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Shortened ALK1 regulatory fragment maintains a specific activity in arteries feeding ischemic tissues

Gene Therapy volume 16, pages 1034–1041 (2009)Cite this article

Abstract

Specific transgene induction in angiogenic blood vessels has been in demand in gene therapies for several cardiovascular and malignant proliferative diseases in which the vasculature is an essential part of the disease process. In addition to improvements of delivery vehicles, promoters specific to angiogenic blood vessels have been sought for driving expression of the therapeutic gene. Earlier, we isolated a mouse activin receptor-like kinase 1 (Alk1; Acvrl1) transcriptional regulatory fragment that specifically induces transgene expression in newly forming and remodeling arteries in tumor and wound-healing lesions. For the purpose of gene therapy, however, this 9.2 kb regulatory fragment is too large to be incorporated into most viral transfer vectors. To bypass this limitation, highly conserved regions within the Alk1 gene were used to generate a shortened regulatory fragment. In transgenic mice, the shortened 4.8 kb Alk1PIB fragment showed comparable specificities in angiogenic and remodeling feeding arteries. In addition, the Alk1PIB fragment in a recombinant adenovirus vector showed transcriptional activity in cultured human iliac arterial endothelial cells (HIAECs). The Alk1PIB fragment may be used to target therapeutic protein expression in the feeding arteries to assist in the regeneration of ischemic tissues or to induce damages to the lesions, such as malignant tumors.

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Acknowledgements

We thank Dongkyoo Park, Fei Lan and Rumi Suzuki for technical assistance as well as Ms Rebecca Key and Dr Rhea–Beth Markowitz for editorial support. In addition, we appreciate the work of the University of Florida Shands Cancer Center Transgenic Core and the Medical College of Georgia Mouse Embryonic Stem Cell and Transgenesis Core Laboratories. This work was supported by an American Heart Association award (SDG 0435214N) to TS.

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  1. X Li and Y Yonenaga: These authors contributed equally to this work.

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  1. Department of Physiology, Medical College of Georgia, Augusta, GA, USA

    X Li, Y Yonenaga & T Seki

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  1. X Li
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Correspondence to T Seki.

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Li, X., Yonenaga, Y. & Seki, T. Shortened ALK1 regulatory fragment maintains a specific activity in arteries feeding ischemic tissues. Gene Ther 16, 1034–1041 (2009). https://doi.org/10.1038/gt.2009.53

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