Understanding Gene Therapy in Acute Respiratory Distress Syndrome

Author(s): Xue-Peng Zhang, Wei-Tao Zhang, Yue Qiu, Min-Jie Ju, Guo-Wei Tu*, Zhe Luo*.

Journal Name: Current Gene Therapy

Volume 19 , Issue 2 , 2019

  Journal Home
Translate in Chinese
Become EABM
Become Reviewer

Graphical Abstract:


Abstract:

Acute Respiratory Distress Syndrome (ARDS) and its complications remain lifethreatening conditions for critically ill patients. The present therapeutic strategies such as prone positioning ventilation strategies, nitric oxide inhalation, restrictive intravenous fluid management, and extracorporeal membrane oxygenation (ECMO) do not contribute much to improving the mortality of ARDS. The advanced understanding of the pathophysiology of acute respiratory distress syndrome suggests that gene-based therapy may be an innovative method for this disease. Many scientists have made beneficial attempts to regulate the immune response genes of ARDS, maintain the normal functions of alveolar epithelial cells and endothelial cells, and inhibit the fibrosis and proliferation of ARDS. Limitations to effective pulmonary gene therapy still exist, including the security of viral vectors and the pulmonary defense mechanisms against inhaled particles. Here, we summarize and review the mechanism of gene therapy for acute respiratory distress syndrome and its application.

Keywords: Gene therapy, acute respiratory distress syndrome, inflammation, viral vector, nonviral vector, mesenchymal stem/stromal cells.

[1]
Fan E, Brodie D, Slutsky AS. Acute respiratory distress syndrome: Advances in diagnosis and treatment. JAMA 2018; 319(7): 698-710.
[http://dx.doi.org/10.1001/jama.2017.21907] [PMID: 29466596]
[2]
Fuller BM, Mohr NM, Kollef MH. Diagnosis and treatment of acute respiratory distress syndrome. JAMA 2018; 320(3): 305-6.
[http://dx.doi.org/10.1001/jama.2018.5928] [PMID: 30027241]
[3]
Herridge MS, Moss M, Hough CL, et al. Recovery and outcomes after the Acute Respiratory Distress Syndrome (ARDS) in patients and their family caregivers. Intensive Care Med 2016; 42(5): 725-38.
[http://dx.doi.org/10.1007/s00134-016-4321-8] [PMID: 27025938]
[4]
Levine BE. Fifty years of research in ARDS. ARDS: How it all began. Am J Respir Crit Care Med 2017; 196(10): 1247-8.
[http://dx.doi.org/10.1164/rccm.201706-1281ED] [PMID: 28731363]
[5]
Dupont H, Depuydt P, Abroug F. Prone position acute respiratory distress syndrome patients: Less prone to ventilator associated pneumonia? Intensive Care Med 2016; 42(5): 937-9.
[http://dx.doi.org/10.1007/s00134-015-4190-6] [PMID: 26768439]
[6]
Alessandri F, Pugliese F, Ranieri VM. The role of rescue therapies in the treatment of severe ARDS. Respir Care 2018; 63(1): 92-101.
[http://dx.doi.org/10.4187/respcare.05752] [PMID: 29066591]
[7]
Abrams D, Brodie D. Extracorporeal membrane oxygenation for adult respiratory failure: 2017 update. Chest 2017; 152(3): 639-49.
[http://dx.doi.org/10.1016/j.chest.2017.06.016] [PMID: 28642106]
[8]
Brackenbury AM, Puligandla PS, McCaig LA, et al. Evaluation of exogenous surfactant in HCL-induced lung injury. Am J Respir Crit Care Med 2001; 163(5): 1135-42.
[http://dx.doi.org/10.1164/ajrccm.163.5.2004049] [PMID: 11316649]
[9]
De Luca D, Minucci A, Zecca E, et al. Bile acids cause secretory phospholipase A2 activity enhancement, revertible by exogenous surfactant administration. Intensive Care Med 2009; 35(2): 321-6.
[http://dx.doi.org/10.1007/s00134-008-1321-3] [PMID: 18853138]
[10]
Matthay MA, Zemans RL, Zimmerman GA, et al. Acute respiratory distress syndrome. Nat Rev Dis Primers 2019; 5(1): 18.
[http://dx.doi.org/10.1038/s41572-019-0069-0] [PMID: 30872586]
[11]
Bhattacharya J, Matthay MA. Regulation and repair of the alveolar-capillary barrier in acute lung injury. Annu Rev Physiol 2013; 75: 593-615.
[http://dx.doi.org/10.1146/annurev-physiol-030212-183756] [PMID: 23398155]
[12]
Matthay MA, Ware LB, Zimmerman GA. The acute respiratory distress syndrome. J Clin Invest 2012; 122(8): 2731-40.
[http://dx.doi.org/10.1172/JCI60331] [PMID: 22850883]
[13]
Matthay MA. Resolution of pulmonary edema. Thirty years of progress. Am J Respir Crit Care Med 2014; 189(11): 1301-8.
[http://dx.doi.org/10.1164/rccm.201403-0535OE] [PMID: 24881936]
[14]
Cheng KT, Xiong S, Ye Z, et al. Caspase-11-mediated endothelial pyroptosis underlies endotoxemia-induced lung injury. J Clin Invest 2017; 127(11): 4124-35.
[http://dx.doi.org/10.1172/JCI94495] [PMID: 28990935]
[15]
Dunbar CE, High KA, Joung JK, Kohn DB, Ozawa K, Sadelain M. Gene therapy comes of age. Science 2018; 359(6372)eaan4672
[http://dx.doi.org/10.1126/science.aan4672] [PMID: 29326244]
[16]
Boyle AJ, McNamee JJ, McAuley DF. Biological therapies in the acute respiratory distress syndrome. Expert Opin Biol Ther 2014; 14(7): 969-81.
[http://dx.doi.org/10.1517/14712598.2014.905536] [PMID: 24702248]
[17]
Qi D, Tang X, He J, et al. Omentin protects against LPS-induced ARDS through suppressing pulmonary inflammation and promoting endothelial barrier via an Akt/eNOS-dependent mechanism. Cell Death Dis 2016; 7(9)e2360
[http://dx.doi.org/10.1038/cddis.2016.265] [PMID: 27607575]
[18]
Dolinay T, Kim YS, Howrylak J, et al. Inflammasome-regulated cytokines are critical mediators of acute lung injury. Am J Respir Crit Care Med 2012; 185(11): 1225-34.
[http://dx.doi.org/10.1164/rccm.201201-0003OC] [PMID: 22461369]
[19]
Rojas M, Parker RE, Thorn N, et al. Infusion of freshly isolated autologous bone marrow derived mononuclear cells prevents endotoxin-induced lung injury in an ex-vivo perfused swine model. Stem Cell Res Ther 2013; 4(2): 26.
[http://dx.doi.org/10.1186/scrt174] [PMID: 23497755]
[20]
Liu X, Yan Z, Luo M, Engelhardt JF. Species-specific differences in mouse and human airway epithelial biology of recombinant adeno-associated virus transduction. Am J Respir Cell Mol Biol 2006; 34(1): 56-64.
[http://dx.doi.org/10.1165/rcmb.2005-0189OC] [PMID: 16195538]
[21]
Gong MN. Genetic epidemiology of acute respiratory distress syndrome: Implications for future prevention and treatment. Clin Chest Med 2006; 27(4): 705-24.
[http://dx.doi.org/10.1016/j.ccm.2006.07.001] [PMID: 17085257]
[22]
Xu ZL, Mizuguchi H, Sakurai F, et al. Approaches to improving the kinetics of adenovirus-delivered genes and gene products. Adv Drug Deliv Rev 2005; 57(5): 781-802.
[http://dx.doi.org/10.1016/j.addr.2004.12.010] [PMID: 15757761]
[23]
Katkin JP, Gilbert BE, Langston C, et al. Aerosol delivery of a beta-galactosidase adenoviral vector to the lungs of rodents. Hum Gene Ther 1995; 6(8): 985-95.
[http://dx.doi.org/10.1089/hum.1995.6.8-985] [PMID: 7578420]
[24]
Dumasius V, Mendez M, Mutlu GM, Factor P. Acute lung injury does not impair adenoviral-mediated gene transfer to the alveolar epithelium. Chest 2002; 121(3): 33S-4S.
[http://dx.doi.org/10.1378/chest.121.3_suppl.33S] [PMID: 11893674]
[25]
Young LS, Mautner V. The promise and potential hazards of adenovirus gene therapy. Gut 2001; 48(5): 733-6.
[http://dx.doi.org/10.1136/gut.48.5.733] [PMID: 11302979]
[26]
Hassett P, Curley GF, Contreras M, et al. Overexpression of pulmonary extracellular superoxide dismutase attenuates endotoxin-induced acute lung injury. Intensive Care Med 2011; 37(10): 1680-7.
[http://dx.doi.org/10.1007/s00134-011-2309-y] [PMID: 21755396]
[27]
Barnard AR, Groppe M, MacLaren RE. Gene therapy for choroideremia using an adeno-associated viral (AAV) vector. Cold Spring Harb Perspect Med 2014; 5(3)a017293
[http://dx.doi.org/10.1101/cshperspect.a017293] [PMID: 25359548]
[28]
Yan Z, Sun X, Feng Z, et al. Optimization of recombinant adeno-associated Virus-Mediated expression for large transgenes, using a synthetic promoter and tandem array enhancers. Hum Gene Ther 2015; 26(6): 334-46.
[http://dx.doi.org/10.1089/hum.2015.001] [PMID: 25763813]
[29]
Buch PK, Bainbridge JW, Ali RR. AAV-mediated gene therapy for retinal disorders: From mouse to man. Gene Ther 2008; 15(11): 849-57.
[http://dx.doi.org/10.1038/gt.2008.66] [PMID: 18418417]
[30]
Aucoin MG, Perrier M, Kamen AA. Critical assessment of current adeno-associated viral vector production and quantification methods. Biotechnol Adv 2008; 26(1): 73-88.
[http://dx.doi.org/10.1016/j.biotechadv.2007.09.001] [PMID: 17964108]
[31]
Barker SE, Broderick CA, Robbie SJ, et al. Subretinal delivery of adeno-associated virus serotype 2 results in minimal immune responses that allow repeat vector administration in immunocompetent mice. J Gene Med 2009; 11(6): 486-97.
[http://dx.doi.org/10.1002/jgm.1327] [PMID: 19340848]
[32]
Liu X, Luo M, Trygg C, et al. Biological differences in rAAV transduction of airway epithelia in humans and in old world Non-human Primates. Mol Ther 2007; 15(12): 2114-23.
[http://dx.doi.org/10.1038/sj.mt.6300277] [PMID: 17667945]
[33]
Gao GP, Wilson JM, Wivel NA. Production of recombinant adeno-associated virus. Adv Virus Res 2000; 55: 529-43.
[http://dx.doi.org/10.1016/S0065-3527(00)55016-7] [PMID: 11050955]
[34]
Zuckerman JB, Robinson CB, McCoy KS, et al. A phase I study of adenovirus-mediated transfer of the human cystic fibrosis transmembrane conductance regulator gene to a lung segment of individuals with cystic fibrosis. Hum Gene Ther 1999; 10(18): 2973-85.
[http://dx.doi.org/10.1089/10430349950016384] [PMID: 10609658]
[35]
Sinn PL, Hickey MA, Staber PD, et al. Lentivirus vectors pseudotyped with filoviral envelope glycoproteins transduce airway epithelia from the apical surface independently of folate receptor alpha. J Virol 2003; 77(10): 5902-10.
[http://dx.doi.org/10.1128/JVI.77.10.5902-5910.2003] [PMID: 12719583]
[36]
Kim SH, Kim S, Robbins PD. Retroviral vectors. Adv Virus Res 2000; 55: 545-63.
[http://dx.doi.org/10.1016/S0065-3527(00)55017-9] [PMID: 11050956]
[37]
Kohn DB. Gene therapy outpaces haplo for SCID-X1. Blood 2015; 125(23): 3521-2.
[http://dx.doi.org/10.1182/blood-2015-04-641720] [PMID: 26045591]
[38]
Wu C, Zhao J, Zhu G, Huang Y, Jin L. SiRNA directed against NF-κB inhibits mononuclear macrophage cells releasing proinflammatory cytokines in vitro. Mol Med Rep 2017; 16(6): 9060-6.
[http://dx.doi.org/10.3892/mmr.2017.7715] [PMID: 28990087]
[39]
Hacein-Bey-Abina S, Garrigue A, Wang GP, et al. Insertional oncogenesis in 4 patients after retrovirus-mediated gene therapy of SCID-X1. J Clin Invest 2008; 118(9): 3132-42.
[http://dx.doi.org/10.1172/JCI35700] [PMID: 18688285]
[40]
Zabner J, Cheng SH, Meeker D, et al. Comparison of DNA-lipid complexes and DNA alone for gene transfer to cystic fibrosis airway epithelia in vivo. J Clin Invest 1997; 100(6): 1529-37.
[http://dx.doi.org/10.1172/JCI119676] [PMID: 9294121]
[41]
Lin X, Dean DA. Gene therapy for ALI/ARDS. Crit Care Clin 2011; 27(3): 705-18.
[http://dx.doi.org/10.1016/j.ccc.2011.04.002] [PMID: 21742224]
[42]
Davies LA, Nunez-Alonso GA, McLachlan G, Hyde SC, Gill DR. Aerosol delivery of DNA/liposomes to the lung for cystic fibrosis gene therapy. Hum Gene Ther Clin Dev 2014; 25(2): 97-107.
[http://dx.doi.org/10.1089/humc.2014.019] [PMID: 24865497]
[43]
Griesenbach U, Sumner-Jones SG, Holder E, et al. Limitations of the murine nose in the development of nonviral airway gene transfer. Am J Respir Cell Mol Biol 2010; 43(1): 46-54.
[http://dx.doi.org/10.1165/rcmb.2009-0075OC] [PMID: 19648474]
[44]
Griesenbach U, Meng C, Farley R, et al. The use of carboxymethylcellulose gel to increase non-viral gene transfer in mouse airways. Biomaterials 2010; 31(9): 2665-72.
[http://dx.doi.org/10.1016/j.biomaterials.2009.12.005] [PMID: 20022367]
[45]
Caplen NJ, Alton EW, Middleton PG, et al. Liposome-mediated CFTR gene transfer to the nasal epithelium of patients with cystic fibrosis. Nat Med 1995; 1(1): 39-46.
[http://dx.doi.org/10.1038/nm0195-39] [PMID: 7584951]
[46]
Noone PG, Hohneker KW, Zhou Z, et al. Safety and biological efficacy of a lipid-CFTR complex for gene transfer in the nasal epithelium of adult patients with cystic fibrosis. Mol Ther 2000; 1(1): 105-14.
[http://dx.doi.org/10.1006/mthe.1999.0009] [PMID: 10933918]
[47]
Laffey JG, Matthay MA. Fifty years of research in ARDS. Cell-based therapy for acute respiratory distress syndrome. Biology and potential therapeutic value. Am J Respir Crit Care Med 2017; 196(3): 266-73.
[http://dx.doi.org/10.1164/rccm.201701-0107CP] [PMID: 28306336]
[48]
Tang XD, Shi L, Monsel A, et al. Mesenchymal stem cell microvesicles attenuate acute lung injury in mice partly mediated by Ang-1 mRNA. Stem Cells 2017; 35(7): 1849-59.
[http://dx.doi.org/10.1002/stem.2619] [PMID: 28376568]
[49]
Chen X, Zhang Y, Wang W, Liu Z, Meng J, Han Z. Mesenchymal stem cells modified with heme oxygenase-1 have enhanced paracrine function and attenuate lipopolysaccharide-induced inflammatory and oxidative damage in pulmonary microvascular endothelial cells. Cell Physiol Biochem 2018; 49(1): 101-22.
[http://dx.doi.org/10.1159/000492847] [PMID: 30153667]
[50]
Mokhber DMR, Jabbari FM, Sadeghian CS, Dehghan MM, Vajhi A, Mokhtari R. Intrapulmonary autologous transplant of bone marrow-derived mesenchymal stromal cells improves lipopolysaccharide-induced acute respiratory distress syndrome in rabbit. Crit Care 2018; 22(1): 353.
[http://dx.doi.org/10.1186/s13054-018-2272-x] [PMID: 30572913]
[51]
Mei SH, McCarter SD, Deng Y, Parker CH, Liles WC, Stewart DJ. Prevention of LPS-induced acute lung injury in mice by mesenchymal stem cells overexpressing angiopoietin 1. PLoS Med 2007; 4(9)e269
[http://dx.doi.org/10.1371/journal.pmed.0040269] [PMID: 17803352]
[52]
McCarter SD, Mei SH, Lai PF, et al. Cell-based angiopoietin-1 gene therapy for acute lung injury. Am J Respir Crit Care Med 2007; 175(10): 1014-26.
[http://dx.doi.org/10.1164/rccm.200609-1370OC] [PMID: 17322110]
[53]
Huang ZW, Liu N, Li D, et al. Angiopoietin-1 modified human umbilical cord mesenchymal stem cell therapy for endotoxin-induced acute lung injury in rats. Yonsei Med J 2017; 58(1): 206-16.
[http://dx.doi.org/10.3349/ymj.2017.58.1.206] [PMID: 27873515]
[54]
Tammela T, Saaristo A, Lohela M, et al. Angiopoietin-1 promotes lymphatic sprouting and hyperplasia. Blood 2005; 105(12): 4642-8.
[http://dx.doi.org/10.1182/blood-2004-08-3327] [PMID: 15746084]
[55]
Sullivan CC, Du L, Chu D, et al. Induction of pulmonary hypertension by an angiopoietin 1/TIE2/serotonin pathway. Proc Natl Acad Sci USA 2003; 100(21): 12331-6.
[http://dx.doi.org/10.1073/pnas.1933740100] [PMID: 14512515]
[56]
Long DA, Price KL, Ioffe E, et al. Angiopoietin-1 therapy enhances fibrosis and inflammation following folic acid-induced acute renal injury. Kidney Int 2008; 74(3): 300-9.
[http://dx.doi.org/10.1038/ki.2008.179] [PMID: 18480750]
[57]
Min JH, Codipilly CN, Nasim S, Miller EJ, Ahmed MN. Synergistic protection against hyperoxia-induced lung injury by neutrophils blockade and EC-SOD overexpression. Respir Res 2012; 13: 58.
[http://dx.doi.org/10.1186/1465-9921-13-58] [PMID: 22816678]
[58]
Makarov SS, Johnston WN, Olsen JC, et al. NF-kappa B as a target for anti-inflammatory gene therapy: Suppression of inflammatory responses in monocytic and stromal cells by stable gene transfer of I kappa B alpha cDNA. Gene Ther 1997; 4(8): 846-52.
[http://dx.doi.org/10.1038/sj.gt.3300461] [PMID: 9338014]
[59]
Jin LY, Li CF, Zhu GF, Wu CT, Wang J, Yan SF. Effect of siRNA against NF-κB on sepsis-induced acute lung injury in a mouse model. Mol Med Rep 2014; 10(2): 631-7.
[http://dx.doi.org/10.3892/mmr.2014.2299] [PMID: 24913772]
[60]
Mutlu GM, Machado-Aranda D, Norton JE, et al. Electroporation-mediated gene transfer of the Na+,K+ -ATPase rescues endotoxin-induced lung injury. Am J Respir Crit Care Med 2007; 176(6): 582-90.
[http://dx.doi.org/10.1164/rccm.200608-1246OC] [PMID: 17556717]
[61]
Factor P, Dumasius V, Saldias F, Brown LA, Sznajder JI. Adenovirus-mediated transfer of an Na+/K+-ATPase beta1 subunit gene improves alveolar fluid clearance and survival in hyperoxic rats. Hum Gene Ther 2000; 11(16): 2231-42.
[http://dx.doi.org/10.1089/104303400750035753] [PMID: 11084680]
[62]
Lin X, Barravecchia M, Kothari P, Young JL, Dean DA. β1-Na(+),K(+)-ATPase gene therapy upregulates tight junctions to rescue lipopolysaccharide-induced acute lung injury. Gene Ther 2016; 23(6): 489-99.
[http://dx.doi.org/10.1038/gt.2016.19] [PMID: 26910760]
[63]
Bromberg Z, Raj N, Goloubinoff P, Deutschman CS, Weiss YG. Enhanced expression of 70-kilodalton heat shock protein limits cell division in a sepsis-induced model of acute respiratory distress syndrome. Crit Care Med 2008; 36(1): 246-55.
[http://dx.doi.org/10.1097/01.CCM.0000295473.56522.EF] [PMID: 17989570]
[64]
Dong HY, Cui Y, Zhang B, et al. Automatic regulation of NF-κB by pHSP70/IκBαm to prevent acute lung injury in mice. Arch Biochem Biophys 2017; 634: 47-56.
[http://dx.doi.org/10.1016/j.abb.2017.07.020] [PMID: 28778458]
[65]
Parmley LA, Elkins ND, Fini MA, Liu YE, Repine JE, Wright RM. Alpha-4/beta-1 and alpha-L/beta-2 integrins mediate cytokine induced lung leukocyte-epithelial adhesion and injury. Br J Pharmacol 2007; 152(6): 915-29.
[http://dx.doi.org/10.1038/sj.bjp.0707443] [PMID: 17828290]
[66]
Takenaka K, Nishimura Y, Nishiuma T, et al. Ventilator-induced lung injury is reduced in transgenic mice that overexpress endothelial nitric oxide synthase. Am J Physiol Lung Cell Mol Physiol 2006; 290(6): L1078-86.
[http://dx.doi.org/10.1152/ajplung.00239.2005] [PMID: 16399791]
[67]
Baba Y, Yazawa T, Kanegae Y, et al. Keratinocyte growth factor gene transduction ameliorates acute lung injury and mortality in mice. Hum Gene Ther 2007; 18(2): 130-41.
[http://dx.doi.org/10.1089/hum.2006.137] [PMID: 17328680]
[68]
Devaney J, Contreras M, Laffey JG. Clinical review: Gene-based therapies for ALI/ARDS: Where are we now? Crit Care 2011; 15(3): 224.
[http://dx.doi.org/10.1186/cc10216] [PMID: 21699743]
[69]
Matthay MA, McAuley DF, Ware LB. Clinical trials in acute respiratory distress syndrome: Challenges and opportunities. Lancet Respir Med 2017; 5(6): 524-34.
[http://dx.doi.org/10.1016/S2213-2600(17)30188-1] [PMID: 28664851]
[70]
Matthay MA, Zimmerman GA, Esmon C, et al. Future research directions in acute lung injury: Summary of a National Heart, Lung and Blood Institute working group. Am J Respir Crit Care Med 2003; 167(7): 1027-35.
[http://dx.doi.org/10.1164/rccm.200208-966WS] [PMID: 12663342]
[71]
Weiss YG, Maloyan A, Tazelaar J, Raj N, Deutschman CS. Adenoviral transfer of HSP-70 into pulmonary epithelium ameliorates experimental acute respiratory distress syndrome. J Clin Invest 2002; 110(6): 801-6.
[http://dx.doi.org/10.1172/JCI0215888] [PMID: 12235111]
[72]
Moss RB, Rodman D, Spencer LT, et al. Repeated adeno-associated virus serotype 2 aerosol-mediated cystic fibrosis transmembrane regulator gene transfer to the lungs of patients with cystic fibrosis: A multicenter, double-blind, placebo-controlled trial. Chest 2004; 125(2): 509-21.
[http://dx.doi.org/10.1378/chest.125.2.509] [PMID: 14769732]
[73]
Joseph PM, O’Sullivan BP, Lapey A, et al. Aerosol and lobar administration of a recombinant adenovirus to individuals with cystic fibrosis. I. Methods, safety, and clinical implications. Hum Gene Ther 2001; 12(11): 1369-82.
[http://dx.doi.org/10.1089/104303401750298535] [PMID: 11485629]
[74]
Arad U, Zeira E, El-Latif MA, et al. Liver-targeted gene therapy by SV40-based vectors using the hydrodynamic injection method. Hum Gene Ther 2005; 16(3): 361-71.
[http://dx.doi.org/10.1089/hum.2005.16.361] [PMID: 15812231]
[75]
Suen CM, Mei SH, Kugathasan L, Stewart DJ. Targeted delivery of genes to endothelial cells and cell- and gene-based therapy in pulmonary vascular diseases. Compr Physiol 2013; 3(4): 1749-79.
[http://dx.doi.org/10.1002/cphy.c120034] [PMID: 24265244]
[76]
Tagalakis AD, McAnulty RJ, Devaney J, et al. A receptor-targeted nanocomplex vector system optimized for respiratory gene transfer. Mol Ther 2008; 16(5): 907-15.
[http://dx.doi.org/10.1038/mt.2008.38] [PMID: 18388925]


Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 19
ISSUE: 2
Year: 2019
Page: [93 - 99]
Pages: 7
DOI: 10.2174/1566523219666190702154817
Price: $58

Article Metrics

PDF: 22
HTML: 2