α1-抗胰蛋白酶相关疾病及其临床应用进展
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摘要
α1-抗胰蛋白酶(AAT),是人类血浆中重要的蛋白酶抑制剂,保护机体正常细胞和器官不受蛋白酶的损伤。α1-抗胰蛋白酶缺乏症(AATD)是常见的1种单基因遗传病,患者会出现肺气肿、肝硬化以及其他疾病,严重者甚至出现死亡。α1-抗胰蛋白酶缺乏症常用的治疗方法是静脉输注AAT制剂进行补充治疗,近年来AAT吸入疗法、基因疗法和干细胞疗法取得了新的进展。本文简述了AAT的分子特性、作用机制以及其相关疾病研究进展,并综述了AAT在AATD相关疾病中的应用情况,进而展望了α1-抗胰蛋白酶产品的市场应用及技术发展前景。
α1-antitrypsin(AAT),an human plasma protease inhibitor,plays an important role in protecting the normal cells and organs from protease damage.α1-antitrypsin deficiency(AATD) is a common single-gene disease.The patients with AATD may develop emphysema,cirrhosis and other diseases,even are at risk of death.AAT replacement therapy with intravenous infusions of purified AAT from human plasma is the most usual clinical treatment method for AATD to elevate the serum AAT level and partially recover the biochemical defect.In recent years,several new therapeutic methods for AATD,including the inhaled AAT,gene therapy and stem cell therapy,have been developed.In the present paper,the molecular characteristics,the functional mechanism of AAT and its related diseases were described.In addition,the application of AAT in the AATD-related diseases was reviewed,and the technological development and market prospects of AAT product were studied.
α1-antitrypsin(AAT),an human plasma protease inhibitor,plays an important role in protecting the normal cells and organs from protease damage.α1-antitrypsin deficiency(AATD) is a common single-gene disease.The patients with AATD may develop emphysema,cirrhosis and other diseases,even are at risk of death.AAT replacement therapy with intravenous infusions of purified AAT from human plasma is the most usual clinical treatment method for AATD to elevate the serum AAT level and partially recover the biochemical defect.In recent years,several new therapeutic methods for AATD,including the inhaled AAT,gene therapy and stem cell therapy,have been developed.In the present paper,the molecular characteristics,the functional mechanism of AAT and its related diseases were described.In addition,the application of AAT in the AATD-related diseases was reviewed,and the technological development and market prospects of AAT product were studied.
引文
[1]Lomas DA,Hurst JR,Gooptu B.Update on alpha-1 antitrypsin deficiency:new therapies.J Hepatol,2016,pii:S0168-8278(16)30083-6.
[2]Stoller JK,Aboussouan LS.Alpha1-antitrypsin deficiency.Lancet,2005,365(9478):2225-2236.
[3]Hopkins PC,Stone SR.The contricution of the conserved hinge region residued of alpha-l-antitrypsin to its reaction with elastase.Biochemistry,1995,34(48):15872-15881.
[4]Barlow I,Sewell WA.Alpha1-antitrypsin deficiency and Pi typing.J Allergy Clin Immunol,2008,122(3):658.
[5]Green CE,Vayalapra S,Hampson JA,et al.Pi SZ alpha-1 antitrypsin deficiency(AATD):pulmonary phenotype and prognosis relative to Pi ZZ AATD and Pi MM COPD.Thorax,2015,70(10):939-945.
[6]de Serres FJ,Blanco I,Fernández-Bustillo E.Estimated numbers and prevalence of PI*S and PI*Z deficiency alleles of a1-antitrypsin deficiency in Asia.Eur Respir J,2006,28(6):1091-1099.
[7]Zuo L,Pannell BK,Zhou T,et al.Historical role of alpha-1-antitrypsin deficiency in respiratory and hepatic complications.Gene,2016,pii:S0378-1119(16)00006-8.
[8]Stockley RA.The multiple facets of alpha-1-antitrypsin.Ann Transl Med,2015,3(10):130.
[9]Bouchecareilh M.Alpha-1-antitrypsin deficiency.Med Sci(Paris),2014,30(10):889-895.
[10]Karnaukhova,E.Recent advances in the research and development of alpha-1 proteinase inhibitor for therapeutic use.Lung Diseases,In Tech,Rijeka,2012:83-104.
[11]Pérez-Holanda S,Blanco I,Menéndez M,et al.Serum concentration of alpha-1 antitrypsin is significantly higher in colorectal cancer patients than in healthy controls.BMC Cancer,2014,14(355):355-363.
[12]Zhou J,Trock B,Tsangaris TN,et al.A unique proteolytic fragment of alpha1-antitrypsin is elevated in ductal fluid of breast cancer patient.Breast Cancer Res Treat,2010,123(1):73-86.
[13]Gadek JE,Klein HG,Holland PV,et al.Replacement therapy of alpha 1-antitrypsin deficiency.Reversal of protease-antiprotease imbalance within the alveolar structures of Pi Z subjects.Journal of Clinical Investigation,1981,68(5):1158-1165.
[14]Petrache I,Hajjar J,Campos M.Safety and efficacy of alpha-1-antitrypsin augmentation therapy in the treatment of patients with alpha-1-antitrypsin deficiency.Biologics,2009,3:193-204.
[15]Strange C,Beiko T.Treatment of Alpha-1 Antitrypsin Deficiency.Semin Respir Crit Care Med,2015,36(4):470-477.
[16]Levy JH,Sniecinski RM,Welsby IJ,et al.Antithrombin:anti-inflammatory properties and clinical applications.Thromb Haemost,2016,115(4):712-728.
[17]Moreno JA,Ortega-Gomez A,Rubio-Navarro A,et al.High-density lipoproteins potentiateα1-antitrypsin therapy in elastase-induced pulmonary emphysema.Am J Respir Cell Mol Biol,2014,51(4):536-549.
[18]Blanco I,Lara B,de Serres F.Efficacy of alpha1-antitrypsin augmentation therapy in conditions other than pulmonary emphysema.Orphanet Journal of Rare Diseases,2011,6(14):14-24.
[19]Hubbard RC,Crystal RG.Strategies for aerosol therapy ofα1-antitrypsin deficiency by the aerosol route.Lung,1990,168(Suppl):565-578.
[20]Brand P,Schulte M,Wencker M,et al.Lung deposition of inhaled alpha1-proteinase inhibitor in cystic fibrosis and alpha1-antitrypsin deficiency.Eur Respir J.2009,34(2):354-360.
[21]Monk R,Graves M,Williams P,et al.Inhaled alpha 1-antitrypsin:gauging patient interest in a new treatment.COPD,2013,10(4):411-415.
[22]Franciosi AN,Mc Carthy C,Mc Elvaney NG.The efficacy and safety of inhaled humanα-1 antitrypsin in people withα-1 antitrypsin deficiency-related emphysema.Expert Rev Respir Med,2015,9(2):143-151.
[23]Rachmiel M,Strauss P,Dror N,et al.Alpha-1 antitrypsin therapy is safe and well tolerated in children and adolescents with recent onset type 1 diabetes mellitus.Pediatr Diabetes.2015,doi:10.1111/pedi.12283.[Epub ahead of print]
[24]Mueller C,Flotte TR.Gene-based therapy for alpha-1 antitrypsin deficiency.COP,2013,10(Suppl)1:44-49.
[25]Brebner JA,Stockley RA.Recent advances inα-1-antitrypsin deficiency-related lung disease.Expert Rev Respir Med,2013,7(3):213-29.
[26]Duan YY,Wu J,Zhu JL et al.Gene therapy for humanα1-antitrypsin defciency in an animal model using SV40-derived vectors.Gastroenterology,2004,127(4):1222-1232.
[27]Cruz PE,Mueller C,Cossette TL,et al.In vivo post-transcriptional gene silencing ofα-1 antitrypsin by adeno-associated virus vectors expressing siRNA.Lab Invest,2007,87(9):893-902.
[28]Mueller C,Tang Q,Gruntman A,et al.Sustained miRNA-mediated knockdown of mutant AAT with simultaneous augmentation of wild-type AAT has minimal effect on global liver miRNA profiles.Mol Ther,2012,20(3):590-600.
[29]Eggenschwiler R,Loya K,Wu G,et al.Sustained knockdown of a disease-causing gene in patient-specific induced pluripotent stem cells using lentiviral vector-based gene therapy.Stem Cells Transl Med,2013,2(9):641-654.
[30]Li H,Lu Y,Witek RP,et al.Ex vivo transduction and transplantation of bone marrow cells for liver gene delivery ofα1-antitrypsin.Mol Ther,2010,18(8):1553-1558.
[31]Li H,Zhang B,Lu Y,et al.Adipose tissue-derived mesenchymal stem cell-based liver gene delivery.J Hepatol,2011,54(5):930-938.
[32]Yusa K,Rashid ST,Strick-Marchand H,et al.Targeted gene correction ofα1-antitrypsin deficiency in induced pluripotent stem cells.Nature,2011,478(7369):391-394.
[2]Stoller JK,Aboussouan LS.Alpha1-antitrypsin deficiency.Lancet,2005,365(9478):2225-2236.
[3]Hopkins PC,Stone SR.The contricution of the conserved hinge region residued of alpha-l-antitrypsin to its reaction with elastase.Biochemistry,1995,34(48):15872-15881.
[4]Barlow I,Sewell WA.Alpha1-antitrypsin deficiency and Pi typing.J Allergy Clin Immunol,2008,122(3):658.
[5]Green CE,Vayalapra S,Hampson JA,et al.Pi SZ alpha-1 antitrypsin deficiency(AATD):pulmonary phenotype and prognosis relative to Pi ZZ AATD and Pi MM COPD.Thorax,2015,70(10):939-945.
[6]de Serres FJ,Blanco I,Fernández-Bustillo E.Estimated numbers and prevalence of PI*S and PI*Z deficiency alleles of a1-antitrypsin deficiency in Asia.Eur Respir J,2006,28(6):1091-1099.
[7]Zuo L,Pannell BK,Zhou T,et al.Historical role of alpha-1-antitrypsin deficiency in respiratory and hepatic complications.Gene,2016,pii:S0378-1119(16)00006-8.
[8]Stockley RA.The multiple facets of alpha-1-antitrypsin.Ann Transl Med,2015,3(10):130.
[9]Bouchecareilh M.Alpha-1-antitrypsin deficiency.Med Sci(Paris),2014,30(10):889-895.
[10]Karnaukhova,E.Recent advances in the research and development of alpha-1 proteinase inhibitor for therapeutic use.Lung Diseases,In Tech,Rijeka,2012:83-104.
[11]Pérez-Holanda S,Blanco I,Menéndez M,et al.Serum concentration of alpha-1 antitrypsin is significantly higher in colorectal cancer patients than in healthy controls.BMC Cancer,2014,14(355):355-363.
[12]Zhou J,Trock B,Tsangaris TN,et al.A unique proteolytic fragment of alpha1-antitrypsin is elevated in ductal fluid of breast cancer patient.Breast Cancer Res Treat,2010,123(1):73-86.
[13]Gadek JE,Klein HG,Holland PV,et al.Replacement therapy of alpha 1-antitrypsin deficiency.Reversal of protease-antiprotease imbalance within the alveolar structures of Pi Z subjects.Journal of Clinical Investigation,1981,68(5):1158-1165.
[14]Petrache I,Hajjar J,Campos M.Safety and efficacy of alpha-1-antitrypsin augmentation therapy in the treatment of patients with alpha-1-antitrypsin deficiency.Biologics,2009,3:193-204.
[15]Strange C,Beiko T.Treatment of Alpha-1 Antitrypsin Deficiency.Semin Respir Crit Care Med,2015,36(4):470-477.
[16]Levy JH,Sniecinski RM,Welsby IJ,et al.Antithrombin:anti-inflammatory properties and clinical applications.Thromb Haemost,2016,115(4):712-728.
[17]Moreno JA,Ortega-Gomez A,Rubio-Navarro A,et al.High-density lipoproteins potentiateα1-antitrypsin therapy in elastase-induced pulmonary emphysema.Am J Respir Cell Mol Biol,2014,51(4):536-549.
[18]Blanco I,Lara B,de Serres F.Efficacy of alpha1-antitrypsin augmentation therapy in conditions other than pulmonary emphysema.Orphanet Journal of Rare Diseases,2011,6(14):14-24.
[19]Hubbard RC,Crystal RG.Strategies for aerosol therapy ofα1-antitrypsin deficiency by the aerosol route.Lung,1990,168(Suppl):565-578.
[20]Brand P,Schulte M,Wencker M,et al.Lung deposition of inhaled alpha1-proteinase inhibitor in cystic fibrosis and alpha1-antitrypsin deficiency.Eur Respir J.2009,34(2):354-360.
[21]Monk R,Graves M,Williams P,et al.Inhaled alpha 1-antitrypsin:gauging patient interest in a new treatment.COPD,2013,10(4):411-415.
[22]Franciosi AN,Mc Carthy C,Mc Elvaney NG.The efficacy and safety of inhaled humanα-1 antitrypsin in people withα-1 antitrypsin deficiency-related emphysema.Expert Rev Respir Med,2015,9(2):143-151.
[23]Rachmiel M,Strauss P,Dror N,et al.Alpha-1 antitrypsin therapy is safe and well tolerated in children and adolescents with recent onset type 1 diabetes mellitus.Pediatr Diabetes.2015,doi:10.1111/pedi.12283.[Epub ahead of print]
[24]Mueller C,Flotte TR.Gene-based therapy for alpha-1 antitrypsin deficiency.COP,2013,10(Suppl)1:44-49.
[25]Brebner JA,Stockley RA.Recent advances inα-1-antitrypsin deficiency-related lung disease.Expert Rev Respir Med,2013,7(3):213-29.
[26]Duan YY,Wu J,Zhu JL et al.Gene therapy for humanα1-antitrypsin defciency in an animal model using SV40-derived vectors.Gastroenterology,2004,127(4):1222-1232.
[27]Cruz PE,Mueller C,Cossette TL,et al.In vivo post-transcriptional gene silencing ofα-1 antitrypsin by adeno-associated virus vectors expressing siRNA.Lab Invest,2007,87(9):893-902.
[28]Mueller C,Tang Q,Gruntman A,et al.Sustained miRNA-mediated knockdown of mutant AAT with simultaneous augmentation of wild-type AAT has minimal effect on global liver miRNA profiles.Mol Ther,2012,20(3):590-600.
[29]Eggenschwiler R,Loya K,Wu G,et al.Sustained knockdown of a disease-causing gene in patient-specific induced pluripotent stem cells using lentiviral vector-based gene therapy.Stem Cells Transl Med,2013,2(9):641-654.
[30]Li H,Lu Y,Witek RP,et al.Ex vivo transduction and transplantation of bone marrow cells for liver gene delivery ofα1-antitrypsin.Mol Ther,2010,18(8):1553-1558.
[31]Li H,Zhang B,Lu Y,et al.Adipose tissue-derived mesenchymal stem cell-based liver gene delivery.J Hepatol,2011,54(5):930-938.
[32]Yusa K,Rashid ST,Strick-Marchand H,et al.Targeted gene correction ofα1-antitrypsin deficiency in induced pluripotent stem cells.Nature,2011,478(7369):391-394.