nbsprotВестник войск РХБ защитыJournal of NBC Protection Corps2587-57283034-279127 Научный центр10.35825/2587-5728-2024-8-1-5-17nbsprot-338Research ArticleХИМИЧЕСКАЯ БЕЗОПАСНОСТЬ И ЗАЩИТА ОТ ХИМИЧЕСКОГО ТЕРРОРИЗМАCHEMICAL SECURITY AND PROTECTION AGAINST CHEMICAL TERRORISMСоматическая генная терапия и предотвращение токсического действия фосфорорганических отравляющих веществ и токсичных химикатовSomatic Gene Therapy in the Prevention of Toxic Effects of Organophosphate Agentshttps://orcid.org/0000-0002-7088-488XЛакотаЯ.LakotaJ.

Лакота Ян. MD, PhD

Дубравская дорога 9, 841 04, Братислава

Ján Lakota. MD, PhD

Dubravska cesta 9, 841 04 Bratislava

jan.lakota@savba.skЦентр экспериментальной медицины, Словацкая Академия наукСловакияCentre of Experimental Medicine, SASSlovakia20241706202481517Copyright © Лакота Я., 20242024Лакота Я.Lakota J.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.nbsprot.ru/jour/article/view/338

Медицинское вмешательство при поражениях фосфорорганическими отравляющими веществами (ФОВ) с использованием сульфата атропина, 2-пиридинальдоксимметилхлорида (2-ПАМ), диазепама и других аналогичных препаратов способно предотвратить смертельный исход отравления. Однако эти средства не защищают от внезапного химического нападения и от постконтактных осложнений, связанных с необратимым повреждением головного мозга. Военное ведомство США финансирует исследования, способные в будущем значительно упростить защиту военнослужащих от поражения ФОВ. Их суть заключается в использовании технологий генной терапии, в ходе которой организм экспериментальных животных вырабатывает собственные белки, разрушающие ФОВ, что обеспечивает защиту на несколько месяцев. Цель работы – выявить достигнутый уровень исследований, использующих технологии генной терапии для создания устойчивых к ФОВ живых объектов. Метод исследования – аналитический. Источниковая база исследования – публикации в научных журналах и описания к патентам. Обсуждение результатов. В качестве фермента, расщепляющего ФОВ в таких экспериментах, наибольшую эффективность показала генно-модифицированная параоксаназа 1 (PON1). PON1 обладает способностью гидролизовать ФОВ G-типа, параоксон, хлорпирифосоксон, диазоксон и ряд других органофосфатов. Для введения в организм животного гена, кодирующего PON1, используются векторы на основе аденоассоциированного вируса (AAV8 и др.). Однократное введение AAV8, несущего рекомбинантный ген PON1-IF11 (AAV8-PON1-IF11), приводило к высокой экспрессии и секреции рекомбинантного белка PON1-IF11 в кровеносное русло и давало бессимптомную защиту от нескольких смертельных доз ФОВ G-типа в течение как минимум 5 мес. Эти исследования пока находятся на ранней стадии. Анализ аффиляции авторов публикаций и патентов показал, что в таких исследованиях активно участвуют военное ведомство США и сотрудничающие с ним организации (DTRA и др.). Заключение. Учитывая интерес на Западе к идеям модификации человека методами генной терапии, можно предположить, что это направление будет интенсивно развиваться в военных целях. В то же время сама идея заблаговременно созданной устойчивости к ФОВ востребована и в гражданской сфере в связи с широким применением органофосфатов в сельском хозяйстве. Автор считает, что более безопасным будет использование аллогенных мезенхимальных стволовых клеток, генетически модифицированных различными вариантами PON1. Эта устойчивость к ФОВ может защитить здоровье и спасти жизнь военнослужащих в реальном бою в случае использования противником ФОВ. Однако такие способы защиты от органофосфатов должны основываться на серьезных экспериментальных исследованиях, гарантирующих безопасность их применения. Дверь на новый уровень защиты от ФОВ открыта, технологии доступны.

Medical intervention in poisoning by organophosphate toxic agents (OPA) using atropine sulfate, 2-pyridinaldoxymethyl chloride (2-PAM), diazepam and other similar drugs can prevent the fatal outcome of poisoning. These drugs do not protect in case of sudden chemical attack and against post-exposure complications associated with permanent brain damage. The U.S. Department of Defense is funding research that can significantly simplify the protection of military personnel from OPA damage in the future. Their essence is in the use of gene therapy technologies, which allow experimental animals to produce their own proteins that destroy OPA and provide them with protection for several months. The aim of the work is to identify the achieved level of knowledge in the research using gene therapy technologies to create living objects resistant to OPA. The research method is analytical. The source base of the research are publications in scientific journals and descriptions of patents. Discussion of the results. As an enzyme that breaks down OPA in such experiments, genetically modified paraoxanase 1 (PON1) showed the greatest efficiency. PON1 hydrolyzes G-type OPAs, paraoxone, chlorpyrifosoxone, diazoxone and several other organophosphates. Adenoassociated virus vectors (AAV8, etc.) were used to introduce the gene encoding PON1 into the animal's body. A single injection of AAV8 carrying the recombinant PON1-IF11 gene (AAV8-PON1-IF11) resulted in high expression and secretion of the recombinant PON1-IF11 protein into the bloodstream and provided asymptomatic protection against multiple lethal doses of G-type OPA for at least 5 months. These studies are still in their early stage. An analysis of the affiliation of the authors of publications and patents showed a high involvement of the U.S. military department and its cooperating organizations (DTRA, etc.) in such research. Conclusion. Given the fascination in the West with the ideas of human modification using gene therapy methods, this direction will be intensively developed for military purposes. At the same time, the idea of pre-created resistance to OPA is in demand by the widespread use of organophosphates in agriculture. The author believes that it would be safer to use allogeneic mesenchymal stem cells transfected with genetically modified PON1 variants with enhanced enzyme activity. This resistance to OP agents can be health protective and lifesaving in soldiers in real combat when the enemy uses these agents. However, this approach must be based on a strong experimental background. The door is open, the technologies are available.

аденоассоциированный вирусбоевые отравляющие вещества нервно-паралитического действиягенетическая модификациягенная терапиязащита солдатнервно-паралитические агентыорганофосфатыпараоксоназа 1PON1rePON1химическое оружиеadeno-associated viruschemical weaponsgene therapygenetic modificationnerve agentsorganophosphatesparaoxonase 1PON1protect soldiersrePON1Выражаю благодарность доктору М.В. Супотницкому за полезные советы и научные рекомендацииI would like to thank Dr. M.V. Supotnitskij for his helpful suggestions and scientific adviceReferencesBetapudi V, Goswami R, Silayeva L, Doctor DM, Chilukuri N. Gene therapy delivering a paraoxonase 1 variant offers long-term prophylactic protection against nerve agents in mice. Sci Transl Med. 2020;12(527):eaay0356. https://doi.org/10.1126/scitranslmed.aay0356Betapudi V, Goswami R, Silayeva L, Doctor DM, Chilukuri N. Gene therapy delivering a paraoxonase 1 variant offers long-term prophylactic protection against nerve agents in mice. Sci Transl Med. 2020;12(527):eaay0356. https://doi.org/10.1126/scitranslmed.aay0356Mukherjee S, Gupta RD. Organophosphorus Nerve Agents: Types, Toxicity, and Treatments. J Toxicol. 2020;2020:3007984. https://doi.org/10.1155/2020/3007984Mukherjee S, Gupta RD. Organophosphorus Nerve Agents: Types, Toxicity, and Treatments. J Toxicol. 2020;2020:3007984. https://doi.org/10.1155/2020/3007984Timperley CM, Abdollahi M, Al-Amri AS, Baulig A, Benachour D, Borrett V, et al. Advice on assistance and protection from the Scientific Advisory Board of the Organisation for the Prohibition of Chemical Weapons: Part 2. On preventing and treating health effects from acute, prolonged, and repeated nerve agent exposure, and the identification of medical countermeasures able to reduce or eliminate the longer term health effects of nerve agents. Toxicology. 2019;413:13–23. https://doi.org/10.1016/j.tox.2018.11.009Timperley CM, Abdollahi M, Al-Amri AS, Baulig A, Benachour D, Borrett V, et al. Advice on assistance and protection from the Scientific Advisory Board of the Organisation for the Prohibition of Chemical Weapons: Part 2. On preventing and treating health effects from acute, prolonged, and repeated nerve agent exposure, and the identification of medical countermeasures able to reduce or eliminate the longer term health effects of nerve agents. Toxicology. 2019;413:13–23. https://doi.org/10.1016/j.tox.2018.11.009Costanzi S, Machado JH, Mitchell M. Nerve Agents: What They Are, How They Work, How to Counter Them. ACS Chem Neurosci. 2018;9(5):873–85. https://doi.org/10.1021/acschemneuro.8b00148Costanzi S, Machado JH, Mitchell M. Nerve Agents: What They Are, How They Work, How to Counter Them. ACS Chem Neurosci. 2018;9(5):873–85. https://doi.org/10.1021/acschemneuro.8b00148Eddleston M, Buckley NA, Eyer P, Dawson AH. Management of acute organophosphorus pesticide poisoning. Lancet. 2008;371(9612):597–607. https://doi.org/10.1016/S0140-6736(07)61202-1Eddleston M, Buckley NA, Eyer P, Dawson AH. Management of acute organophosphorus pesticide poisoning. Lancet. 2008;371(9612):597–607. https://doi.org/10.1016/S0140-6736(07)61202-1Moshiri M, Darchini-Maragheh E, Balali-Mood M. Advances in toxicology and medical treatment of chemical warfare nerve agents. Daru. 2012;20(1):81. https://doi.org/10.1186/2008-2231-20-81Moshiri M, Darchini-Maragheh E, Balali-Mood M. Advances in toxicology and medical treatment of chemical warfare nerve agents. Daru. 2012;20(1):81. https://doi.org/10.1186/2008-2231-20-81Jokanović M. Medical treatment of acute poisoning with organophosphorus and carbamate pesticides. Toxicol Lett. 2009;190(2):107–15. https://doi.org/10.1016/j.toxlet.2009.07.025Jokanović M. Medical treatment of acute poisoning with organophosphorus and carbamate pesticides. Toxicol Lett. 2009;190(2):107–15. https://doi.org/10.1016/j.toxlet.2009.07.025Gorecki L, Korabecny J, Musilek K, Nepovimova E, Malinak D, Kucera T, et al. Progress in acetylcholinesterase reactivators and in the treatment of organophosphorus intoxication: a patent review (2006–2016). Expert Opin Ther Pat. 2017;27(9):971–85. https://doi.org/10.1080/13543776.2017.1338275Gorecki L, Korabecny J, Musilek K, Nepovimova E, Malinak D, Kucera T, et al. Progress in acetylcholinesterase reactivators and in the treatment of organophosphorus intoxication: a patent review (2006–2016). Expert Opin Ther Pat. 2017;27(9):971–85. https://doi.org/10.1080/13543776.2017.1338275White RF, Steele L, O'Callaghan JP, Sullivan K, Binns JH, Golomb BA, et al. Recent research on Gulf War illness and other health problems in veterans of the 1991 Gulf War: Effects of toxicant exposures during deployment. Cortex. 2016;74:449–75. https://doi.org/10.1016/j.cortex.2015.08.022White RF, Steele L, O'Callaghan JP, Sullivan K, Binns JH, Golomb BA, et al. Recent research on Gulf War illness and other health problems in veterans of the 1991 Gulf War: Effects of toxicant exposures during deployment. Cortex. 2016;74:449–75. https://doi.org/10.1016/j.cortex.2015.08.022Iyengar AR, Pande AH. Organophosphate-Hydrolyzing Enzymes as First-Line of Defence Against Nerve Agent-Poisoning: Perspectives and the Road Ahead. Protein J. 2016;35(6):424–39. https://doi.org/10.1007/s10930-016-9686-6Iyengar AR, Pande AH. Organophosphate-Hydrolyzing Enzymes as First-Line of Defence Against Nerve Agent-Poisoning: Perspectives and the Road Ahead. Protein J. 2016;35(6):424–39. https://doi.org/10.1007/s10930-016-9686-6Ashani Y, Leader H, Aggarwal N, Silman I, Worek F, Sussman JL, Goldsmith M. In vitro evaluation of the catalytic activity of paraoxonases and phosphotriesterases predicts the enzyme circulatory levels required for in vivo protection against organophosphate intoxications. Chem Biol Interact. 2016;259(Pt B):252–56. https://doi.org/10.1016/j.cbi.2016.04.039Ashani Y, Leader H, Aggarwal N, Silman I, Worek F, Sussman JL, Goldsmith M. In vitro evaluation of the catalytic activity of paraoxonases and phosphotriesterases predicts the enzyme circulatory levels required for in vivo protection against organophosphate intoxications. Chem Biol Interact. 2016;259(Pt B):252–56. https://doi.org/10.1016/j.cbi.2016.04.039Mukherjee S, Gupta RD. Organophosphorus Nerve Agents: Types, Toxicity, and Treatments. J Toxicol. 2020;2020:3007984. https://doi.org/10.1155/2020/3007984Mukherjee S, Gupta RD. Organophosphorus Nerve Agents: Types, Toxicity, and Treatments. J Toxicol. 2020;2020:3007984. https://doi.org/10.1155/2020/3007984Reed BA, Sabourin CL, Lenz DE. Human butyrylcholinesterase efficacy against nerve agent exposure. J Biochem Mol Toxicol. 2017;31(5). https://doi.org/10.1002/jbt.21886Reed BA, Sabourin CL, Lenz DE. Human butyrylcholinesterase efficacy against nerve agent exposure. J Biochem Mol Toxicol. 2017;31(5). https://doi.org/10.1002/jbt.21886Lushchekina SV, Schopfer LM, Grigorenko BL, Nemukhin AV, Varfolomeev SD, Lockridge O, Masson P. Optimization of Cholinesterase-Based Catalytic Bioscavengers Against Organophosphorus Agents. Front Pharmacol. 2018;9:211. https://doi.org/10.3389/fphar.2018.00211Lushchekina SV, Schopfer LM, Grigorenko BL, Nemukhin AV, Varfolomeev SD, Lockridge O, Masson P. Optimization of Cholinesterase-Based Catalytic Bioscavengers Against Organophosphorus Agents. Front Pharmacol. 2018;9:211. https://doi.org/10.3389/fphar.2018.00211Smirnov IV, Vorobiev II, Belogurov AA, Genkin DD, Deyev SM, Gabibov AG. Chemical Polysialylation of Recombinant Human Proteins. Methods Mol Biol. 2015;1321:389–404. https://doi.org/10.1007/978-1-4939-2760-9_26Smirnov IV, Vorobiev II, Belogurov AA, Genkin DD, Deyev SM, Gabibov AG. Chemical Polysialylation of Recombinant Human Proteins. Methods Mol Biol. 2015;1321:389–404. https://doi.org/10.1007/978-1-4939-2760-9_26Rajkovic MG, Rumora L, Barisic K. The paraoxonase 1, 2 and 3 in humans. Biochem Med (Zagreb). 2011;21(2):122–30. https://doi.org/10.11613/bm.2011.020Rajkovic MG, Rumora L, Barisic K. The paraoxonase 1, 2 and 3 in humans. Biochem Med (Zagreb). 2011;21(2):122–30. https://doi.org/10.11613/bm.2011.020Mackness B, Durrington PN, Mackness MI. Human serum paraoxonase. Gen Pharmacol. 1998;31(3): 329–36. https://doi.org/10.1016/s0306-3623(98)00028-7Mackness B, Durrington PN, Mackness MI. Human serum paraoxonase. Gen Pharmacol. 1998;31(3): 329–36. https://doi.org/10.1016/s0306-3623(98)00028-7Taler-Verčič A, Goličnik M, Bavec A. The Structure and Function of Paraoxonase-1 and Its Comparison to Paraoxonase-2 and -3. Molecules. 2020;25(24):5980. https://doi.org/10.3390/molecules25245980Taler-Verčič A, Goličnik M, Bavec A. The Structure and Function of Paraoxonase-1 and Its Comparison to Paraoxonase-2 and -3. Molecules. 2020;25(24):5980. https://doi.org/10.3390/molecules25245980Primo-Parmo SL, Sorenson RC, Teiber J, La Du BN. The human serum paraoxonase/arylesterase gene (PON1) is one member of a multigene family. Genomics. 1996;33(3):498–507. https://doi.org/10.1006/geno.1996.0225Primo-Parmo SL, Sorenson RC, Teiber J, La Du BN. The human serum paraoxonase/arylesterase gene (PON1) is one member of a multigene family. Genomics. 1996;33(3):498–507. https://doi.org/10.1006/geno.1996.0225Deakin SP, Bioletto S, Bochaton-Piallat ML, James RW. HDL-associated paraoxonase-1 can redistribute to cell membranes and influence sensitivity to oxidative stress. Free Radic Biol Med. 2011;50(1):102–9. https://doi.org/10.1016/j.freeradbiomed.2010.09.002Deakin SP, Bioletto S, Bochaton-Piallat ML, James RW. HDL-associated paraoxonase-1 can redistribute to cell membranes and influence sensitivity to oxidative stress. Free Radic Biol Med. 2011;50(1):102–9. https://doi.org/10.1016/j.freeradbiomed.2010.09.002Grzegorzewska AE, Adamska P, Iwańczyk-Skalska E, Ostromecka K, Niepolski L, Marcinkowski W, et al. Paraoxonase 1 concerning dyslipidaemia, cardiovascular diseases, and mortality in haemodialysis patients. Sci Rep. 2021;11(1):6773. https://doi.org/10.1038/s41598-021-86231-0Grzegorzewska AE, Adamska P, Iwańczyk-Skalska E, Ostromecka K, Niepolski L, Marcinkowski W, et al. Paraoxonase 1 concerning dyslipidaemia, cardiovascular diseases, and mortality in haemodialysis patients. Sci Rep. 2021;11(1):6773. https://doi.org/10.1038/s41598-021-86231-0Shunmoogam N, Naidoo P, Chilton R. Paraoxonase (PON)-1: a brief overview on genetics, structure, polymorphisms and clinical relevance. Vasc Health Risk Manag. 2018;14:137–43. https://doi.org/10.2147/VHRM.S165173Shunmoogam N, Naidoo P, Chilton R. Paraoxonase (PON)-1: a brief overview on genetics, structure, polymorphisms and clinical relevance. Vasc Health Risk Manag. 2018;14:137–43. https://doi.org/10.2147/VHRM.S165173Draganov DI, Teiber JF, Speelman A, Osawa Y, Sunahara R, La Du BN. Human paraoxonases (PON1, PON2, and PON3) are lactonases with overlapping and distinct substrate specificities. J Lipid Res. 2005;46(6):1239–47. https://doi.org/10.1194/jlr.M400511-JLR200Draganov DI, Teiber JF, Speelman A, Osawa Y, Sunahara R, La Du BN. Human paraoxonases (PON1, PON2, and PON3) are lactonases with overlapping and distinct substrate specificities. J Lipid Res. 2005;46(6):1239–47. https://doi.org/10.1194/jlr.M400511-JLR200Gupta RD, Goldsmith M, Ashani Y, Simo Y, Mullokandov G, Bar H, et al. Directed evolution of hydrolases for prevention of G-type nerve agent intoxication. Nat Chem Biol. 2011;7(2):120–5. https://doi.org/10.1038/nchembio.510Gupta RD, Goldsmith M, Ashani Y, Simo Y, Mullokandov G, Bar H, et al. Directed evolution of hydrolases for prevention of G-type nerve agent intoxication. Nat Chem Biol. 2011;7(2):120–5. https://doi.org/10.1038/nchembio.510Li WS, Lum KT, Chen-Goodspeed M, Sogorb MA, Raushel FM. Stereoselective detoxification of chiral sarin and soman analogues by phosphotriesterase. Bioorg Med Chem. 2001;9(8):2083–91. https://doi.org/10.1016/s0968-0896(01)00113-4Li WS, Lum KT, Chen-Goodspeed M, Sogorb MA, Raushel FM. Stereoselective detoxification of chiral sarin and soman analogues by phosphotriesterase. Bioorg Med Chem. 2001;9(8):2083–91. https://doi.org/10.1016/s0968-0896(01)00113-4Goldsmith M, Tawfik DS. Enzyme engineering: reaching the maximal catalytic efficiency peak. Curr Opin Struct Biol. 2017;47(12):140-150. https://doi.org/10.1016/j.sbi.2017.09.002Goldsmith M, Tawfik DS. Enzyme engineering: reaching the maximal catalytic efficiency peak. Curr Opin Struct Biol. 2017;47(12):140-150. https://doi.org/10.1016/j.sbi.2017.09.002Goldsmith M, Ashani Y, Simo Y, Ben-David M, Leader H, Silman I, et al. Evolved stereoselective hydrolases for broad-spectrum G-type nerve agent detoxification. Chem Biol. 2012;19(4):456–66. https://doi.org/10.1016/j.chembiol.2012.01.017Goldsmith M, Ashani Y, Simo Y, Ben-David M, Leader H, Silman I, et al. Evolved stereoselective hydrolases for broad-spectrum G-type nerve agent detoxification. Chem Biol. 2012;19(4):456–66. https://doi.org/10.1016/j.chembiol.2012.01.017Mata DG, Sabnekar P, Watson CA, Rezk PE, Chilukuri N. Assessing the stoichiometric efficacy of mammalian expressed paraoxonase-1 variant I-F11 to afford protection against G-type nerve agents. Chem Biol Interact. 2016;259(B):233–41. https://doi.org/10.1016/j.cbi.2016.04.013Mata DG, Sabnekar P, Watson CA, Rezk PE, Chilukuri N. Assessing the stoichiometric efficacy of mammalian expressed paraoxonase-1 variant I-F11 to afford protection against G-type nerve agents. Chem Biol Interact. 2016;259(B):233–41. https://doi.org/10.1016/j.cbi.2016.04.013Haider K.H. Handbook of Stem Cell Therapy, Springer Nature Singapore, 1st ed. 2022. ISBN 978-981-19-2654-9. https://doi.org/10.1007/978-981-19-2655-6Haider K.H. Handbook of Stem Cell Therapy, Springer Nature Singapore, 1st ed. 2022. ISBN 978-981-19-2654-9. https://doi.org/10.1007/978-981-19-2655-6Pawitan JA, Bui TA, Mubarok W, Antarianto RD, Nurhayati RW, Dilogo IH, Oceandy D. Enhancement of the Therapeutic Capacity of Mesenchymal Stem Cells by Genetic Modification: A Systematic Review. Front Cell Dev Biol. 2020;8:587776. https://doi.org/10.3389/fcell.2020.587776Pawitan JA, Bui TA, Mubarok W, Antarianto RD, Nurhayati RW, Dilogo IH, Oceandy D. Enhancement of the Therapeutic Capacity of Mesenchymal Stem Cells by Genetic Modification: A Systematic Review. Front Cell Dev Biol. 2020;8:587776. https://doi.org/10.3389/fcell.2020.587776Lakota J. Fate of human mesenchymal stem cells (MSCs) in humans and rodents-Is the current paradigm obtained on rodents applicable to humans? J Cell Mol Med. 2018;22(44):2523–4. https://doi.org/10.1111/jcmm.13561Lakota J. Fate of human mesenchymal stem cells (MSCs) in humans and rodents-Is the current paradigm obtained on rodents applicable to humans? J Cell Mol Med. 2018;22(44):2523–4. https://doi.org/10.1111/jcmm.13561Nathwani AC, Tuddenham EG, Rangarajan S, Rosales C, McIntosh J, Linch DC, et al. Adenovirusassociated virus vector-mediated gene transfer in hemophilia B. N Engl J Med. 2011;365(25):2357–65. https://doi.org/10.1056/NEJMoa1108046Nathwani AC, Tuddenham EG, Rangarajan S, Rosales C, McIntosh J, Linch DC, et al. Adenovirusassociated virus vector-mediated gene transfer in hemophilia B. N Engl J Med. 2011;365(25):2357–65. https://doi.org/10.1056/NEJMoa1108046Dhungel BP, Winburn I, Pereira CDF, Huang K, Chhabra A, Rasko JEJ. Understanding AAV vector immunogenicity: from particle to patient. Theranostics. 2024;14(3):1260–88. https://doi.org/10.7150/thno.89380Dhungel BP, Winburn I, Pereira CDF, Huang K, Chhabra A, Rasko JEJ. Understanding AAV vector immunogenicity: from particle to patient. Theranostics. 2024;14(3):1260–88. https://doi.org/10.7150/thno.89380Lakota J, Gocarova K, Spanik S. Treatment of metastatic head and neck cancer with mesenchymal stem cells combined with prodrug gene therapy. Exp Oncol. 2015;37(4):298. PMID: 26710845.Lakota J, Gocarova K, Spanik S. Treatment of metastatic head and neck cancer with mesenchymal stem cells combined with prodrug gene therapy. Exp Oncol. 2015;37(4):298. PMID: 26710845.

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