Lessons learned from lung and liver in-vivo gene therapy: implications for the future

References

• Somia N, Verma IM. Gene therapy: trials and tribulations. Nat Reviews Genet. 2000 Nov;1(2):91–99.
   PubMed Web of Science ®Google Scholar
• Dunbar CE, High KA, Joung JK, et al. Gene therapy comes of age. Science (New York, NY). 2018 Jan 12;359(6372):eaan4672.
   Google Scholar
• Mueller C, Gernoux G, Gruntman AM, et al. 5 year expression and neutrophil defect repair after gene therapy in Alpha-1 antitrypsin deficiency. Mol Therapy: J Am Soc Gene Ther. 2017 Jun 7;25(6):1387–1394.
   PubMed Web of Science ®Google Scholar
• Riordan JR, Rommens JM, Kerem B, et al. Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA. Science (New York, NY). 1989 Sep 8;245(4922):1066–1073.
   Google Scholar
• Laube BL. Aerosolized medications for gene and peptide therapy. Respir Care. 2015 Jun;60(6):806–21;discussion 821–824.
   PubMed Web of Science ®Google Scholar
• 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 Aug;34(2):354–360.
   PubMed Web of Science ®Google Scholar
• McCaskill J, Singhania R, Burgess M, et al. Efficient biodistribution and gene silencing in the lung epithelium via intravenous liposomal delivery of siRNA. Mol Ther Nucleic Acids. 2013;2:e96.
   PubMedGoogle Scholar
• Rowe SM, Clancy JP, Wilschanski M. Nasal potential difference measurements to assess CFTR ion channel activity. Methods in Molecular Biology (Clifton, NJ). 2011;741:69–86.
   PubMedGoogle Scholar
• Fajac I, Lacronique J, Lockhart A, et al. Silver/silver chloride electrodes for measurement of potential difference in human bronchi. Thorax. 1998 Oct;53(10):879–881.
   PubMed Web of Science ®Google Scholar
• Chiuchiolo MJ, Kaminsky SM, Sondhi D, et al. Phase I/II study of intrapleural administration of a serotype rh.10 replication-deficient adeno-associated virus gene transfer vector expressing the human alpha1-antitrypsin cDNA to individuals with alpha1-antitrypsin deficiency. Human Gene Therapy Clinical Development. 2014 Sep;25(3):112–133.
   PubMed Web of Science ®Google Scholar
• Harvey BG, Leopold PL, Hackett NR, et al. Airway epithelial CFTR mRNA expression in cystic fibrosis patients after repetitive administration of a recombinant adenovirus. J Clin Invest. 1999 Nov;104(9):1245–1255.
   PubMed Web of Science ®Google Scholar
• Yew NS, Zhao H, Wu IH, et al. Reduced inflammatory response to plasmid DNA vectors by elimination and inhibition of immunostimulatory CpG motifs. Mol Therapy: J Am Soc Gene Ther. 2000 Mar;1(3):255–262.
   PubMed Web of Science ®Google Scholar
• Hyde SC, Pringle IA, Abdullah S, et al. CpG-free plasmids confer reduced inflammation and sustained pulmonary gene expression. Nat Biotechnol. 2008 May;26(5):549–551.
   PubMed Web of Science ®Google Scholar
• Hyde SC, Southern KW, Gileadi U, et al. Repeat administration of DNA/liposomes to the nasal epithelium of patients with cystic fibrosis. Gene Ther. 2000 7;Jul(13):1156–1165.
   Google Scholar
• Alton E, Armstrong DK, Ashby D, et al. Repeated nebulisation of non-viral CFTR gene therapy in patients with cystic fibrosis: a randomised, double-blind, placebo-controlled, phase 2b trial. Lancet Respir Med. 2015 Sep;3(9):684–691.
   PubMed Web of Science ®Google Scholar
• Davies LA, Nunez-Alonso GA, McLachlan G, et al. Aerosol delivery of DNA/liposomes to the lung for cystic fibrosis gene therapy. Human Gene Therapy Clinical Development. 2014 Jun;25(2):97–107.
   PubMed Web of Science ®Google Scholar
• Manunta MD, Tagalakis AD, Attwood M, et al. Delivery of ENaC siRNA to epithelial cells mediated by a targeted nanocomplex: a therapeutic strategy for cystic fibrosis. Sci Rep. 2017 Apr 6;7(1):700.
   PubMed Web of Science ®Google Scholar
• Davies LA, McLachlan G, Sumner-Jones SG, et al. Enhanced lung gene expression after aerosol delivery of concentrated pDNA/PEI complexes. Mol Therapy: J Am Soc Gene Ther. 2008 Jul;16(7):1283–1290.
   PubMed Web of Science ®Google Scholar
• Degiulio JV, Kaufman CD, Dean DA, et al. promoter facilitates alveolar type II epithelial cell-specific plasmid nuclear import and gene expression. Gene Ther. 2010 Apr;17(4):541–549.
   PubMed Web of Science ®Google Scholar
• Flotte TR, Zeitlin PL, Reynolds TC, et al. Phase I trial of intranasal and endobronchial administration of a recombinant adeno-associated virus serotype 2 (rAAV2)-CFTR vector in adult cystic fibrosis patients: a two-part clinical study. Hum Gene Ther. 2003 Jul 20;14(11):1079–1088.
   PubMed Web of Science ®Google Scholar
• Flotte TR, Solow R, Owens RA, et al. Gene expression from adeno-associated virus vectors in airway epithelial cells. Am J Respir Cell Mol Biol. 1992 Sep;7(3):349–356.
   PubMed Web of Science ®Google Scholar
• Conrad CK, Allen SS, Afione SA, et al. Safety of single-dose administration of an adeno-associated virus (AAV)-CFTR vector in the primate lung. Gene Ther. 1996 Aug;3(8):658–668.
   PubMed Web of Science ®Google Scholar
• Sondhi D, Stiles KM, De BP, et al. Genetic modification of the lung directed toward treatment of human disease. Hum Gene Ther. 2017 Jan;28(1):3–84.
   PubMed Web of Science ®Google Scholar
• Summerford C, Samulski RJ. Membrane-associated heparan sulfate proteoglycan is a receptor for adeno-associated virus type 2 virions. J Virol. 1998 Feb;72(2):1438–1445.
   PubMed Web of Science ®Google Scholar
• Farrow N, Donnelley M, Cmielewski P, et al. Role of basal cells in producing persistent lentivirus-mediated airway gene expression. Hum Gene Ther. 2018 Jan 3. DOI:10.1089/hum.2017.059.
   PubMed Web of Science ®Google Scholar
• Montoro DT, Haber AL,Biton M, et al. A revised airway epithelial hierarchy includes CFTR-expressing ionocytes. Nature. 2018 Aug 1. DOI:10.1038/s41586-018-0393-7.
   PubMed Web of Science ®Google Scholar
• Plasschaert LW, Zilionis-R, Choo-Wing R, et al. A single-cell atlas of the airway epithelium reveals the CFTR-rich pulmonary ionocyte. Nature.2018 Aug 1. DOI:10.1038/s41586-018-0394-6.
   PubMed Web of Science ®Google Scholar
• Tata PR, Rajagopal J. Plasticity in the lung: making and breaking cell identity. Development. 2017 Mar 1;144(5):755–766.
   PubMed Web of Science ®Google Scholar
• Lee JH, Rawlins EL. Developmental mechanisms and adult stem cells for therapeutic lung regeneration. Dev Biol. 2018 Jan 15;433(2):166–176.
   PubMed Web of Science ®Google Scholar
• Excoffon KJ, Koerber JT, Dickey DD, et al. Directed evolution of adeno-associated virus to an infectious respiratory virus. Proc Natl Acad Sci U S A. 2009 Mar 10;106(10):3865–3870.
   PubMed Web of Science ®Google Scholar
• Li W, Zhang L, Johnson JS, et al. Generation of novel AAV variants by directed evolution for improved CFTR delivery to human ciliated airway epithelium. Mol Therapy: J Am Soc Gene Ther. 2009 Dec;17(12):2067–2077.
   PubMed Web of Science ®Google Scholar
• Limberis MP, Vandenberghe LH, Zhang L, et al. Transduction efficiencies of novel AAV vectors in mouse airway epithelium in vivo and human ciliated airway epithelium in vitro. Mol Therapy: J Am Soc Gene Ther. 2009 Feb;17(2):294–301.
   PubMed Web of Science ®Google Scholar
• Kushwah R, Cao H, Hu J. Characterization of pulmonary T cell response to helper-dependent adenoviral vectors following intranasal delivery. J Immunol. 2008 Mar 15;180(6):4098–4108.
   PubMed Web of Science ®Google Scholar
• Cao H, Ouyang H, Grasemann H, et al. Transducing airway basal cells with a helper-dependent adenoviral vector for lung gene therapy. Hum Gene Ther. 2018 Jan 10. DOI:10.1089/hum.2017.201.
   Web of Science ®Google Scholar
• Joglekar AV, Sandoval S. Pseudotyped lentiviral vectors: one vector, many guises. Hum Gene Ther Methods. 2017 Dec;28(6):291–301.
   PubMed Web of Science ®Google Scholar
• Alton EW, Beekman JM, Boyd AC, et al. Preparation for a first-in-man lentivirus trial in patients with cystic fibrosis. Thorax. 2017 Feb;72(2):137–147.
   PubMed Web of Science ®Google Scholar
• Kobayashi M, Iida A, Ueda Y, et al. Pseudotyped lentivirus vectors derived from simian immunodeficiency virus SIVagm with envelope glycoproteins from paramyxovirus [Evaluation Studies]. J Virol. 2003 Feb;77(4):2607–2614.
   PubMed Web of Science ®Google Scholar
• Sinn PL, Hwang BY, Li N, et al. Novel GP64 envelope variants for improved delivery to human airway epithelial cells. Gene Ther. 2017 Oct;24(10):674–679.
   PubMed Web of Science ®Google Scholar
• Payne JG, Takahashi A, Higgins MI, et al. Multilineage transduction of resident lung cells in vivo by AAV2/8 for alpha1-antitrypsin gene therapy. Molecular Therapy Methods Clinical Development. 2016;3:16042.
   PubMedGoogle Scholar
• Bohinski RJ, Huffman JA, Whitsett JA, et al. Cis-active elements controlling lung cell-specific expression of human pulmonary surfactant protein B gene. J Biol Chem. 1993 May 25;268(15):11160–11166.
   PubMed Web of Science ®Google Scholar
• Glasser SW, Korfhagen TR, Wert SE, et al. Genetic element from human surfactant protein SP-C gene confers bronchiolar-alveolar cell specificity in transgenic mice. Am J Physiol. 1991 Oct;261(4 Pt 1):L349–56.
   PubMedGoogle Scholar
• Smith MJ, Rousculp MD, Goldsmith KT, et al. Surfactant protein A-directed toxin gene kills lung cancer cells in vitro. Hum Gene Ther. 1994 Jan;5(1):29–35.
   PubMed Web of Science ®Google Scholar
• Barnett RC, Lin X, Barravecchia M, et al. Featured Article: electroporation-mediated gene delivery of surfactant protein B (SP-B) restores expression and improves survival in mouse model of SP-B deficiency. Experimental Biology and Medicine (Maywood, NJ). 2017 Jul;242(13):1345–1354.
   PubMed Web of Science ®Google Scholar
• Kim N, Duncan GA, Hanes J, et al. Barriers to inhaled gene therapy of obstructive lung diseases: A review. Journal of Controlled Release: Official Journal of the Controlled Release Society. 2016;240:465–488.
   PubMed Web of Science ®Google Scholar
• Mastorakos P, Da Silva AL, Chisholm J, et al. Highly compacted biodegradable DNA nanoparticles capable of overcoming the mucus barrier for inhaled lung gene therapy. Proc Natl Acad Sci U S A. 2015 Jul 14;112(28):8720–8725.
   PubMed Web of Science ®Google Scholar
• Ning ZY, Luo MY, Qi WB, et al. Detection of expression of influenza virus receptors in tissues of BALB/c mice by histochemistry. Vet Res Commun. 2009 Dec;33(8):895–903. .
   PubMed Web of Science ®Google Scholar
• Shinya K, Ebina M, Yamada S, et al. Avian flu: influenza virus receptors in the human airway. Nature. 2006 Mar 23;440(7083):435–436.
   PubMed Web of Science ®Google Scholar
• Walters RW, Grunst T, Bergelson JM, et al. Basolateral localization of fiber receptors limits adenovirus infection from the apical surface of airway epithelia. J Biol Chem. 1999 Apr 9;274(15):10219–10226.
   PubMed Web of Science ®Google Scholar
• Grubb BR, Pickles RJ, Ye H, et al. Inefficient gene transfer by adenovirus vector to cystic fibrosis airway epithelia of mice and humans. Nature. 1994 Oct 27;371(6500):802–806.
   PubMed Web of Science ®Google Scholar
• Rawlins EL, Hogan BL. Ciliated epithelial cell lifespan in the mouse trachea and lung. American Journal of Physiology Lung Cellular and Molecular Physiology. 2008 Jul;295(1):L231–L234.
   PubMed Web of Science ®Google Scholar
• Grossman M, Raper SE, Kozarsky K, et al. Successful ex vivo gene therapy directed to liver in a patient with familial hypercholesterolaemia. Nat Genet. 1994 Apr;6(4):335–341.
   PubMed Web of Science ®Google Scholar
• Yokoo T, Kamimura K, Abe H, et al. Liver-targeted hydrodynamic gene therapy: recent advances in the technique. World Journal of Gastroenterology. 2016 Oct 28;22(40):8862–8868.
   PubMed Web of Science ®Google Scholar
• Greig JA, Peng H, Ohlstein J, et al. Intramuscular injection of AAV8 in mice and macaques is associated with substantial hepatic targeting and transgene expression. PloS One. 2014;9(11):e112268.
   PubMed Web of Science ®Google Scholar
• Chen ZY, He CY, Ehrhardt A, et al. Minicircle DNA vectors devoid of bacterial DNA result in persistent and high-level transgene expression in vivo. Mol Therapy: J Am Soc Gene Ther. 2003 Sep;8(3):495–500.
   PubMed Web of Science ®Google Scholar
• Lu J, Zhang F, Kay MA. A mini-intronic plasmid (MIP): a novel robust transgene expression vector in vivo and in vitro. Mol Therapy: J Am Soc Gene Ther. 2013 May;21(5):954–963.
   PubMed Web of Science ®Google Scholar
• Cantore A, Ranzani M, Bartholomae CC, et al. Liver-directed lentiviral gene therapy in a dog model of hemophilia B. Sci Transl Med. 2015 Mar 4;7(277):277ra28.
   PubMed Web of Science ®Google Scholar
• Castello R, Borzone R, D’Aria S, et al. Helper-dependent adenoviral vectors for liver-directed gene therapy of primary hyperoxaluria type 1. Gene Ther. 2016 Feb;23(2):129–134.
   PubMed Web of Science ®Google Scholar
• Meliani A, Boisgerault F, Fitzpatrick Z, et al. Enhanced liver gene transfer and evasion of preexisting humoral immunity with exosome-enveloped AAV vectors. Blood Advances. 2017 Oct 24;1(23):2019–2031.
   PubMed Web of Science ®Google Scholar
• Manno CS, Pierce GF, Arruda VR, et al. Successful transduction of liver in hemophilia by AAV-Factor IX and limitations imposed by the host immune response. Nat Med. 2006 Mar;12(3):342–347.
   PubMed Web of Science ®Google Scholar
• Rangarajan S, Walsh L, Lester W, et al. AAV5-factor VIII gene transfer in severe hemophilia A. N Engl J Med. 2017 Dec 28;377(26):2519–2530.
   PubMed Web of Science ®Google Scholar
• George LA, Sullivan SK, Giermasz A, et al. Hemophilia B gene therapy with a high-specific-activity factor IX variant. N Engl J Med. 2017 Dec 7;377(23):2215–2227.
   PubMed Web of Science ®Google Scholar
• Lisowski L, Dane AP, Chu K, et al. Selection and evaluation of clinically relevant AAV variants in a xenograft liver model. Nature. 2014 Feb 20;506(7488):382–386.
   PubMed Web of Science ®Google Scholar
• Wang L, Bell P, Somanathan S, et al. Comparative study of liver gene transfer with AAV vectors based on natural and engineered AAV capsids. Mol Therapy: J Am Soc Gene Ther. 2015 Dec;23(12):1877–1887.
   PubMed Web of Science ®Google Scholar
• Paulk NK, Pekrun K, Zhu E, et al. Bioengineered AAV capsids with combined high human liver transduction in vivo and unique humoral seroreactivity. Mol Therapy: J Am Soc Gene Ther. 2018 Jan 3;26(1):289–303.
   PubMed Web of Science ®Google Scholar
• Matsui H, Hegadorn C, Ozelo M, et al. A microRNA-regulated and GP64-pseudotyped lentiviral vector mediates stable expression of FVIII in a murine model of hemophilia A. Mol Therapy: J Am Soc Gene Ther. 2011 Apr;19(4):723–730.
   PubMed Web of Science ®Google Scholar
• Schauber CA, Tuerk MJ, Pacheco CD, et al. Lentiviral vectors pseudotyped with baculovirus gp64 efficiently transduce mouse cells in vivo and show tropism restriction against hematopoietic cell types in vitro. Gene Ther. 2004 Feb;11(3):266–275.
   PubMed Web of Science ®Google Scholar
• Preclinical HY. Clinical advances of GalNAc-decorated nucleic acid therapeutics. Mol Ther Nucleic Acids. 2017 Mar 17;6: 116–132.
   PubMedGoogle Scholar
• Nakai H, Herzog RW, Hagstrom JN, et al. Adeno-associated viral vector-mediated gene transfer of human blood coagulation factor IX into mouse liver. Blood. 1998 Jun 15;91(12):4600–4607.
   PubMed Web of Science ®Google Scholar
• Kyostio-Moore S, Berthelette P, Piraino S, et al. The impact of minimally oversized adeno-associated viral vectors encoding human factor VIII on vector potency in vivo. Molecular Therapy Methods Clinical Development. 2016;3:16006.
   PubMed Web of Science ®Google Scholar
• Nathwani AC, Reiss UM, Tuddenham EG, et al. Long-term safety and efficacy of factor IX gene therapy in hemophilia B. N Engl J Med. 2014 Nov 20;371(21):1994–2004.
   PubMed Web of Science ®Google Scholar
• Nair N, Rincon MY, Evens H, et al. Computationally designed liver-specific transcriptional modules and hyperactive factor IX improve hepatic gene therapy. Blood. 2014 May 15;123(20):3195–3199.
   PubMed Web of Science ®Google Scholar
• Logan GJ, Dane AP, Hallwirth CV, et al. Identification of liver-specific enhancer-promoter activity in the 3ʹ untranslated region of the wild-type AAV2 genome. Nat Genet. 2017 Aug;49(8):1267–1273.
   PubMed Web of Science ®Google Scholar
• Li ZY, Xi Y, Zhu WN, et al. Positive regulation of hepatic miR-122 expression by HNF4alpha. J Hepatol. 2011 Sep;55(3):602–611.
   PubMed Web of Science ®Google Scholar
• Brown BD, Gentner B, Cantore A, et al. Endogenous microRNA can be broadly exploited to regulate transgene expression according to tissue, lineage and differentiation state. Nat Biotechnol. 2007 Dec;25(12):1457–1467.
   PubMed Web of Science ®Google Scholar
• Brown BD, Venneri MA, Zingale A, et al. Endogenous microRNA regulation suppresses transgene expression in hematopoietic lineages and enables stable gene transfer. Nat Med. 2006 May;12(5):585–591.
   PubMed Web of Science ®Google Scholar
• Mingozzi F, High KA. Overcoming the host immune response to adeno-associated virus gene delivery vectors: the race between clearance, tolerance, neutralization, and escape. Annual Review of Virology. 2017 Sep 29;4(1):511–534.
   PubMed Web of Science ®Google Scholar
• Annoni A, Cantore A, Della Valle P, et al. Liver gene therapy by lentiviral vectors reverses anti-factor IX pre-existing immunity in haemophilic mice. EMBO Mol Med. 2013 Nov;5(11):1684–1697.
   PubMed Web of Science ®Google Scholar
• Markusic DM, Hoffman BE, Perrin GQ, et al. Effective gene therapy for haemophilic mice with pathogenic factor IX antibodies. EMBO Mol Med. 2013 Nov;5(11):1698–1709.
   PubMed Web of Science ®Google Scholar
• Donsante A, Miller DG, Li Y, et al. AAV vector integration sites in mouse hepatocellular carcinoma. Science (New York, NY). 2007 Jul 27;317(5837):477.
   Google Scholar
• Nault JC, Datta S, Imbeaud S, et al. Recurrent AAV2-related insertional mutagenesis in human hepatocellular carcinomas. Nat Genet. 2015 Oct;47(10):1187–1193.
   PubMed Web of Science ®Google Scholar
• Howe SJ, Mansour MR, Schwarzwaelder K, et al. Insertional mutagenesis combined with acquired somatic mutations causes leukemogenesis following gene therapy of SCID-X1 patients. J Clin Invest. 2008 Sep;118(9):3143–3150.
   PubMed Web of Science ®Google Scholar
• Berns KI, Byrne BJ, Flotte TR, et al. Adeno-associated virus type 2 and hepatocellular carcinoma? Hum Gene Ther. 2015 Dec;26(12):779–781.
   PubMed Web of Science ®Google Scholar
• Gil-Farina I, Fronza R, Kaeppel C, et al. Recombinant AAV integration is not associated with hepatic genotoxicity in nonhuman primates and patients. Mol Therapy: J Am Soc Gene Ther. 2016 Jun;24(6):1100–1105.
   PubMed Web of Science ®Google Scholar
• Aiuti A, Roncarolo MG, Naldini L. Gene therapy for ADA-SCID, the first marketing approval of an ex vivo gene therapy in Europe: paving the road for the next generation of advanced therapy medicinal products. EMBO Mol Med. 2017 Jun;9(6):737–740.
   PubMed Web of Science ®Google Scholar
• Mukherjee S, Thrasher AJ. Gene therapy for PIDs: progress, pitfalls and prospects. Gene. 2013 Aug 10;525(2):174–181.
   PubMed Web of Science ®Google Scholar
• Kelly ME, Zhuo J, Bharadwaj AS, et al. Induction of immune tolerance to FIX following muscular AAV gene transfer is AAV-dose/FIX-level dependent. Mol Therapy: J Am Soc Gene Ther. 2009 May;17(5):857–863.
   PubMed Web of Science ®Google Scholar
• Borel F, Tang Q, Gernoux G, et al. Survival advantage of both human hepatocyte xenografts and genome-edited hepatocytes for treatment of alpha-1 antitrypsin deficiency. Mol Therapy: J Am Soc Gene Ther. 2017 Nov 1;25(11):2477–2489.
   PubMed Web of Science ®Google Scholar
• Nygaard S, Barzel A, Haft A, et al. A universal system to select gene-modified hepatocytes in vivo. Sci Transl Med. 2016 Jun 8;8(342):342ra79.
   PubMed Web of Science ®Google Scholar
• Morrisey EE, Hogan BL. Preparing for the first breath: genetic and cellular mechanisms in lung development. Dev Cell. 2010 Jan 19;18(1):8–23.
   PubMed Web of Science ®Google Scholar
• Mingozzi F, Anguela XM, Pavani G, et al. Overcoming preexisting humoral immunity to AAV using capsid decoys. Sci Transl Med. 2013 Jul 17;5(194):194ra92.
   PubMed Web of Science ®Google Scholar
• Hinderer C, Katz N, Buza EL, et al. Severe toxicity in nonhuman primates and piglets following high-dose intravenous administration of an adeno-associated virus vector expressing human SMN. Hum Gene Ther. 2018 Mar;29(3):285–298.
   PubMed Web of Science ®Google Scholar
• Hordeaux J, Wang Q, Katz N, et al. The neurotropic properties of AAV-PHP.B are limited to C57BL/6J mice. Mol Therapy: J Am Soc Gene Ther. 2018 Mar 7;26(3):664–668.
   PubMed Web of Science ®Google Scholar
• Mendell JR, Al-Zaidy S, Shell R, et al. Single-dose gene-replacement therapy for spinal muscular atrophy. N Engl J Med. 2017 Nov 2;377(18):1713–1722.
   PubMed Web of Science ®Google Scholar
• Flotte TR, Buning H. Severe toxicity in nonhuman primates and piglets with systemic high-dose administration of adeno-associated virus serotype 9-like vectors: putting patients first. Hum Gene Ther. 2018 Mar;29(3):283–284.
   PubMed Web of Science ®Google Scholar
• Sumner-Jones SG, Gill DR, Hyde SC. Lack of repeat transduction by recombinant adeno-associated virus type 5/5 vectors in the mouse airway. J Virol. 2007 Nov;81(22):12360–12367.
   PubMed Web of Science ®Google Scholar
• Griesenbach U, Inoue M, Meng C, et al. Assessment of F/HN-pseudotyped lentivirus as a clinically relevant vector for lung gene therapy. Am J Respir Crit Care Med. 2012 Nov 1;186(9):846–856.
   PubMed Web of Science ®Google Scholar
• Sinn PL, Burnight ER, McCray PB Jr. Progress and prospects: prospects of repeated pulmonary administration of viral vectors. Gene Ther. 2009 Sep;16(9):1059–1065.
   PubMed Web of Science ®Google Scholar
• Sangamo Therapeutics Presents Initial Safety Data from CHAMPIONS Genome Editing Study for MPS II at WORLDSymposium: PR Newswire; 2018 Feb 06 [cited 2018 Feb 11]. Available from: https://www.prnewswire.com/news-releases/sangamo-therapeutics-presents-initial-safety-data-from-champions-genome-editing-study-for-mps-ii-at-worldsymposium-300594628.html
   Google Scholar
• Charlesworth CT, Deshpande PS, Dever DP, et al. Identification of pre-existing adaptive immunity to Cas9 proteins in humans. In: bioRxiv. 2018. p. 243345.
   Google Scholar
• Meliani A, Boisgerault F, Ronzitti G, et al. 77. antigen-specific modulation of capsid immunogenicity with tolerogenic nanoparticles results in successful AAV vector readministration. Mol Ther. 2016;24:S34.
   PubMed Web of Science ®Google Scholar
• Valkama AJ, Leinonen HM, Lipponen EM, et al. Optimization of lentiviral vector production for scale-up in fixed-bed bioreactor. Gene Ther. 2018 Jan;25(1):39–46.
   PubMed Web of Science ®Google Scholar
• Gardner J, Webster A, Barry J. Anticipating the clinical adoption of regenerative medicine: building institutional readiness in the UK. Regen Med. 2018 Jan;13(1):29–39.
   PubMed Web of Science ®Google Scholar
• Clement N, Grieger JC. Manufacturing of recombinant adeno-associated viral vectors for clinical trials. Molecular Therapy Methods Clinical Development. 2016;3:16002.
   PubMed Web of Science ®Google Scholar
• Vormittag P, Gunn R, Ghorashian S, et al. A guide to manufacturing CAR T cell therapies. Curr Opin Biotechnol. 2018;53:164–181.
   PubMed Web of Science ®Google Scholar
• Maunder HE, Wright J, Kolli BR, et al. Enhancing titres of therapeutic viral vectors using the transgene repression in vector production (TRiP) system. Nat Commun. 2017;8:14834.
   PubMed Web of Science ®Google Scholar
• Mietzsch M, Grasse S, Zurawski C, et al. OneBac: platform for scalable and high-titer production of adeno-associated virus serotype 1-12 vectors for gene therapy. Hum Gene Ther. 2014 Mar;25(3):212–222.
   PubMed Web of Science ®Google Scholar
• McCarron A, Donnelley M, McIntyre C, et al. Challenges of up-scaling lentivirus production and processing. J Biotechnol. 2016;240:23–30.
   PubMed Web of Science ®Google Scholar