Lonafarnib and everolimus reduce pathology in iPSC-derived tissue engineered blood vessel model of Hutchinson-Gilford Progeria Syndrome
Abstract Hutchinson-Gilford Progeria Syndrome (HGPS) is a rare, fatal genetic disease that accelerates atherosclerosis. With a limited pool of HGPS patients, clinical trials face unique challenges and require reliable preclinical testing. We previously reported a 3D tissue engineered blood vessel (T...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-03-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-023-32035-3 |
| _version_ | 1797853856483246080 |
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| author | Nadia O. Abutaleb Leigh Atchison Leandro Choi Akhil Bedapudi Kevin Shores Yantenew Gete Kan Cao George A. Truskey |
| author_facet | Nadia O. Abutaleb Leigh Atchison Leandro Choi Akhil Bedapudi Kevin Shores Yantenew Gete Kan Cao George A. Truskey |
| author_sort | Nadia O. Abutaleb |
| collection | DOAJ |
| description | Abstract Hutchinson-Gilford Progeria Syndrome (HGPS) is a rare, fatal genetic disease that accelerates atherosclerosis. With a limited pool of HGPS patients, clinical trials face unique challenges and require reliable preclinical testing. We previously reported a 3D tissue engineered blood vessel (TEBV) microphysiological system fabricated with iPSC-derived vascular cells from HGPS patients. HGPS TEBVs exhibit features of HGPS atherosclerosis including loss of smooth muscle cells, reduced vasoactivity, excess extracellular matrix (ECM) deposition, inflammatory marker expression, and calcification. We tested the effects of HGPS therapeutics Lonafarnib and Everolimus separately and together, currently in Phase I/II clinical trial, on HGPS TEBVs. Everolimus decreased reactive oxygen species levels, increased proliferation, reduced DNA damage in HGPS vascular cells, and improved vasoconstriction in HGPS TEBVs. Lonafarnib improved shear stress response of HGPS iPSC-derived endothelial cells (viECs) and reduced ECM deposition, inflammation, and calcification in HGPS TEBVs. Combination treatment with Lonafarnib and Everolimus produced additional benefits such as improved endothelial and smooth muscle marker expression and reduced apoptosis, as well as increased TEBV vasoconstriction and vasodilation. These results suggest that a combined trial of both drugs may provide cardiovascular benefits beyond Lonafarnib, if the Everolimus dose can be tolerated. |
| first_indexed | 2024-04-09T19:57:33Z |
| format | Article |
| id | doaj.art-795072a3654d418481cb34a30863502b |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-04-09T19:57:33Z |
| publishDate | 2023-03-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-795072a3654d418481cb34a30863502b2023-04-03T05:23:06ZengNature PortfolioScientific Reports2045-23222023-03-0113111510.1038/s41598-023-32035-3Lonafarnib and everolimus reduce pathology in iPSC-derived tissue engineered blood vessel model of Hutchinson-Gilford Progeria SyndromeNadia O. Abutaleb0Leigh Atchison1Leandro Choi2Akhil Bedapudi3Kevin Shores4Yantenew Gete5Kan Cao6George A. Truskey7Department of Biomedical Engineering, Duke UniversityDepartment of Biomedical Engineering, Duke UniversityDepartment of Biomedical Engineering, Duke UniversityDepartment of Biomedical Engineering, Duke UniversityDepartment of Biomedical Engineering, Duke UniversityDepartment of Cell Biology and Molecular Genetics, University of MarylandDepartment of Cell Biology and Molecular Genetics, University of MarylandDepartment of Biomedical Engineering, Duke UniversityAbstract Hutchinson-Gilford Progeria Syndrome (HGPS) is a rare, fatal genetic disease that accelerates atherosclerosis. With a limited pool of HGPS patients, clinical trials face unique challenges and require reliable preclinical testing. We previously reported a 3D tissue engineered blood vessel (TEBV) microphysiological system fabricated with iPSC-derived vascular cells from HGPS patients. HGPS TEBVs exhibit features of HGPS atherosclerosis including loss of smooth muscle cells, reduced vasoactivity, excess extracellular matrix (ECM) deposition, inflammatory marker expression, and calcification. We tested the effects of HGPS therapeutics Lonafarnib and Everolimus separately and together, currently in Phase I/II clinical trial, on HGPS TEBVs. Everolimus decreased reactive oxygen species levels, increased proliferation, reduced DNA damage in HGPS vascular cells, and improved vasoconstriction in HGPS TEBVs. Lonafarnib improved shear stress response of HGPS iPSC-derived endothelial cells (viECs) and reduced ECM deposition, inflammation, and calcification in HGPS TEBVs. Combination treatment with Lonafarnib and Everolimus produced additional benefits such as improved endothelial and smooth muscle marker expression and reduced apoptosis, as well as increased TEBV vasoconstriction and vasodilation. These results suggest that a combined trial of both drugs may provide cardiovascular benefits beyond Lonafarnib, if the Everolimus dose can be tolerated.https://doi.org/10.1038/s41598-023-32035-3 |
| spellingShingle | Nadia O. Abutaleb Leigh Atchison Leandro Choi Akhil Bedapudi Kevin Shores Yantenew Gete Kan Cao George A. Truskey Lonafarnib and everolimus reduce pathology in iPSC-derived tissue engineered blood vessel model of Hutchinson-Gilford Progeria Syndrome Scientific Reports |
| title | Lonafarnib and everolimus reduce pathology in iPSC-derived tissue engineered blood vessel model of Hutchinson-Gilford Progeria Syndrome |
| title_full | Lonafarnib and everolimus reduce pathology in iPSC-derived tissue engineered blood vessel model of Hutchinson-Gilford Progeria Syndrome |
| title_fullStr | Lonafarnib and everolimus reduce pathology in iPSC-derived tissue engineered blood vessel model of Hutchinson-Gilford Progeria Syndrome |
| title_full_unstemmed | Lonafarnib and everolimus reduce pathology in iPSC-derived tissue engineered blood vessel model of Hutchinson-Gilford Progeria Syndrome |
| title_short | Lonafarnib and everolimus reduce pathology in iPSC-derived tissue engineered blood vessel model of Hutchinson-Gilford Progeria Syndrome |
| title_sort | lonafarnib and everolimus reduce pathology in ipsc derived tissue engineered blood vessel model of hutchinson gilford progeria syndrome |
| url | https://doi.org/10.1038/s41598-023-32035-3 |
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