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

Autor:	Andreou T; School of Medicine, University of Leeds, Leeds, UK., Rippaus N; School of Medicine, University of Leeds, Leeds, UK., Wronski K; School of Medicine, University of Leeds, Leeds, UK., Williams J; School of Medicine, University of Leeds, Leeds, UK., Taggart D; School of Medicine, University of Leeds, Leeds, UK., Cherqui S; Department of Pediatrics, University of California San Diego, CA., Sunderland A; School of Medicine, University of Leeds, Leeds, UK., Kartika YD; School of Medicine, University of Leeds, Leeds, UK., Egnuni T; School of Medicine, University of Leeds, Leeds, UK., Brownlie RJ; School of Medicine, University of Leeds, Leeds, UK., Mathew RK; School of Medicine, University of Leeds, Leeds, UK.; Department of Neurosurgery, Leeds Teaching Hospitals NHS Trust, Leeds, UK., Holmen SL; Huntsman Cancer Institute, University of Utah, Salt Lake City, UT., Fife C; School of Medicine, University of Leeds, Leeds, UK., Droop A; Leeds Institute for Data Analytics, University of Leeds, Leeds, UK., Lorger M; School of Medicine, University of Leeds, Leeds, UK.
Jazyk:	angličtina
Zdroj:	Journal of the National Cancer Institute [J Natl Cancer Inst] 2020 Jun 01; Vol. 112 (6), pp. 617-627.
DOI:	10.1093/jnci/djz181
Abstrakt:	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. (© The Author(s) 2019. Published by Oxford University Press.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu