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Novel Coagulation Factor VIII Gene Therapy in a Mouse Model of Hemophilia A by Lipid-Coated Fe(3)O(4) Nanoparticles
Hemophilia A is a bleeding disease caused by loss of coagulation factor VIII (FVIII) function. Although prophylactic FVIII infusion prevents abnormal bleeding, disability and joint damage in hemophilia patients are common. The cost of treatment is among the highest for a single disease, and the adve...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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MDPI
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8464966/ https://www.ncbi.nlm.nih.gov/pubmed/34572302 http://dx.doi.org/10.3390/biomedicines9091116 |
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author | Kao, Yung-Tsung Chen, Yen-Ting Fan, Hueng-Chuen Tsai, Tung-Chou Cheng, Shin-Nan Lai, Ping-Shan Chen, Jen-Kun Chen, Chuan-Mu |
author_facet | Kao, Yung-Tsung Chen, Yen-Ting Fan, Hueng-Chuen Tsai, Tung-Chou Cheng, Shin-Nan Lai, Ping-Shan Chen, Jen-Kun Chen, Chuan-Mu |
author_sort | Kao, Yung-Tsung |
collection | PubMed |
description | Hemophilia A is a bleeding disease caused by loss of coagulation factor VIII (FVIII) function. Although prophylactic FVIII infusion prevents abnormal bleeding, disability and joint damage in hemophilia patients are common. The cost of treatment is among the highest for a single disease, and the adverse effects of repeated infusion are still an issue that has not been addressed. In this study, we established a nonviral gene therapy strategy to treat FVIII knockout (FVIII KO) mice. A novel gene therapy approach was developed using dipalmitoylphosphatidylcholine formulated with iron oxide (DPPC-Fe(3)O(4)) to carry the B-domain-deleted (BDD)-FVIII plasmid, which was delivered into the FVIII KO mice via tail vein injection. Here, a liver-specific albumin promoter-driven BDD-FVIII plasmid was constructed, and the binding ability of circular DNA was confirmed to be more stable than that of linear DNA when combined with DPPC-Fe(3)O(4) nanoparticles. The FVIII KO mice that received the DPPC-Fe(3)O(4) plasmid complex were assessed by staining the ferric ion of DPPC-Fe(3)O(4) nanoparticles with Prussian blue in liver tissue. The bleeding of the FVIII KO mice was improved in a few weeks, as shown by assessing the activated partial thromboplastin time (aPTT). Furthermore, no liver toxicity, thromboses, deaths, or persistent changes after nonviral gene therapy were found, as shown by serum liver indices and histopathology. The results suggest that this novel gene therapy can successfully improve hemostasis disorder in FVIII KO mice and might be a promising approach to treating hemophilia A patients in clinical settings. |
format | Online Article Text |
id | pubmed-8464966 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-84649662021-09-27 Novel Coagulation Factor VIII Gene Therapy in a Mouse Model of Hemophilia A by Lipid-Coated Fe(3)O(4) Nanoparticles Kao, Yung-Tsung Chen, Yen-Ting Fan, Hueng-Chuen Tsai, Tung-Chou Cheng, Shin-Nan Lai, Ping-Shan Chen, Jen-Kun Chen, Chuan-Mu Biomedicines Article Hemophilia A is a bleeding disease caused by loss of coagulation factor VIII (FVIII) function. Although prophylactic FVIII infusion prevents abnormal bleeding, disability and joint damage in hemophilia patients are common. The cost of treatment is among the highest for a single disease, and the adverse effects of repeated infusion are still an issue that has not been addressed. In this study, we established a nonviral gene therapy strategy to treat FVIII knockout (FVIII KO) mice. A novel gene therapy approach was developed using dipalmitoylphosphatidylcholine formulated with iron oxide (DPPC-Fe(3)O(4)) to carry the B-domain-deleted (BDD)-FVIII plasmid, which was delivered into the FVIII KO mice via tail vein injection. Here, a liver-specific albumin promoter-driven BDD-FVIII plasmid was constructed, and the binding ability of circular DNA was confirmed to be more stable than that of linear DNA when combined with DPPC-Fe(3)O(4) nanoparticles. The FVIII KO mice that received the DPPC-Fe(3)O(4) plasmid complex were assessed by staining the ferric ion of DPPC-Fe(3)O(4) nanoparticles with Prussian blue in liver tissue. The bleeding of the FVIII KO mice was improved in a few weeks, as shown by assessing the activated partial thromboplastin time (aPTT). Furthermore, no liver toxicity, thromboses, deaths, or persistent changes after nonviral gene therapy were found, as shown by serum liver indices and histopathology. The results suggest that this novel gene therapy can successfully improve hemostasis disorder in FVIII KO mice and might be a promising approach to treating hemophilia A patients in clinical settings. MDPI 2021-08-30 /pmc/articles/PMC8464966/ /pubmed/34572302 http://dx.doi.org/10.3390/biomedicines9091116 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Kao, Yung-Tsung Chen, Yen-Ting Fan, Hueng-Chuen Tsai, Tung-Chou Cheng, Shin-Nan Lai, Ping-Shan Chen, Jen-Kun Chen, Chuan-Mu Novel Coagulation Factor VIII Gene Therapy in a Mouse Model of Hemophilia A by Lipid-Coated Fe(3)O(4) Nanoparticles |
title | Novel Coagulation Factor VIII Gene Therapy in a Mouse Model of Hemophilia A by Lipid-Coated Fe(3)O(4) Nanoparticles |
title_full | Novel Coagulation Factor VIII Gene Therapy in a Mouse Model of Hemophilia A by Lipid-Coated Fe(3)O(4) Nanoparticles |
title_fullStr | Novel Coagulation Factor VIII Gene Therapy in a Mouse Model of Hemophilia A by Lipid-Coated Fe(3)O(4) Nanoparticles |
title_full_unstemmed | Novel Coagulation Factor VIII Gene Therapy in a Mouse Model of Hemophilia A by Lipid-Coated Fe(3)O(4) Nanoparticles |
title_short | Novel Coagulation Factor VIII Gene Therapy in a Mouse Model of Hemophilia A by Lipid-Coated Fe(3)O(4) Nanoparticles |
title_sort | novel coagulation factor viii gene therapy in a mouse model of hemophilia a by lipid-coated fe(3)o(4) nanoparticles |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8464966/ https://www.ncbi.nlm.nih.gov/pubmed/34572302 http://dx.doi.org/10.3390/biomedicines9091116 |
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