Extended Toxicity, Genotoxicity, and Mutagenicity of Combination of pBudK-coVEGF-coANG and pBudK-coGDNF Plasmids in Preclinical Trials
Chronic lower limb ischemia is a debilitating condition, particularly prevalent among elderly patients and individuals ineligible for revascularization procedures. Gene therapy aimed at promoting therapeutic angiogenesis presents a promising alternative treatment strategy. <b>Objectives:</b...
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2025-05-01
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| author | Igor V. Samatoshenkov Alexander M. Aimaletdinov Elena Y. Zakirova Egan L. Kalmykov Rustam Khodzhibaev Yulia M. Samatoshenkova Ilnur M. Ganiev Marat S. Kadyrov Yana O. Mukhamedshina |
| author_facet | Igor V. Samatoshenkov Alexander M. Aimaletdinov Elena Y. Zakirova Egan L. Kalmykov Rustam Khodzhibaev Yulia M. Samatoshenkova Ilnur M. Ganiev Marat S. Kadyrov Yana O. Mukhamedshina |
| author_sort | Igor V. Samatoshenkov |
| collection | DOAJ |
| description | Chronic lower limb ischemia is a debilitating condition, particularly prevalent among elderly patients and individuals ineligible for revascularization procedures. Gene therapy aimed at promoting therapeutic angiogenesis presents a promising alternative treatment strategy. <b>Objectives:</b> This study evaluated the preclinical safety of a gene therapy drug composed of the plasmids pBudK-coVEGF-coANG and pBudK-coGDNF in laboratory animals. Safety assessment followed a single intramuscular injection at a dose 30 times higher than the proposed therapeutic level. <b>Methods:</b> Acute toxicity was monitored over a 24-h period. Genotoxicity was assessed using the micronucleus test at doses of 200, 1000, and 5000 μg/kg. Bone marrow cytology was analyzed to detect hematopoietic toxicity. Delayed toxicity was evaluated over a two-week recovery period. <b>Results:</b> No signs of acute toxicity were observed, even at the highest dose. The micronucleus test revealed no genotoxic effects, with no significant increase in micronucleated polychromatic erythrocytes compared to control groups. Bone marrow erythroblast parameters remained within normal physiological ranges. Additionally, no delayed adverse effects were detected during the recovery period. <b>Conclusions:</b> The gene therapy drug demonstrated a favorable preclinical safety profile, exhibiting no evidence of toxicity or genotoxicity, even at substantially elevated doses. These findings support the continued development of this therapy as a potential treatment for chronic lower limb ischemia in patients who are not candidates for surgical intervention. |
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| institution | Kabale University |
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| language | English |
| publishDate | 2025-05-01 |
| publisher | MDPI AG |
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| series | Biomedicines |
| spelling | doaj-art-656d8e4f1cb24afd928a827f4911fa382025-08-20T03:47:49ZengMDPI AGBiomedicines2227-90592025-05-01135122310.3390/biomedicines13051223Extended Toxicity, Genotoxicity, and Mutagenicity of Combination of pBudK-coVEGF-coANG and pBudK-coGDNF Plasmids in Preclinical TrialsIgor V. Samatoshenkov0Alexander M. Aimaletdinov1Elena Y. Zakirova2Egan L. Kalmykov3Rustam Khodzhibaev4Yulia M. Samatoshenkova5Ilnur M. Ganiev6Marat S. Kadyrov7Yana O. Mukhamedshina8Medizinische Hochschule Brandenburg Theodor Fontane, 14770 Brandenburg, GermanyInstitute of Fundamental Medicine and Biology, Kazan (Volga Region) Federal University, 420008 Kazan, RussiaInstitute of Fundamental Medicine and Biology, Kazan (Volga Region) Federal University, 420008 Kazan, RussiaDepartment of Vascular and Endovascular Surgery, Brandenburg University Clinic, 14770 Brandenburg, GermanyDepartment of Vascular and Endovascular Surgery, Brandenburg University Clinic, 14770 Brandenburg, GermanySAHI Republican Clinical Hospital of the Ministry of Health of the Republic of Tatarstan, 420138 Kazan, RussiaInstitute of Fundamental Medicine and Biology, Kazan (Volga Region) Federal University, 420008 Kazan, RussiaLimited Liability Company “Angiolife”, 420015 Kazan, RussiaInstitute of Fundamental Medicine and Biology, Kazan (Volga Region) Federal University, 420008 Kazan, RussiaChronic lower limb ischemia is a debilitating condition, particularly prevalent among elderly patients and individuals ineligible for revascularization procedures. Gene therapy aimed at promoting therapeutic angiogenesis presents a promising alternative treatment strategy. <b>Objectives:</b> This study evaluated the preclinical safety of a gene therapy drug composed of the plasmids pBudK-coVEGF-coANG and pBudK-coGDNF in laboratory animals. Safety assessment followed a single intramuscular injection at a dose 30 times higher than the proposed therapeutic level. <b>Methods:</b> Acute toxicity was monitored over a 24-h period. Genotoxicity was assessed using the micronucleus test at doses of 200, 1000, and 5000 μg/kg. Bone marrow cytology was analyzed to detect hematopoietic toxicity. Delayed toxicity was evaluated over a two-week recovery period. <b>Results:</b> No signs of acute toxicity were observed, even at the highest dose. The micronucleus test revealed no genotoxic effects, with no significant increase in micronucleated polychromatic erythrocytes compared to control groups. Bone marrow erythroblast parameters remained within normal physiological ranges. Additionally, no delayed adverse effects were detected during the recovery period. <b>Conclusions:</b> The gene therapy drug demonstrated a favorable preclinical safety profile, exhibiting no evidence of toxicity or genotoxicity, even at substantially elevated doses. These findings support the continued development of this therapy as a potential treatment for chronic lower limb ischemia in patients who are not candidates for surgical intervention.https://www.mdpi.com/2227-9059/13/5/1223genetic therapyischemic diseaseplasmidglial-derived neurotrophic factorvascular endothelial growth factorangiogenin |
| spellingShingle | Igor V. Samatoshenkov Alexander M. Aimaletdinov Elena Y. Zakirova Egan L. Kalmykov Rustam Khodzhibaev Yulia M. Samatoshenkova Ilnur M. Ganiev Marat S. Kadyrov Yana O. Mukhamedshina Extended Toxicity, Genotoxicity, and Mutagenicity of Combination of pBudK-coVEGF-coANG and pBudK-coGDNF Plasmids in Preclinical Trials Biomedicines genetic therapy ischemic disease plasmid glial-derived neurotrophic factor vascular endothelial growth factor angiogenin |
| title | Extended Toxicity, Genotoxicity, and Mutagenicity of Combination of pBudK-coVEGF-coANG and pBudK-coGDNF Plasmids in Preclinical Trials |
| title_full | Extended Toxicity, Genotoxicity, and Mutagenicity of Combination of pBudK-coVEGF-coANG and pBudK-coGDNF Plasmids in Preclinical Trials |
| title_fullStr | Extended Toxicity, Genotoxicity, and Mutagenicity of Combination of pBudK-coVEGF-coANG and pBudK-coGDNF Plasmids in Preclinical Trials |
| title_full_unstemmed | Extended Toxicity, Genotoxicity, and Mutagenicity of Combination of pBudK-coVEGF-coANG and pBudK-coGDNF Plasmids in Preclinical Trials |
| title_short | Extended Toxicity, Genotoxicity, and Mutagenicity of Combination of pBudK-coVEGF-coANG and pBudK-coGDNF Plasmids in Preclinical Trials |
| title_sort | extended toxicity genotoxicity and mutagenicity of combination of pbudk covegf coang and pbudk cogdnf plasmids in preclinical trials |
| topic | genetic therapy ischemic disease plasmid glial-derived neurotrophic factor vascular endothelial growth factor angiogenin |
| url | https://www.mdpi.com/2227-9059/13/5/1223 |
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