biopreparatБИОпрепараты. Профилактика, диагностика, лечениеBiological Products. Prevention, Diagnosis, Treatment2221-996X2619-1156Scientific Centre for Expert Evaluation of Medicinal Products10.30895/2221-996X-2022-22-1-6-22biopreparat-362Research ArticleОБЗОРЫREVIEWSПроблемные аспекты разработки и регистрации генотерапевтических препаратовChallenges in development and authorisation of gene therapy productshttps://orcid.org/0000-0001-6624-2692СолдатовА. А.SoldatovA. A.

Солдатов Александр Алексеевич, доктор медицинских наук

Петровский б-р, д. 8, стр. 2, Москва, 127051

Aleksandr A. Soldatov, Dr. Sci. (Med.)

8/2 Petrovsky Blvd, Moscow 127051

soldatov@expmed.ruhttps://orcid.org/0000-0002-9377-1378АвдееваЖ. И.AvdeevaZh. I.

Авдеева Жанна Ильдаровна, доктор медицинских наук, профессор 

Петровский б-р, д. 8, стр. 2, Москва, 127051

Zhanna I. Avdeeva, Dr. Sci. (Med.), Professor

8/2 Petrovsky Blvd, Moscow 127051

avdeeva@expmed.ruhttps://orcid.org/0000-0003-0940-8080ГоренковД. В.GorenkovD. V.

Горенков Дмитрий Витальевич

Петровский б-р, д. 8, стр. 2, Москва, 127051

Dmitry V. Gorenkov

8/2 Petrovsky Blvd, Moscow 127051

gorenkov@expmed.ruhttps://orcid.org/0000-0001-6269-0201ХантимироваЛ. М.KhantimirovaL. M.

Хантимирова Лейсан Маратовна, кандидат биологических наук

Петровский б-р, д. 8, стр. 2, Москва, 127051

 Leysan M. Khantimirova, Cand. Sci. (Biol.)

8/2 Petrovsky Blvd, Moscow 127051

khantimirova@expmed.ruhttps://orcid.org/0000-0001-7341-101XГусеваС. Г.GusevaS. G.

Гусева Светлана Геннадиевна

Петровский б-р, д. 8, стр. 2, Москва, 127051

Svetlana G. Guseva

8/2 Petrovsky Blvd, Moscow 127051

guseva@expmed.ruhttps://orcid.org/0000-0003-4891-973XМеркуловВ. А.MerkulovV. A.

Меркулов Вадим Анатольевич, доктор медицинских наук, профессор

Петровский б-р, д. 8, стр. 2, Москва, 127051

Vadim A. Merkulov, Dr. Sci. (Med.), Professor

8/2 Petrovsky Blvd, Moscow 127051

merkulov@expmed.ruФедеральное государственное бюджетное учреждение «Научный центр экспертизы средств медицинского применения» Министерства здравоохранения Российской ФедерацииРоссияScientific Centre for Expert Evaluation of Medicinal ProductsRussian Federation202210032022221622Copyright © Солдатов А.А., Авдеева Ж.И., Горенков Д.В., Хантимирова Л.М., Гусева С.Г., Меркулов В.А., 20222022Солдатов А.А., Авдеева Ж.И., Горенков Д.В., Хантимирова Л.М., Гусева С.Г., Меркулов В.А.Soldatov A.A., Avdeeva Z.I., Gorenkov D.V., Khantimirova L.M., Guseva S.G., Merkulov V.A.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.biopreparations.ru/jour/article/view/362

В настоящее время известно большое количество заболеваний, патогенез которых обусловлен генетическими нарушениями. Достижения в области генетики и биотехнологии привели к созданию методов, которые позволяют получить практически любой ген, что в конечном счете привело к появлению нового класса лекарственных средств – генотерапевтических препаратов (ГТП). Цель работы – критический анализ международного опыта создания и регистрации генотерапевтических лекарственных препаратов. В обзоре освещены проблемы разработки ГТП, связанные с поиском оптимального подхода для доставки терапевтического гена в клетки-мишени. Обосновано, что перспективными средствами доставки генов являются вирусные векторы, среди которых наибольшей эффективностью и безопасностью обладают препараты на основе аденовируса (AV) и аденоассоциированного вируса (AAV). Рассмотрены современные подходы для генного редактирования, позволяющие модифицировать AV и AAV для повышения эффективности и безопасности ГТП. Данные модификации необходимы для включения в вирусный вектор терапевтического гена большого размера, снижения уровня экспрессии вирусных белков и снижения иммуногенности вирусного вектора. Представлен опыт регистрации ГТП в регуляторных органах США и Европейского союза, в том числе сведения о подкомитетах в структурах FDA и EMA, выполняющих рекомендательные функции. Отмечено, что в Российской Федерации зарегистрирован один ГТП отечественного производства и активно ведутся разработки других препаратов данной группы. Сделано заключение о необходимости формирования отечественной нормативной базы для разработки и регистрации ГТП, а также нормативных рекомендаций в рамках государств – членов Евразийского экономического союза.

There are a lot of diseases known today, which are caused by genetic abnormalities. Advances in genetics and biotechnology brought about gene editing technologies that can produce almost any gene, which ultimately led to the emergence of a new class of medicines - gene therapy products (GTPs). The aim of the study was to analyse international experience in development and authorisation of GTPs. The review highlights the challenges in GTP development, related to the search for an optimal approach to therapeutic gene delivery to the target cells. Viral vectors were shown to be a promising gene delivery system, with adenovirus (AV) and adeno-associated virus (AAV) based products demonstrating the highest efficacy and safety. The paper reviews current approaches to gene editing that allow modification of AVs and AAVs to improve GTP efficacy and safety. These modifications are carried out with the aim of, e.g., including a large therapeutic gene into a viral vector, decreasing viral protein expression levels, and decreasing viral vector immunogenicity. The review summarises GTP authorisation procedures in the USA and the European Union, including data on FDA and EMA subcommittees and departments entrusted with advisory functions. The paper mentions that there is one Russian-produced GTP authorised in the Russian Federation, and some other GTPs are in the pipeline. Therefore, the Russian regulatory framework and the Eurasian regulations and recommendations should be updated in order to accommodate for GTP development and authorisation.

генотерапевтические препаратыаденовирусный вектораденоассоциированный векторбезопасность генотерапевтических препаратовgene therapy productsadenoviral vectoradeno-associated vectorsafety of gene therapy productsРабота выполнена в рамках государственного задания ФГБУ «НЦЭСМП» Минздрава России № 056-00001-22-00 на проведение прикладных научных исследований (номер государственного учета НИР 121022000147-4)The study reported in this publication was carried out as part of a publicly funded research project No. 056-00001-22-00 and was supported by the Scientific Centre for Expert Evaluation of Medicinal Products (R&D public accounting No. 121022000147-4)ReferencesСолдатов АА, Авдеева ЖИ, Медуницын НВ, Крючков НА. Механизмы развития нежелательного иммунного ответа при применении биотехнологических препаратов. Иммунология. 2017;38(5):271–83. https://doi.org/10.18821/0206-4952-2017-38-5-271-283Soldatov AA, Avdeeva ZhI, Medunitsyn NV, Kryuchkov NA. Mechanisms of development of the undesirable immune response at use of biotechnological medicines. Immunologiya = Immunology. 2017;38(5):271–83 (In Russ.) https://doi.org/10.18821/0206-4952-2017-38-5-271-283Wirth T, Parker N, Ylä-Herttuala S. History of gene therapy. Gene. 2013;525:162–9. https://doi.org/10.1016/j.gene.2013.03.137Wirth T, Parker N, Ylä-Herttuala S. History of gene therapy. Gene. 2013;525:162–9. https://doi.org/10.1016/j.gene.2013.03.137Cartier-Lacave N, Ali R, Yla-Herttuala S, Kato K, Baetschi B, Lovell-Badge R, et al. Debate on germline gene editing. Hum Gene Ther Methods. 2016;27(4):135–42. https://doi.org/10.1089/hgtb.2016.28999.debCartier-Lacave N, Ali R, Yla-Herttuala S, Kato K, Baetschi B, Lovell-Badge R, et al. Debate on germline gene editing. Hum Gene Ther Methods. 2016;27(4):135–42. https://doi.org/10.1089/hgtb.2016.28999.debMcCarthy M. Scientists call for moratorium on clinical use of human germline editing. BMJ. 2015;351:h6603. https://doi.org/10.1136/bmj.h6603McCarthy M. Scientists call for moratorium on clinical use of human germline editing. BMJ. 2015;351:h6603. https://doi.org/10.1136/bmj.h6603Morrow T. Novartis’s Kymriah: harnessing immune system comes with worry about reining in costs. Manag Care. 2017;26(10):28–30.Morrow T. Novartis’s Kymriah: harnessing immune system comes with worry about reining in costs. Manag Care. 2017;26(10):28–30.Yano K, Watanabe N, Tsuyuki K, Ikawa T, Kasanuki H, Yamato M. Regulatory approval for autologous human cells and tissue products in the United States, the European Union, and Japan. Regen Ther. 2015;1:45–56. https://doi.org/10.1016/j.reth.2014.10.001Yano K, Watanabe N, Tsuyuki K, Ikawa T, Kasanuki H, Yamato M. Regulatory approval for autologous human cells and tissue products in the United States, the European Union, and Japan. Regen Ther. 2015;1:45–56. https://doi.org/10.1016/j.reth.2014.10.001Deev R, Plaksa I, Bozo I, Mzhavanadze N, Suchkov I, Chervyakov Y, et al. Results of 5-year follow-up study in patients with peripheral artery disease treated with PL-VEGF165 for intermittent claudication. Ther Adv Cardiovasc Dis. 2018;12(9):237–46. https://doi.org/10.1177/1753944718786926Deev R, Plaksa I, Bozo I, Mzhavanadze N, Suchkov I, Chervyakov Y, et al. Results of 5-year follow-up study in patients with peripheral artery disease treated with PL-VEGF165 for intermittent claudication. Ther Adv Cardiovasc Dis. 2018;12(9):237–46. https://doi.org/10.1177/1753944718786926Wade N. UCLA gene therapy racked by friendly fire. Science. 1980;210(4469):509–11. https://doi.org/10.1126/science.6932738Wade N. UCLA gene therapy racked by friendly fire. Science. 1980;210(4469):509–11. https://doi.org/10.1126/science.6932738Rosenberg SA, Aebersold P, Cornetta K, Kasid A, Morgan RA, Moen R, et al. Gene transfer into humans—immunotherapy of patients with advanced melanoma, using tumor-infiltrating lymphocytes modified by retroviral gene transduction. N Engl J Med. 1990:323:570–8. https://doi.org/10.1056/NEJM199008303230904Rosenberg SA, Aebersold P, Cornetta K, Kasid A, Morgan RA, Moen R, et al. Gene transfer into humans—immunotherapy of patients with advanced melanoma, using tumor-infiltrating lymphocytes modified by retroviral gene transduction. N Engl J Med. 1990:323:570–8. https://doi.org/10.1056/NEJM199008303230904Gaspar HB, Cooray S, Gilmour KC, Parsley KL, Zhang F, Adams S, et al. Hematopoietic stem cell gene therapy for adenosine deaminase – deficient severe combined immunodeficiency leads to long-term immunological recovery and metabolic correction. Sci Transl Med. 2011;3(97):97ra80. https://doi.org/10.1126/scitranslmed.3002716Gaspar HB, Cooray S, Gilmour KC, Parsley KL, Zhang F, Adams S, et al. Hematopoietic stem cell gene therapy for adenosine deaminase — deficient severe combined immunodeficiency leads to longterm immunological recovery and metabolic correction. Sci Transl Med. 2011;3(97):97ra80. https://doi.org/10.1126/scitranslmed.3002716Vile RG, Russell SJ, Lemoine NR. Cancer gene therapy: hard lessons and new courses. Gene Ther. 2000;7:2–8. https://doi.org/10.1038/sj.gt.3301084Vile RG, Russell SJ, Lemoine NR. Cancer gene therapy: hard lessons and new courses. Gene Ther. 2000;7:2–8. https://doi.org/10.1038/sj.gt.3301084Wang B, Li J, Xiao X. Adeno-associated virus vector carrying human minidystrophin genes effectively ameliorates muscular dystrophy in mdx mouse model. Proc Natl Acad Sci USA. 2000;97(25):13714–9. https://doi.org/10.1073/pnas.240335297Wang B, Li J, Xiao X. Adeno-associated virus vector carrying human minidystrophin genes effectively ameliorates muscular dystrophy in mdx mouse model. Proc Natl Acad Sci USA. 2000;97(25):13714–9. https://doi.org/10.1073/pnas.240335297Raper SE, Chirmule N, Lee FS, Wivel NA, Bagg A, Gao GP, et al. Fatal systemic inflammatory response syndrome in a ornithine transcarbamylase deficient patient following adenoviral gene transfer. Mol Genet Metab. 2003;80:148–58. https://doi.org/10.1016/j.ymgme.2003.08.016Raper SE, Chirmule N, Lee FS, Wivel NA, Bagg A, Gao GP, et al. Fatal systemic inflammatory response syndrome in a ornithine transcarbamylase deficient patient following adenoviral gene transfer. Mol Genet Metab. 2003;80:148–58. https://doi.org/10.1016/j.ymgme.2003.08.016Hacein-Bey-Abina S, Von Kalle C, Schmidt M, McCormack MP, Wulffraat N, Leboulch P, et al. LMO2-associated clonal T cell proliferation in two patients after gene therapy for SCID-X1. Science. 2003;302(5644):415–9. https://doi.org/10.1126/science.1088547Hacein-Bey-Abina S, Von Kalle C, Schmidt M, McCormack MP, Wulffraat N, Leboulch P, et al. LMO2-associated clonal T cell proliferation in two patients after gene therapy for SCID-X1. Science. 2003;302(5644):415–9. https://doi.org/10.1126/science.1088547Nam CH, Rabbitts TH. The role of LM02 in development and in T cell leukemia after chromosomal translocation or retroviral insertion. Mol Ther. 2006;13(1):15–25. https://doi.org/10.1016/j.ymthe.2005.09.010Nam CH, Rabbitts TH. The role of LM02 in development and in T cell leukemia after chromosomal translocation or retroviral insertion. Mol Ther. 2006;13(1):15–25. https://doi.org/10.1016/j.ymthe.2005.09.010Lawler SE, Speranza MC, Cho CF, Chiocca EA. Oncolytic viruses in cancer treatment: a review. JAMA Oncol. 2017;3(6):841–9. https://doi.org/10.1001/jamaoncol.2016.2064Lawler SE, Speranza MC, Cho CF, Chiocca EA. Oncolytic viruses in cancer treatment: a review. JAMA Oncol. 2017;3(6):841–9. https://doi.org/10.1001/ja-maoncol.2016.2064Giacca M, Zacchigna S. Virus-mediated gene delivery for human gene therapy. J Control Release. 2012;161(2):377–88. https://doi.org/10.1016/j.jconrel.2012.04.008Giacca M, Zacchigna S. Virus-mediated gene delivery for human gene therapy. J Control Release. 2012;161(2):377–88. https://doi.org/10.1016/j.jcon-rel.2012.04.008Chattopadhyay S, Sen GC. dsRNA-activation of TLR3 and RLR signaling: gene induction-dependent and independent effects. J Interferon Cytokine Res. 2014;34(6):427–36. https://doi.org/10.1089/jir.2014.0034Chattopadhyay S, Sen GC. dsRNA-activation of TLR3 and RLR signaling: gene induction-dependent and independent effects. J Interferon Cytokine Res. 2014;34(6):427–36.https://doi.org/10.1089/jir.2014.0034Herrero MJ, Sabater L, Guenechea G, Sendra L, Montilla AI, Abargues R, et al. DNA delivery to ’ex vivo’ human liver segments. Gene Ther. 2012;19:504–12. https://doi.org/10.1038/gt.2011.144Herrero MJ, Sabater L, Guenechea G, Sendra L, Montilla AI, Abargues R, et al. DNA delivery to ’ex vivo’ human liver segments. Gene Ther. 2012;19:504–12.https://doi.org/10.1038/gt.2011.144Wold WS, Toth K. Adenovirus vectors for gene therapy, vaccination and cancer gene therapy. Curr Gene Ther. 2013;13(6):421–33 https://doi.org/10.2174/1566523213666131125095046Wold WS, Toth K. Adenovirus vectors for gene therapy, vaccination and cancer gene therapy. Curr Gene Ther. 2013;13(6):421–33 https://doi.org/10.2174/1566523213666131125095046Majhen D, Ambriović-Ristov A. Adenoviral vectors–how to use them in cancer gene therapy? Virus Res. 2006;119(2):121–33. https://doi.org/10.1016/j.virusres.2006.02.001Majhen D, Ambriović-Ristov A. Adenoviral vectors– how to use them in cancer gene therapy? Virus Res. 2006;119(2):121–33. https://doi.org/10.1016/j.virus-res.2006.02.001Wen S, Schneider DB, Driscoll RM, Vassalli G, Sassani AB, Dichek DA. Second-generation adenoviral vectors do not prevent rapid loss of transgene expression and vector DNA from the arterial wall. Arterioscler Thromb Vasc Biol. 2000;20:1452–8. https://doi.org/10.1161/01.atv.20.6.1452Wen S, Schneider DB, Driscoll RM, Vassalli G, Sassani AB, Dichek DA. Second-generation adenoviral vectors do not prevent rapid loss of transgene expression and vector DNA from the arterial wall. Arterioscler Thromb Vasc Biol. 2000;20:1452–8. https://doi.org/10.1161/01.atv.20.6.1452Sakhuja K, Reddy PS, Ganesh S, Cantaniag F, Pattison S, Limbach P, et al. Optimization of the generation and propagation of gutless adenoviral vectors. Hum Gene Ther. 2003;14(3):243–54. https://doi.org/10.1089/10430340360535797Sakhuja K, Reddy PS, Ganesh S, Cantaniag F, Pattison S, Limbach P, et al. Optimization of the generation and propagation of gutless adenoviral vectors. Hum Gene Ther. 2003;14(3):243–54. https://doi.org/10.1089/10430340360535797Alba R, Bosch A, Chillon M. Gutless adenovirus: last-generation adenovirus for gene therapy. Gene Ther. 2005;12:S18–27. https://doi.org/10.1038/sj.gt.3302612Alba R, Bosch A, Chillon M. Gutless adenovirus: last-generation adenovirus for gene therapy. Gene Ther. 2005;12:S18–27. https://doi.org/10.1038/sj.gt.3302612Fausther-Bovendo H, Kobinger GP. Pre-existing immunity against Ad vectors: humoral, cellular, and innate response, what's important? Hum Vaccin Immunother. 2014;10(10):2875–84. https://doi.org/10.4161/hv.29594Fausther-Bovendo H, Kobinger GP. Pre-existing immunity against Ad vectors: humoral, cellular, and innate response, what’s important? Hum Vaccin Immunother. 2014;10(10):2875–84. https://doi.org/10.4161/hv.29594Wang X, Xing M, Zhang C, Yang Y, Chi Y, Tang X, et al. Neutralizing antibody responses to enterovirus and adenovirus in healthy adults in China. Emerg Microbes Infect. 2014;3(5):e30. https://doi.org/10.1038/emi.2014.30Wang X, Xing M, Zhang C, Yang Y, Chi Y, Tang X, et al. Neutralizing antibody responses to enterovirus and adenovirus in healthy adults in China. Emerg Microbes Infect. 2014;3(5):e30. https://doi.org/10.1038/emi.2014.30Atkinson RL, Dhurandhar NV, Allison DB, Bowen RL, Israel BA, Albu JB, Augustus AS. Human adenovirus-36 is associated with increased body weight and paradoxical reduction of serum lipids. Int J Obes (Lond). 2005;29:281–6. https://doi.org/10.1038/sj.ijo.0802830Atkinson RL, Dhurandhar NV, Allison DB, Bowen RL, Israel BA, Albu JB, Augustus AS. Human adenovirus-36 is associated with increased body weight and paradoxical reduction of serum lipids. Int J Obes (Lond). 2005;29:281–6. https://doi.org/10.1038/sj.ijo.0802830Trinh HV, Lesage G, Chennamparampil V, Vollenweider B, Burckhardt CJ, Schauer S, et al. Avidity binding of human adenovirus serotypes 3 and 7 to the membrane cofactor CD46 triggers infection. J Virol. 2012;86(2):1623–37. https://doi.org/10.1128/jvi.06181-11Trinh HV, Lesage G, Chennamparampil V, Vollenweider B, Burckhardt CJ, Schauer S, et al. Avidity binding of human adenovirus serotypes 3 and 7 to the membrane cofactor CD46 triggers infection. J Virol. 2012;86(2):1623–37. https://doi.org/10.1128/jvi.06181-11Cho YS, Do MH, Kwon SY, Moon C, Kim K, Lee K, et al. Efficacy of CD46-targeting chimeric Ad5/35 adenoviral gene therapy for colorectal cancers. Oncotarget. 2016;7:38210–23. https://doi.org/10.18632/oncotarget.9427Cho YS, Do MH, Kwon SY, Moon C, Kim K, Lee K, et al. Efficacy of CD46-targeting chimeric Ad5/35 adenoviral gene therapy for colorectal cancers. Oncotarget. 2016;7:38210–23. https://doi.org/10.18632/oncotar-get.9427Li X, Mao Q, Wang D, Xia H. A novel Ad5/11 chimeric oncolytic adenovirus for improved glioma therapy. Int J Oncol. 2012;41:2159–65. https://doi.org/10.3892/ijo.2012.1674Li X, Mao Q, Wang D, Xia H. A novel Ad5/11 chimeric oncolytic adenovirus for improved glioma therapy. Int J Oncol. 2012;41:2159–65. https://doi.org/10.3892/ijo.2012.1674Tapia MD, Sow SO, Lyke KE, Haidara FC, Diallo F, Doumbia M, et al. Use of ChAd3-EBO-Z Ebola virus vaccine in Malian and US adults, and boosting of Malian adults with MVA-BN-Filo: a phase 1, single-blind, randomised trial, a phase 1b, open-label and double-blind, dose-escalation trial, and a nested, randomised, double-blind, placebo-controlled trial. Lancet Infect Dis. 2016;16(1):31–42. https://doi.org/10.1016/s1473-3099(15)00362-xTapia MD, Sow SO, Lyke KE, Haidara FC, Diallo F, Doumbia M, et al. Use of ChAd3-EBO-Z Ebola virus vaccine in Malian and US adults, and boosting of Malian adults with MVA-BN-Filo: a phase 1, single-blind, randomised trial, a phase 1b, open-label and double-blind, dose-escalation trial, and a nested, randomised, double-blind, placebo-controlled trial. Lancet Infect Dis. 2016;16(1):31–42. https://doi.org/10.1016/s1473-3099(15)00362-xIrons EE, Flatt JW, Doronin K, Fox TL, Acchione M, Stewart PL, Shayakhmetov DM. Coagulation factor binding orientation and dimerization may influence infectivity of adenovirus-coagulation factor complexes. J Virol. 2013;87(17):9610–9. https://doi.org/10.1128/JVI.01070-13Irons EE, Flatt JW, Doronin K, Fox TL, Acchione M, Stewart PL, Shayakhmetov DM. Coagulation factor binding orientation and dimerization may influence infectivity of adenovirus-coagulation factor complexes. J Virol. 2013;87(17):9610–9. https://doi.org/10.1128/JVI.01070-13Ledgerwood JE, DeZure AD, Stanley DA, Coates EE, Novik L, Enama ME, et al. Chimpanzee adenovirus vector Ebola vaccine. N Engl J Med. 2017;376:928–38. https://doi.org/10.1056/NEJMoa1410863Ledgerwood JE, DeZure AD, Stanley DA, Coates EE, Novik L, Enama ME, et al. Chimpanzee adenovirus vector Ebola vaccine. N Engl J Med. 2017;376:928–38. https://doi.org/10.1056/NEJMoa1410863Miura Y, Yamasaki S, Davydova J, Brown E, Aoki K, Vickers S, Yamamoto M. Infectivity-selective oncolytic adenovirus developed by high-throughput screening of adenovirus-formatted library. Mol Ther. 2013;21(1):139–48. https://doi.org/10.1038/mt.2012.205Miura Y, Yamasaki S, Davydova J, Brown E, Aoki K, Vickers S, Yamamoto M. Infectivity-selective oncolytic adenovirus developed by high-throughput screening of adenovirus-formatted library. Mol Ther. 2013;21(1):139–48. https://doi.org/10.1038/mt.2012.205Yamamoto Y, Nagasato M, Rin Y, Henmi M, Ino Y, Yachida S, et al. Strong antitumor efficacy of a pancreatic tumor-targeting oncolytic adenovirus for neuroendocrine tumors. Cancer Med. 2017;6(10):2385–97. https://doi.org/10.1002/cam4.1185Yamamoto Y, Nagasato M, Rin Y, Henmi M, Ino Y, Yachida S, et al. Strong antitumor efficacy of a pancreatic tumor-targeting oncolytic adenovirus for neuroendocrine tumors. Cancer Med. 2017;6(10):2385–97. https://doi.org/10.1002/cam4.1185Hausl MA, Zhang W, Müther N, Rauschhuber C, Franck HG, Merricks EP, et al. Hyperactive sleeping beauty transposase enables persistent phenotypic correction in mice and a canine model for hemophilia B. Mol Ther. 2010;18(11):1896–906. https://doi.org/10.1038/mt.2010.169Hausl MA, Zhang W, Müther N, Rauschhuber C, Franck HG, Merricks EP, et al. Hyperactive sleeping beauty transposase enables persistent phenotypic correction in mice and a canine model for hemophilia B. Mol Ther. 2010;18(11):1896–906. https://doi.org/10.1038/mt.2010.169Castello R, Borzone R, D’Aria S, Annunziata P, Piccolo P, Brunetti-Pierri N. Helper-dependent adenoviral vectors for liver-directed gene therapy of primary hyperoxaluria type 1. Gene Ther. 2016;23:129–34. https://doi.org/10.1038/gt.2015.107Castello R, Borzone R, D’Aria S, Annunziata P, Piccolo P, Brunetti-Pierri N. Helper-dependent adenoviral vectors for liver-directed gene therapy of primary hyperoxaluria type 1. Gene Ther. 2016;23:129–34. https://doi.org/10.1038/gt.2015.107Rosewell Shaw A, Suzuki M. Recent advances in oncolytic adenovirus therapies for cancer. Curr Opin Virol. 2016;21:9–15. https://doi.org/10.1016/j.coviro.2016.06.009Rosewell Shaw A, Suzuki M. Recent advances in oncolytic adenovirus therapies for cancer. Curr Opin Virol. 2016;21:9–15. https://doi.org/10.1016/j.covi-ro.2016.06.009Samulski RJ, Muzyczka N. AAV-mediated gene therapy for research and therapeutic purposes. Annu Rev Virol. 2014;1(1):427–51. https://doi.org/10.1146/annurev-virology-031413-085355Samulski RJ, Muzyczka N. AAV-mediated gene therapy for research and therapeutic purposes. Annu Rev Virol. 2014;1(1):427–51. https://doi.org/10.1146/an-nurev-virology-031413-085355Carter BJ. Adeno-associated virus and the development of adenoassociated virus vectors: a historical perspective. Mol Ther. 2004;10:981–9. https://doi.org/10.1016/j.ymthe.2004.09.011Carter BJ. Adeno-associated virus and the development of adenoassociated virus vectors: a historical perspective. Mol Ther. 2004;10:981–9. https://doi.org/10.1016/j.ymthe.2004.09.011Grieger JC, Samulski RJ. Adeno-associated virus vectorology, manufacturing, and clinical applications. Methods Enzymol. 2012;507:229–54. https://doi.org/10.1016/B978-0-12-386509-0.00012-0Grieger JC, Samulski RJ. Adeno-associated virus vectorology, manufacturing, and clinical applications. Methods Enzymol. 2012;507:229–54. https://doi.org/10.1016/B978-0-12-386509-0.00012-0Buchlis G, Podsakoff GM, Radu A, Hawk SM, Flake AW, Mingozzi F, High KA. Factor IX expression in skeletal muscle of a severe hemophilia B patient 10 years after AAV-mediated gene transfer. Blood. 2012;119(13):3038–41. https://doi.org/10.1182/blood-2011-09-382317Buchlis G, Podsakoff GM, Radu A, Hawk SM, Flake AW, Mingozzi F, High KA. Factor IX expression in skeletal muscle of a severe hemophilia B patient 10 years after AAV-mediated gene transfer. Blood. 2012;119(13):3038–41. https://doi.org/10.1182/blood-2011-09-382317Strobel B, Duechs MJ, Schmid R, Stierstorfer BE, Bucher H, Quast K, et al. Modeling pulmonary disease pathways using recombinant adeno-associated virus 6.2. Am J Respir Cell Mol Biol. 2015;53(3):291–302. https://doi.org/10.1165/rcmb.2014-0338MAStrobel B, Duechs MJ, Schmid R, Stierstorfer BE, Bucher H, Quast K, et al. Modeling pulmonary disease pathways using recombinant adeno-associated virus 6.2. Am J Respir Cell Mol Biol. 2015;53(3):291–302. https://doi.org/10.1165/rcmb.2014-0338MANathwani AC, Nienhuis AW, Davidoff AM. Our journey to successful gene therapy for hemophilia B. Hum Gene Ther. 2014;25(11):923–6. https://doi.org/10.1089/hum.2014.2540Nathwani AC, Nienhuis AW, Davidoff AM. Our journey to successful gene therapy for hemophilia B. Hum Gene Ther. 2014;25(11):923–6. https://doi.org/10.1089/hum.2014.2540Smith LJ, Ul-Hasan T, Carvaines SK, Van Vliet K, Yang E,Wong KK Jr, et al. Gene transfer properties and structural modeling of human stemcell-derived AAV. Mol Ther. 2014;22(9):1625–34. https://doi.org/10.1038/mt.2014.107Smith LJ, Ul-Hasan T, Carvaines SK, Van Vliet K, Yang E, Wong KK Jr, et al. Gene transfer properties and structural modeling of human stemcell-derived AAV. Mol Ther. 2014;22(9):1625–34. https://doi.org/10.1038/mt.2014.107Murphy SL, Li H, Zhou S, Schlachterman A, High KA. Prolonged susceptibility to antibody-mediated neutralization for adenoassociated vectors targeted to the liver. Mol Ther. 2008;16(1):138–45. https://doi.org/10.1038/sj.mt.6300334Murphy SL, Li H, Zhou S, Schlachterman A, High KA. Prolonged susceptibility to antibody-mediated neutralization for adenoassociated vectors targeted to the liver. Mol Ther. 2008;16(1):138–45. https://doi.org/10.1038/sj.mt.6300334Calcedo R, Vandenberghe LH, Gao G, Lin J, Wilson JM. Worldwide epidemiology of neutralizing antibodies to adeno-associated viruses. J Infect Dis. 2009;199(3):381–90. https://doi.org/10.1086/595830Calcedo R, Vandenberghe LH, Gao G, Lin J, Wilson JM. Worldwide epidemiology of neutralizing antibodies to adeno-associated viruses. J Infect Dis. 2009;199(3):381–90. https://doi.org/10.1086/595830Mingozzi F, High KA. Immune responses to AAV in clinical trials. Curr Gene Ther. 2011;11(4):321–30. https://doi.org/10.2174/156652311796150354Mingozzi F, High KA. Immune responses to AAV-in clinical trials. Curr Gene Ther. 2011;11(4):321–30. https://doi.org/10.2174/156652311796150354Nathwani AC, Tuddenham EG, Rangarajan S, Rosales C, McIntosh J, Linch DC, et al. Adenovirus-associated virus vector-mediated gene transfer in hemophilia B. N Engl J Med. 2011;365:2357–65. https://doi.org/10.1056/NEJMoa1108046Nathwani AC, Tuddenham EG, Rangarajan S, Rosales C, McIntosh J, Linch DC, et al. Adenovirus-associated virus vector-mediated gene transfer in hemophilia B. N Engl J Med. 2011;365:2357–65. https://doi.org/10.1056/NEJMoa1108046Greenberg B, Butler J, Felker GM, Ponikowski P, Voors AA, Pogoda JM, et al. Prevalence of AAV1 neutralizing antibodies and consequences for a clinical trial of gene transfer for advanced heart failure. Gene Ther. 2016;23(3):313–9. https://doi.org/10.1038/gt.2015.109Greenberg B, Butler J, Felker GM, Ponikowski P, Voors AA, Pogoda JM, et al. Prevalence of AAV1 neutralizing antibodies and consequences for a clinical trial of gene transfer for advanced heart failure. Gene Ther. 2016;23(3):313–9. https://doi.org/10.1038/gt.2015.109Zinn E, Pacouret S, Khaychuk V, Turunen HT, Carvalho LS, Andres-Mateos E, et al. In silico reconstruction of the viral evolutionary lineage yields a potent gene therapy vector. Cell Rep. 2015;12(6):1056–68. https://doi.org/10.1016/j.celrep.2015.07.019Zinn E, Pacouret S, Khaychuk V, Turunen HT, Carvalho LS, Andres-Mateos E, et al. In silico reconstruction of the viral evolutionary lineage yields a potent gene therapy vector. Cell Rep. 2015;12(6):1056–68. https://doi.org/10.1016/j.celrep.2015.07.019Bowles DE, McPhee SW, Li C, Gray SJ, Samulski JJ, Camp AS, et al. Phase 1 gene therapy for Duchenne muscular dystrophy using a translational optimized AAV vector. Mol Ther. 2012;20(2):443–55. https://doi.org/10.1038/mt.2011.237Bowles DE, McPhee SW, Li C, Gray SJ, Samulski JJ, Camp AS, et al. Phase 1 gene therapy for Duchenne muscular dystrophy using a translational optimized AAV-vector. Mol Ther. 2012;20(2):443–55. https://doi.org/10.1038/mt.2011.237Faust SM, Bell P, Cutler BJ, Ashley SN, Zhu Y, Rabinowitz JE, Wilson JM. CpG-depleted adeno-associated virus vectors evade immune detection. J Clin Invest. 2013;123(7):2994–3001. https://doi.org/10.1172/jci68205Faust SM, Bell P, Cutler BJ, Ashley SN, Zhu Y, Rabinowitz JE, Wilson JM. CpG-depleted adeno-associated virus vectors evade immune detection. J Clin Invest. 2013;123(7):2994–3001. https://doi.org/10.1172/jci68205Mays LE, Vandenberghe LH, Xiao R, Bell P, Nam HJ, Agbandje-McKenna M, Wilson JM. Adeno-associated virus capsid structure drives CD4-dependent CD8+ T cell response to vector encoded proteins. J Immunol. 2009;182(10):6051–60. https://doi.org/10.4049/jimmunol.0803965Mays LE, Vandenberghe LH, Xiao R, Bell P, Nam HJ, Agbandje-McKenna M, Wilson JM. Adeno-associated virus capsid structure drives CD4-dependent CD8+ T cell response to vector encoded proteins. J Immunol. 2009;182(10):6051–60. https://doi.org/10.4049/jimmunol.0803965Chandler RJ, Sands MS, Venditti CP. Recombinant adeno-associated viral integration and genotoxicity: insights from animal models. Hum Gene Ther. 2017;28(4):314–22. https://doi.org/10.1089/hum.2017.009Chandler RJ, Sands MS, Venditti CP. Recombinant adeno-associated viral integration and genotoxicity: insights from animal models. Hum Gene Ther. 2017;28(4):314–22. https://doi.org/10.1089/hum.2017.009Brandon EF, Hermsen HP, van Eijkeren JC, Tiesjema B. Effect of administration route on the biodistribution and shedding of replication-deficient AAV2: a qualitative modelling approach. Curr Gene Ther. 2010;10(2):91–106. https://doi.org/10.2174/156652310791111047Brandon EF, Hermsen HP, van Eijkeren JC, Tiesjema B. Effect of administration route on the biodistribution and shedding of replication-deficient AAV2: a qualitative modelling approach. Curr Gene Ther. 2010;10(2):91–106. https://doi.org/10.2174/156652310791111047Grieger JC, Samulski RJ. Adeno-associated virus vectorology, manufacturing, and clinical applications. Methods Enzymol. 2012;507:229–54. https://doi.org/10.1016/B978-0-12-386509-0.00012-0Grieger JC, Samulski RJ. Adeno-associated virus vectorology, manufacturing, and clinical applications. Methods Enzymol. 2012;507:229–54. https://doi.org/10.1016/B978-0-12-386509-0.00012-0Wright JF. Manufacturing and characterizing AAV-based vectors for use in clinical studies. Gene Ther. 2008;15(11):840–8. https://doi.org/10.1038/gt.2008.65Wright JF. Manufacturing and characterizing AAVbased vectors for use in clinical studies. Gene Ther. 2008;15(11):840–8. https://doi.org/10.1038/gt.2008.65Ertl HCJ, High KA. Impact of AAV capsid-specific T-cell responses on design and outcome of clinical gene transfer trials with recombinant adenoassociated viral vectors: an evolving controversy. Hum Gene Ther. 2017;28(4):328–37. https://doi.org/10.1089/hum.2016.172Ertl HCJ, High KA. Impact of AAV-capsid-specific T-cell responses on design and outcome of clinical gene transfer trials with recombinant adenoassociated viral vectors: an evolving controversy. Hum Gene Ther. 2017;28(4):328–37. https://doi.org/10.1089/hum.2016.172Zhang WW, Li L, Li D, Liu J, Li X, Li W, et al. The first approved gene therapy product for cancer Ad-p53 (Gendicine): 12 years in the clinic. Hum Gene Ther. 2018;29(2):160–79. https://doi.org/10.1089/hum.2017.218Zhang WW, Li L, Li D, Liu J, Li X, Li W, et al. The first approved gene therapy product for cancer Adp53 (Gendicine): 12 years in the clinic. Hum Gene Ther. 2018;29(2):160–79. https://doi.org/10.1089/hum.2017.218Sheridan C. Gene therapy finds its niche. Nat Biotechnol. 2011;29:121–8. https://doi.org/10.1038/nbt.1769Sheridan C. Gene therapy finds its niche. Nat Biotechnol. 2011;29:121–8. https://doi.org/10.1038/nbt.1769Kim S, Federman N, Gordon EM, Hall FL, Chawla SP. Rexin-G®, a tumor-targeted retrovector for malignant peripheral nerve sheath tumor: a case report. Mol Clin Oncol. 2017;6:861–5. https://doi.org/10.3892/mco.2017.1231Kim S, Federman N, Gordon EM, Hall FL, Chawla SP. Rexin-G®, a tumor-targeted retrovector for malignant peripheral nerve sheath tumor: a case report. Mol Clin Oncol. 2017;6:861–5. https://doi.org/10.3892/mco.2017.1231Wang D, Zhong L, Nahid MA, Gao G. The potential of adeno-associated viral vectors for gene delivery to muscle tissue. Expert Opin Drug Deliv. 2014;11(3):345–64. https://doi.org/10.1517/17425247.2014.871258Wang D, Zhong L, Nahid MA, Gao G. The potential of adeno-associated viral vectors for gene delivery to muscle tissue. Expert Opin Drug Deliv. 2014;11(3):345–64. https://doi.org/10.1517/17425247.2014.871258MacLaren RE, Groppe M, Barnard AR, Cottriall CL, Tolmachova T, Seymour L, et al. Retinal gene therapy in patients with choroideremia: initial findings from a phase 1/2 clinical trial. Lancet. 2014;383(9923):1129–37. https://doi.org/10.1016/S0140-6736(13)62117-0MacLaren RE, Groppe M, Barnard AR, Cottriall CL, Tolmachova T, Seymour L, et al. Retinal gene therapy in patients with choroideremia: initial findings from a phase 1/2 clinical trial. Lancet. 2014;383(9923):1129–37. https://doi.org/10.1016/S0140-6736(13)62117-0Breitbach CJ, Lichty BD, Bell JC. Oncolytic viruses: therapeutics with an identity crisis. EBioMedicine. 2016;9:31–6. https://doi.org/10.1016/j.ebiom.2016.06.046Breitbach CJ, Lichty BD, Bell JC. Oncolytic viruses: therapeutics with an identity crisis. EBioMedicine. 2016;9:31–6. https://doi.org/10.1016/j.ebi-om.2016.06.046Hocquemiller M, Giersch L, Audrain M, Parker S, Cartier N. Adeno-associated virus-based gene therapy for CNS diseases. Hum Gene Ther. 2016;27(7):478–96. https://doi.org/10.1089/hum.2016.087Hocquemiller M, Giersch L, Audrain M, Parker S, Cartier N. Adeno-associated virus-based gene therapy for CNS diseases. Hum Gene Ther. 2016;27(7):478– 96. https://doi.org/10.1089/hum.2016.087Nathwani AC, Reiss UM, Tuddenham EG, Rosales C, Chowdary P, McIntosh J, et al. Long-term safety and efficacy of factor IX gene therapy in hemophilia B. N Engl J Med. 2014;371:1994–2004. https://doi.org/10.1056/NEJMoa1407309Nathwani AC, Reiss UM, Tuddenham EG, Rosales C, Chowdary P, McIntosh J, et al. Long-term safety and efficacy of factor IX gene therapy in hemophilia B. N Engl J Med. 2014;371:1994–2004. https://doi.org/10.1056/NEJMoa1407309Roossinck MJ, Bazán ER. Symbiosis: viruses as intimate partners. Annu Rev Virol. 2017;4:123–39. https://doi.org/10.1146/annurev-virology-110615-042323Roossinck MJ, Bazán ER. Symbiosis: viruses as intimate partners. Annu Rev Virol. 2017;4:123–39. https://doi.org/10.1146/annurev-virology-110615-042323Carvalho M, Martins AP, Sepodes B. Hurdles in gene therapy regulatory approval: a retrospective analysis of European Marketing Authorization Applications. Drug Discovery Today. 2019;24(3):823–8. https://doi.org/10.1016/j.drudis.2018.12.007Carvalho M, Martins AP, Sepodes B. Hurdles in gene therapy regulatory approval: a retrospective analysis of European Marketing Authorization Applications. Drug Discovery Today. 2019;24(3):823–8. https://doi.org/10.1016/j.drudis.2018.12.007Dabisch I, Dethling J, Dintsios CM, Drechsler M, Kalanovic D, Kaskel P, et al. Patient relevant endpoints in oncology: current issues in the context of early benefit assessment in Germany. Health Econ. Rev. 2014;4(1):2. https://doi.org/10.1186/2191-1991-4-2Dabisch I, Dethling J, Dintsios CM, Drechsler M, Kalanovic D, Kaskel P, et al. Patient relevant endpoints in oncology: current issues in the context of early benefit assessment in Germany. Health Econ. Rev. 2014;4(1):2. https://doi.org/10.1186/2191-1991-4-2

The authors declare that there are no conflicts of interest present.