, and the leading genetic cause of it is a monogenic disease, α1-antitrypsin deficiency (AATD).1Strange C. Alpha-1 antitrypsin deficiency associated COPD.Clin. Chest Med. 2020; 41: 339-345Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar, 2Cazzola M. Stolz D. Rogliani P. Matera M.G. α1-Antitrypsin deficiency and chronic respiratory disorders.Eur. Respir. Rev. 2020; 29: 190073Crossref PubMed Scopus (25) Google Scholar, 3Lomas D.A. New therapeutic targets for alpha-1 antitrypsin deficiency.Chronic Obstr. Pulm. Dis. 2018; 5: 233-243PubMed Google Scholar, 4Larsson C. Natural history and life expectancy in severe alpha1-antitrypsin deficiency, Pi Z.Acta Med. Scand. 1978; 204: 345-351Crossref PubMed Scopus (397) Google Scholar AATD is an autosomal codominant disorder caused by variants in the SERPINA1 gene encoding serine protease inhibitor α1-antitrypsin (AAT) protein. AATD has been recognized in all populations worldwide.5de Serres F.J. Blanco I. Prevalence of α1-antitrypsin deficiency alleles PI∗S and PI∗Z worldwide and effective screening for each of the five phenotypic classes PI∗MS, PI∗MZ, PI∗SS, PI∗SZ, and PI∗ZZ: a comprehensive review.Ther. Adv. Respir. Dis. 2012; 6: 277-295Crossref PubMed Scopus (117) Google Scholar However, it is a largely underdiagnosed monogenic condition, and less than 10% of severely deficient individuals are currently identified.6Craig T.J. Henao M.P. Advances in managing COPD related to α(1) -antitrypsin deficiency: an under-recognized genetic disorder.Allergy. 2018; 73: 2110-2121Crossref PubMed Scopus (7) Google Scholar, 7Stoller J.K. Aboussouan L.S. A review of α1-antitrypsin deficiency.Am. J. Respir. Crit. Care Med. 2012; 185: 246-259Crossref PubMed Scopus (313) Google Scholar, 8Bornhorst J.A. Greene D.N. Ashwood E.R. α1-Antitrypsin and associated protein in a Full Text Full Text PDF PubMed Scopus Google of is and by and the alveolar with to Serres Blanco I. of alpha-1 antitrypsin in human and Med. PubMed Scopus Google Scholar The of protein is to to to on it is that levels the of the of lung J.K. Aboussouan L.S. Full Text Full Text PDF PubMed Scopus Google levels of have been to in of and in the alveolar by a of and serine protease emphysema in deficiency a of J. PubMed Scopus Google Scholar, The of in lung J. PubMed Scopus Google Scholar, J. and cause severe lung and J. Full Text Full Text PDF PubMed Scopus Google Scholar, J. J. are associated with in the COPD PubMed Scopus Google Scholar, in with deficiency and Respir. J. 41: PubMed Scopus Google Scholar, D. J.A. in -antitrypsin Scopus Google Scholar, and and PubMed Scopus Google Scholar is in pulmonary the of I. I. J. P. alpha-1 antitrypsin lung J. Full Text Full Text PDF PubMed Scopus Google M. I. J. of cigarette exposure and on the with Med. 2012; PubMed Scopus Google to serine by caused by respiratory and cigarette the alveolar and and of the pulmonary The of Med. Google Scholar, J. The of alpha1-antitrypsin on 2018; PubMed Scopus Google Scholar, of the human alveolar for the protease-antiprotease of PubMed Scopus Google Scholar deficiency is in the of deficiency in the respiratory of PubMed Scopus Google is by of the loss of lung elastic and lung a respiratory in human AATD can liver disease of a lung disease is the cause of C. Natural history and life expectancy in severe alpha1-antitrypsin deficiency, Pi Z.Acta Med. Scand. 1978; 204: 345-351Crossref PubMed Scopus (397) Google J.A. Greene D.N. Ashwood E.R. α1-Antitrypsin and associated protein in a Full Text Full Text PDF PubMed Scopus Google M. and history of the lung disease associated with deficiency of with pulmonary Rev. Respir. Dis. PubMed Scopus Google is no cure for protein augmentation therapy is and effective emphysema in it infusions of human in to levels of protein in and lung J. M. P. J. and of inhibitor treatment for emphysema caused by severe antitrypsin deficiency: an Respir. Med. 5: Full Text Full Text PDF PubMed Scopus Google gene therapy may treatment of AATD a administration of a recombinant adeno-associated viral vector (rAAV) that SERPINA1 gene and Gene therapy for alpha-1 antitrypsin deficiency lung PubMed Scopus Google Advances in alpha-1 antitrypsin gene J. Respir. 2020; PubMed Google Scholar have of in T.J. M. M. J. and expression a recombinant adeno-associated 8 α1-antitrypsin Full Text Full Text PDF PubMed Scopus Google Scholar, J. therapeutic levels of human alpha-1 antitrypsin (AAT) of recombinant adeno-associated (rAAV) PubMed Scopus Google Scholar, J. a vector for gene PubMed Google Scholar C. M. M. expression and gene therapy in alpha-1 antitrypsin Full Text Full Text PDF PubMed Scopus Google Scholar, M. J. M. M. of human with adeno-associated PubMed Scopus Google Scholar, J.A. M. of a recombinant adeno-associated vector human alpha-1 antitrypsin using a recombinant Gene PubMed Scopus Google Scholar or administration of a serotype adeno-associated for alpha1-antitrypsin lung and levels of Full Text Full Text PDF PubMed Scopus Google Scholar, D. J.A. administration of an vector for human α1-antitrypsin for the treatment of α1-antitrypsin Gene PubMed Scopus Google Scholar, of human alpha1-antitrypsin in mice and gene to the Full Text Full Text PDF PubMed Scopus Google Scholar, J. levels of expression of alpha1-antitrypsin by the serotype adeno-associated to human adeno-associated Full Text Full Text PDF PubMed Scopus Google this study the therapeutic of rAAV-mediated of the human SERPINA1 gene for emphysema the Serpina1a-e mouse in a model of spontaneous and cigarette genetic to the of mouse mice the of emphysema in J. Alpha-1 antitrypsin and of Med. Full Text Full Text PDF PubMed Scopus Google M. five to a mouse model of genetic 2018; PubMed Scopus Google Scholar provide here of therapeutic gene augmentation that for the loss of function protease-antiprotease in Serpina1a-e knockout mice an emphysema a therapeutic Serpina1a-e knockout mice for pulmonary the of and and the of mouse compared with of mice. The of that the lung of Serpina1a-e knockout mice increased to to mice a lung of and lung compliance increased in and in to in compared with and mice tissue decreased in and in to in knockout no in mice and of of the alveolar by of the lung may the of the therefore alveolar in lung The of alveolar the decreased in the alveolar and increased in the in Serpina1a-e knockout mice of all compared with mice and to an of a lung emphysema in Serpina1a-e knockout mice. the in pulmonary function and of alveolar in knockout mice are associated with a in lung elastic which emphysema disease expression of SERPINA1 therapeutic levels of biologically active inhibitor and Serpina1a-e mice treatment Serpina1a-e knockout mice treated and rAAV vector human knockout mice and and the for study pulmonary and mouse of knockout mice and for the and to that of that of and compliance decreased in and for the and compared with mice and to that of preserved in mice treated with compared with mice treated with no and a tissue to that in mice rAAV treatment levels of that the of the study and the of the protein human that the protein active and could of an of in and and in and knockout mice. However, increased of in compared with a of and in the and lung in and knockout mice. increased in the alveolar and decreased in the alveolar in mice compared with and of the SERPINA1 expression therapeutic levels of biologically active inhibitor and pulmonary function in Serpina1a-e knockout of the vector The expression a with serotype a gene encoding human α1-antitrypsin (AAT) with and an The expression in the liver-specific serotype 8 capsid. the the vector by a single the of knockout and the for to levels of human by and respiratory in mice and compared with knockout and mice of of mouse are with the and vector mouse untreated compliance and tissue knockout knockout of and decreased lung compliance and increased elastic recoil indicate that mice human largely the elastic of the lung tissue compared with knockout mice. vector expression to levels of human protein the the each active inhibitor protein. of human by human in and with expression of human of of and increased of in knockout mice compared with of in mouse lung the either by or the with for the SERPINA1 expression alveolar wall integrity in Serpina1a-e knockout in lung of lung and alveolar in and and and and of the increased in the alveolar and decreased in the in knockout mice treated with rAAV or rAAV compared with knockout mice the by exposure emphysema in knockout knockout and mice to cigarette for a of 8 to the emphysema the exposure cigarette can the and the the of therefore a of exposure to levels of in knockout and and to for levels of in and knockout mice by in and mice to either cigarette or of in the to cigarette to increased compliance to and decreased tissue to There no in lung compliance or tissue in cigarette mice to the lung in cigarette knockout mice of alveolar in the alveolar and a in alveolar in cigarette knockout mice compared with knockout mice in alveolar in mice in to exposure the of cigarette exposure the of alveolar and in the accelerated of lung function in Serpina1a-e knockout in which it exposure emphysema in Serpina1a-e knockout the knockout and mice to cigarette for 8 and The of exposure in knockout and mice. to for levels of in and knockout mice by respiratory in cigarette and and mice and the of mouse are with the cigarette cigarette compliance and tissue are in lung of lung and alveolar cigarette and and of decreased in the alveolar and increased in the in cigarette knockout mice in compared with knockout in alveolar in mice in A in increased compliance and decreased tissue are to cigarette of the alveolar in of the which of in cigarette knockout mice and the cigarette the by for the expression of SERPINA1 lung and pulmonary function in Serpina1a-e knockout mice to cigarette knockout mice and the mice to cigarette for a of 8 which pulmonary knockout mice decreased lung and compared with in and decreased lung compliance and compared with in and and increased elastic recoil and compared with in and The lung function that treatment to the elastic of lung tissue and the integrity of alveolar compared with untreated knockout mice. of the alveolar increased in the alveolar and decreased in the alveolar in Serpina1a-e knockout mice to cigarette compared with mice and protein levels of the and the and the in to the in mice and for and for increased of and in cigarette compared with to The in compared with mice. the and the and in cigarette knockout mice treated with of vector and to in cigarette mice and in knockout mice treated with compared with knockout and mouse SERPINA1 expression lung and pulmonary function in Serpina1a-e knockout mice to cigarette of the vector The expression a with serotype a gene encoding human α1-antitrypsin (AAT) protein with and an The recombinant is by a the of the human The expression in the liver-specific rAAV serotype 8 capsid. the the vector by a single the of knockout and the mice to cigarette for a of 8 to human and respiratory in cigarette and and the of mouse are with the knockout compliance and 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model of genetic 2018; PubMed Scopus Google Scholar mouse which and that the is with of A and on the work and a cigarette exposure which accelerated the in lung function in Serpina1a-e knockout mice that in the of cigarette of alveolar and in the lung associated with loss of lung tissue elastic that for individuals with is a major for lung disease. in is associated with chronic increased of of disease and life M. α1-Antitrypsin and PubMed Scopus Google of this study to the of rAAV-mediated human SERPINA1 gene for therapy of and accelerated pulmonary emphysema in Serpina1a-e knockout mice. the of the for human SERPINA1 gene and protein expression by using mice. to the or the of the the vector to the vector to The an in the protein of to which is in with the This has no on the function or of the protein and it is to M. M. of the of a PubMed Scopus Google with rAAV dose-dependent levels of protein that the of the levels to a of are to the human levels to to of the of human that the liver active which could levels to restore the protease-antiprotease and the of that and elasticity to the lung lung compliance and increased elastic recoil indicate that mice treated with largely the elastic of lung tissue compared with a of in lung with of emphysema in the spontaneous and the cigarette exposure the that a in this mouse it in increased of in knockout and mice in the is This increased of would by the in and P. of with in the human PubMed Scopus Google C. C. and in the mouse PubMed Scopus Google Scholar the here and can that alveolar is largely by increased levels of J. and cause severe lung and J. Full Text Full Text PDF PubMed Scopus Google D. J.A. in -antitrypsin Scopus Google J. The of alpha1-antitrypsin on 2018; PubMed Scopus Google M. five to a mouse model of genetic 2018; PubMed Scopus Google C. M. and disease in the Full Text Full Text PDF PubMed Scopus Google of in of and Rev. Respir. Dis. PubMed Scopus Google Scholar the Serpina1a-e knockout mouse a model of genetic and cigarette provide that rAAV-mediated gene therapy can compensate for the disease and restore protease-antiprotease and of or slow down the of lung disease. of the protease-antiprotease may lead to of therapy for AATD of D.N. and Med. PubMed Scopus Google Scholar, and therapeutic J. Scopus Google Scholar, J. for chronic obstructive pulmonary of and Dis. 2018; PubMed Scopus Google Scholar, J. D. of infusions on lung function in COPD with PubMed Scopus Google Scholar Gene therapy for AATD is in the of for the have to the levels of and the of viral M. of with a alpha1-antitrypsin gene in with protein Gene PubMed Scopus Google Scholar, M. T.J. D. of of a recombinant adeno-associated serotype α1-antitrypsin (AAT) vector in Gene PubMed Scopus Google Scholar, C. M. T.J. expression in a of gene PubMed Scopus Google Scholar, C. M. sustained recombinant adeno-associated PubMed Scopus Google Scholar, C. therapy for alpha-1 antitrypsin PubMed Scopus Google Scholar, M. M. of a recombinant adeno-associated viral vector Gene PubMed Scopus Google the presented here the of gene augmentation therapy in the model of on to may in the of for with to the of the gene augmentation are major in this study that in the study is on However, protease in the have no that is mouse which could the mouse the of increased levels and of in the mouse lung would to the of the and the can using and the that here for is that preclinical are the to the of a disease, are for the therapeutic study major of human disease associated with an mouse model have no mouse expression and a single of human in the of the on a mouse However, each model has and and of on the of the study to this study are on the respiratory disease and integrity of lung for human expression the of the protein The knockout mouse model of genetic emphysema on the of emphysema and the associated disease respiratory to a for the AATD gene by the in the in to levels in the therapeutic with a gene may than a protein the has and this has been that in mice for that a of therapeutic for the of AATD lung and by the Care and the of Serpina1a-e gene knockout M. five to a mouse model of genetic 2018; PubMed Scopus Google Scholar and mice in of five on a and had to a mouse and mice in all Serpina1a-e knockout mice and in the study the of or Serpina1a-e knockout mice and in the cigarette emphysema study of Serpina1a-e knockout mice to of the treatment or the of in the of cigarette emphysema or or the of in the of spontaneous emphysema mice in the of cigarette emphysema study the of cigarette Serpina1a-e knockout and mice for the of in mouse the of rAAV serotype 8 in this study and the of Gene J. adeno-associated for human gene PubMed Scopus Google Scholar The vector a with serotype a gene encoding either in vector or the of the with in a vector and an J. therapeutic levels of human alpha-1 antitrypsin (AAT) of recombinant adeno-associated (rAAV) PubMed Scopus Google Scholar The recombinant is by a the of the C. J. of with augmentation of has on liver 2012; Full Text Full Text PDF PubMed Scopus Google Scholar of in the accelerated cigarette emphysema study and vector in the spontaneous emphysema study in viral vector or or a single in a of for the of pulmonary lung function the study using the the for pulmonary function tests in with an of a of or and or to a of the The mouse in a on a the of the The with and a to the the and the and the with a in the a to the and a the using and the a single in the the by of a the The on this and a The mouse to the the The to the to a or the mouse is a to the a of a and this the of a a to pulmonary The can provide with of pulmonary and respiratory and respiratory using a or and using of respiratory in mice using the PubMed Scopus Google Scholar the the and the mouse the and by by a the of each the for with the of on of the The repeated for each mouse to and the of the the disease model and the of the therapeutic the respiratory the the elastic of the respiratory and the of the and wall and The and to of the alveolar wall in the loss of the lung elastic the is to to a are a in a in elasticity is compliance is the a the elastic of the respiratory to the of the to and can by by is emphysema is an of tissue the elastic the tissue the and therefore the of the tissue to and to is the of compliance and is decreased in emphysema to elastic of respiratory in mice using the PubMed Scopus Google of of the PubMed Scopus Google and the of pulmonary or to alveolar to emphysema in with using a down for and and The in of with of and using a of the for using a The and using to of 2012; PubMed Scopus Google Scholar for the of and by and to of the lung tissue for the lung using a with A in the to a and the the The lung on the with 10% The a of a for and in The lung and in using a a of and with and mouse lung using a and with with a using of the of to alveolar using a of in PubMed Scopus Google M. for in lung and alpha-1 J. Respir. 2018; PubMed Scopus Google Scholar The a of and using the in the the and of with cigarette by the for to cigarette a exposure in a mice to the with cigarette smoke. cigarette and of mice of each to a for a for an to mice the in the and levels of in the mouse an the A the for the of levels in mouse of cigarette The human using using or by for of in respiratory by the for with or by to with IntroductionEmphysema is a major life-limiting chronic obstructive pulmonary disease (COPD) condition, and the leading genetic cause of it is a monogenic disease, α1-antitrypsin deficiency (AATD).1Strange C. Alpha-1 antitrypsin deficiency associated COPD.Clin. Chest Med. 2020; 41: 339-345Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar, 2Cazzola M. Stolz D. Rogliani P. Matera M.G. α1-Antitrypsin deficiency and chronic respiratory disorders.Eur. Respir. Rev. 2020; 29: 190073Crossref PubMed Scopus (25) Google Scholar, 3Lomas D.A. New therapeutic targets for alpha-1 antitrypsin deficiency.Chronic Obstr. Pulm. Dis. 2018; 5: 233-243PubMed Google Scholar, 4Larsson C. Natural history and life expectancy in severe alpha1-antitrypsin deficiency, Pi Z.Acta Med. Scand. 1978; 204: 345-351Crossref PubMed Scopus (397) Google Scholar AATD is an autosomal codominant disorder caused by variants in the SERPINA1 gene encoding serine protease inhibitor α1-antitrypsin (AAT) protein. AATD has been recognized in all populations worldwide.5de Serres F.J. Blanco I. Prevalence of α1-antitrypsin deficiency alleles PI∗S and PI∗Z worldwide and effective screening for each of the five phenotypic classes PI∗MS, PI∗MZ, PI∗SS, PI∗SZ, and PI∗ZZ: a comprehensive review.Ther. Adv. Respir. Dis. 2012; 6: 277-295Crossref PubMed Scopus (117) Google Scholar However, it is a largely underdiagnosed monogenic condition, and less than 10% of severely deficient individuals are currently identified.6Craig T.J. Henao M.P. Advances in managing COPD related to α(1) -antitrypsin deficiency: an under-recognized genetic disorder.Allergy. 2018; 73: 2110-2121Crossref PubMed Scopus (7) Google Scholar, 7Stoller J.K. Aboussouan L.S. A review of α1-antitrypsin deficiency.Am. J. Respir. Crit. Care Med. 2012; 185: 246-259Crossref PubMed Scopus (313) Google Scholar, 8Bornhorst J.A. Greene D.N. Ashwood E.R. α1-Antitrypsin and associated protein in a Full Text Full Text PDF PubMed Scopus Google of is and by and the alveolar with to Serres Blanco I. of alpha-1 antitrypsin in human and Med. PubMed Scopus Google Scholar The of protein is to to to on it is that levels the of the of lung J.K. Aboussouan L.S. Full Text Full Text PDF PubMed Scopus Google levels of have been to in of and in the alveolar by a of and serine protease emphysema in deficiency a of J. PubMed Scopus Google Scholar, The of in lung J. PubMed Scopus Google Scholar, J. and cause severe lung and J. Full Text Full Text PDF PubMed Scopus Google Scholar, J. J. are associated with in the COPD PubMed Scopus Google Scholar, in with deficiency and Respir. J. 41: PubMed Scopus Google Scholar, D. J.A. in -antitrypsin Scopus Google Scholar, and and PubMed Scopus Google Scholar is in pulmonary the of I. I. J. P. alpha-1 antitrypsin lung J. Full Text Full Text PDF PubMed Scopus Google M. I. J. of cigarette exposure and on the with Med. 2012; PubMed Scopus Google to serine by caused by respiratory and cigarette the alveolar and and of the pulmonary The of Med. Google Scholar, J. The of alpha1-antitrypsin on 2018; PubMed Scopus Google Scholar, of the human alveolar for the protease-antiprotease of PubMed Scopus Google Scholar deficiency is in the of deficiency in the respiratory of PubMed Scopus Google is by of the loss of lung elastic and lung a respiratory in human AATD can liver disease of a lung disease is the cause of C. Natural history and life expectancy in severe alpha1-antitrypsin deficiency, Pi Z.Acta Med. Scand. 1978; 204: 345-351Crossref PubMed Scopus (397) Google J.A. Greene D.N. Ashwood E.R. α1-Antitrypsin and associated protein in a Full Text Full Text PDF PubMed Scopus Google M. and history of the lung disease associated with deficiency of with pulmonary Rev. Respir. Dis. PubMed Scopus Google is no cure for protein augmentation therapy is and effective emphysema in it infusions of human in to levels of protein in and lung J. M. P. J. and of inhibitor treatment for emphysema caused by severe antitrypsin deficiency: an Respir. Med. 5: Full Text Full Text PDF PubMed Scopus Google gene therapy may treatment of AATD a administration of a recombinant adeno-associated viral vector (rAAV) that SERPINA1 gene and Gene therapy for alpha-1 antitrypsin deficiency lung PubMed Scopus Google Advances in alpha-1 antitrypsin gene J. Respir. 2020; PubMed Google Scholar have of in T.J. M. M. J. and expression a recombinant adeno-associated 8 α1-antitrypsin Full Text Full Text PDF PubMed Scopus Google Scholar, J. therapeutic levels of human alpha-1 antitrypsin (AAT) of recombinant adeno-associated (rAAV) PubMed Scopus Google Scholar, J. a vector for gene PubMed Google Scholar C. M. M. expression and gene therapy in alpha-1 antitrypsin Full Text Full Text PDF PubMed Scopus Google Scholar, M. J. M. M. of human with adeno-associated PubMed Scopus Google Scholar, J.A. M. of a recombinant adeno-associated vector human alpha-1 antitrypsin using a recombinant Gene PubMed Scopus Google Scholar or administration of a serotype adeno-associated for alpha1-antitrypsin lung and levels of Full Text Full Text PDF PubMed Scopus Google Scholar, D. J.A. administration of an vector for human α1-antitrypsin for the treatment of α1-antitrypsin Gene PubMed Scopus Google Scholar, of human alpha1-antitrypsin in mice and gene to the Full Text Full Text PDF PubMed Scopus Google Scholar, J. levels of expression of alpha1-antitrypsin by the serotype adeno-associated to human adeno-associated Full Text Full Text PDF PubMed Scopus Google this study the therapeutic of rAAV-mediated of the human SERPINA1 gene for emphysema the Serpina1a-e mouse in a model of spontaneous and cigarette genetic to the of mouse mice the of emphysema in J. Alpha-1 antitrypsin and of Med. Full Text Full Text PDF PubMed Scopus Google M. five to a mouse model of genetic 2018; PubMed Scopus Google Scholar provide here of therapeutic gene augmentation that for the loss of function protease-antiprotease in

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