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Hematopoietic Stem Cell Gene Therapy for Brain Metastases Using Myeloid Cell–Specific Gene Promoters

BACKGROUND: Brain metastases (BrM) develop in 20–40% of cancer patients and represent an unmet clinical need. Limited access of drugs into the brain because of the blood-brain barrier is at least partially responsible for therapeutic failure, necessitating improved drug delivery systems. METHODS: Gr...

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Autores principales: Andreou, Tereza, Rippaus, Nora, Wronski, Krzysztof, Williams, Jennifer, Taggart, David, Cherqui, Stephanie, Sunderland, Ashley, Kartika, Yolanda D, Egnuni, Teklu, Brownlie, Rebecca J, Mathew, Ryan K, Holmen, Sheri L, Fife, Christopher, Droop, Alastair, Lorger, Mihaela
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7301153/
https://www.ncbi.nlm.nih.gov/pubmed/31501884
http://dx.doi.org/10.1093/jnci/djz181
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author Andreou, Tereza
Rippaus, Nora
Wronski, Krzysztof
Williams, Jennifer
Taggart, David
Cherqui, Stephanie
Sunderland, Ashley
Kartika, Yolanda D
Egnuni, Teklu
Brownlie, Rebecca J
Mathew, Ryan K
Holmen, Sheri L
Fife, Christopher
Droop, Alastair
Lorger, Mihaela
author_facet Andreou, Tereza
Rippaus, Nora
Wronski, Krzysztof
Williams, Jennifer
Taggart, David
Cherqui, Stephanie
Sunderland, Ashley
Kartika, Yolanda D
Egnuni, Teklu
Brownlie, Rebecca J
Mathew, Ryan K
Holmen, Sheri L
Fife, Christopher
Droop, Alastair
Lorger, Mihaela
author_sort Andreou, Tereza
collection PubMed
description BACKGROUND: Brain metastases (BrM) develop in 20–40% of cancer patients and represent an unmet clinical need. Limited access of drugs into the brain because of the blood-brain barrier is at least partially responsible for therapeutic failure, necessitating improved drug delivery systems. METHODS: Green fluorescent protein (GFP)-transduced murine and nontransduced human hematopoietic stem cells (HSCs) were administered into mice (n = 10 and 3). The HSC progeny in mouse BrM and in patient-derived BrM tissue (n = 6) was characterized by flow cytometry and immunofluorescence. Promoters driving gene expression, specifically within the BrM-infiltrating HSC progeny, were identified through differential gene-expression analysis and subsequent validation of a series of promoter-green fluorescent protein-reporter constructs in mice (n = 5). One of the promoters was used to deliver tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) to BrM in mice (n = 17/21 for TRAIL vs control group). RESULTS: HSC progeny (consisting mostly of macrophages) efficiently homed to macrometastases (mean [SD] = 37.6% [7.2%] of all infiltrating cells for murine HSC progeny; 27.9% mean [SD] = 27.9% [4.9%] of infiltrating CD45+ hematopoietic cells for human HSC progeny) and micrometastases in mice (19.3–53.3% of all macrophages for murine HSCs). Macrophages were also abundant in patient-derived BrM tissue (mean [SD] = 8.8% [7.8%]). Collectively, this provided a rationale to optimize the delivery of gene therapy to BrM within myeloid cells. MMP14 promoter emerged as the strongest promoter construct capable of limiting gene expression to BrM-infiltrating myeloid cells in mice. TRAIL delivered under MMP14 promoter statistically significantly prolonged survival in mice (mean [SD] = 19.0 [3.4] vs mean [SD] = 15.0 [2.0] days for TRAIL vs control group; two-sided P = .006), demonstrating therapeutic and translational potential of our approach. CONCLUSIONS: Our study establishes HSC gene therapy using a myeloid cell–specific promoter as a new strategy to target BrM. This approach, with strong translational value, has potential to overcome the blood-brain barrier, target micrometastases, and control multifocal lesions.
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spelling pubmed-73011532020-06-23 Hematopoietic Stem Cell Gene Therapy for Brain Metastases Using Myeloid Cell–Specific Gene Promoters Andreou, Tereza Rippaus, Nora Wronski, Krzysztof Williams, Jennifer Taggart, David Cherqui, Stephanie Sunderland, Ashley Kartika, Yolanda D Egnuni, Teklu Brownlie, Rebecca J Mathew, Ryan K Holmen, Sheri L Fife, Christopher Droop, Alastair Lorger, Mihaela J Natl Cancer Inst Articles BACKGROUND: Brain metastases (BrM) develop in 20–40% of cancer patients and represent an unmet clinical need. Limited access of drugs into the brain because of the blood-brain barrier is at least partially responsible for therapeutic failure, necessitating improved drug delivery systems. METHODS: Green fluorescent protein (GFP)-transduced murine and nontransduced human hematopoietic stem cells (HSCs) were administered into mice (n = 10 and 3). The HSC progeny in mouse BrM and in patient-derived BrM tissue (n = 6) was characterized by flow cytometry and immunofluorescence. Promoters driving gene expression, specifically within the BrM-infiltrating HSC progeny, were identified through differential gene-expression analysis and subsequent validation of a series of promoter-green fluorescent protein-reporter constructs in mice (n = 5). One of the promoters was used to deliver tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) to BrM in mice (n = 17/21 for TRAIL vs control group). RESULTS: HSC progeny (consisting mostly of macrophages) efficiently homed to macrometastases (mean [SD] = 37.6% [7.2%] of all infiltrating cells for murine HSC progeny; 27.9% mean [SD] = 27.9% [4.9%] of infiltrating CD45+ hematopoietic cells for human HSC progeny) and micrometastases in mice (19.3–53.3% of all macrophages for murine HSCs). Macrophages were also abundant in patient-derived BrM tissue (mean [SD] = 8.8% [7.8%]). Collectively, this provided a rationale to optimize the delivery of gene therapy to BrM within myeloid cells. MMP14 promoter emerged as the strongest promoter construct capable of limiting gene expression to BrM-infiltrating myeloid cells in mice. TRAIL delivered under MMP14 promoter statistically significantly prolonged survival in mice (mean [SD] = 19.0 [3.4] vs mean [SD] = 15.0 [2.0] days for TRAIL vs control group; two-sided P = .006), demonstrating therapeutic and translational potential of our approach. CONCLUSIONS: Our study establishes HSC gene therapy using a myeloid cell–specific promoter as a new strategy to target BrM. This approach, with strong translational value, has potential to overcome the blood-brain barrier, target micrometastases, and control multifocal lesions. Oxford University Press 2019-09-10 /pmc/articles/PMC7301153/ /pubmed/31501884 http://dx.doi.org/10.1093/jnci/djz181 Text en © The Author(s) 2019. Published by Oxford University Press. http://creativecommons.org/licenses/by/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Articles
Andreou, Tereza
Rippaus, Nora
Wronski, Krzysztof
Williams, Jennifer
Taggart, David
Cherqui, Stephanie
Sunderland, Ashley
Kartika, Yolanda D
Egnuni, Teklu
Brownlie, Rebecca J
Mathew, Ryan K
Holmen, Sheri L
Fife, Christopher
Droop, Alastair
Lorger, Mihaela
Hematopoietic Stem Cell Gene Therapy for Brain Metastases Using Myeloid Cell–Specific Gene Promoters
title Hematopoietic Stem Cell Gene Therapy for Brain Metastases Using Myeloid Cell–Specific Gene Promoters
title_full Hematopoietic Stem Cell Gene Therapy for Brain Metastases Using Myeloid Cell–Specific Gene Promoters
title_fullStr Hematopoietic Stem Cell Gene Therapy for Brain Metastases Using Myeloid Cell–Specific Gene Promoters
title_full_unstemmed Hematopoietic Stem Cell Gene Therapy for Brain Metastases Using Myeloid Cell–Specific Gene Promoters
title_short Hematopoietic Stem Cell Gene Therapy for Brain Metastases Using Myeloid Cell–Specific Gene Promoters
title_sort hematopoietic stem cell gene therapy for brain metastases using myeloid cell–specific gene promoters
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7301153/
https://www.ncbi.nlm.nih.gov/pubmed/31501884
http://dx.doi.org/10.1093/jnci/djz181
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