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Roxadustat (FG-4592) accelerates pulmonary growth, development, and function in a compensatory lung growth model

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Abstract

Children with hypoplastic lung disease associated with congenital diaphragmatic hernia (CDH) continue to suffer significant morbidity and mortality secondary to progressive pulmonary disease. Current management of CDH is primarily supportive and mortality rates of the most severely affected children have remained unchanged in the last few decades. Previous work in our lab has demonstrated the importance of vascular endothelial growth factor (VEGF)-mediated angiogenesis in accelerating compensatory lung growth. In this study, we evaluated the potential for Roxadustat (FG-4592), a prolyl hydroxylase inhibitor known to increase endogenous VEGF, in accelerating compensatory lung growth. Treatment with Roxadustat increased lung volume, total lung capacity, alveolarization, and exercise tolerance compared to controls following left pneumonectomy. However, this effect was likely modulated not only by increased VEGF, but rather also by decreased pigment epithelium-derived factor (PEDF), an anti-angiogenic factor. Furthermore, this mechanism of action may be specific to Roxadustat. Vadadustat (AKB-6548), a structurally similar prolyl hydroxylase inhibitor, did not demonstrate accelerated compensatory lung growth or decreased PEDF expression following left pneumonectomy. Given that Roxadustat is already in Phase III clinical studies for the treatment of chronic kidney disease-associated anemia with minimal side effects, its use for the treatment of pulmonary hypoplasia could potentially proceed expeditiously.

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Abbreviations

CKD:

Chronic kidney disease

CLG:

Compensatory lung growth

DMSO:

Dimethyl sulfoxide

H&E:

Hematoxylin and eosin

HIF:

Hypoxia inducible factor

IPF:

Idiopathic pulmonary fibrosis

PBS:

Phosphate-buffered saline

PBST:

Phosphate-buffered saline with 0.5% Triton-X

PEDF:

Pigment-epithelial derived factor

PHD:

Prolyl hydroxylase

POD:

Post-operative day

P-VEGFR2:

Phosphorylated-vascular endothelial growth factor receptor 2

TBST:

Tris-buffered saline and Tween 20

TLC:

Total lung capacity

VEGF:

Vascular endothelial growth factor

VEGFR2:

Vascular endothelial growth factor receptor 2

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Acknowledgements

Research funding is provided by the Boston Children’s Hospital Surgical Foundation and the Vascular Biology Program at Boston Children’s Hospital, the National Institutes of Health Grants 5T32HL007734 (DTD), the Corkin and Maher Family Fund (PDM), and the Neurodevelopmental Behavior Core of Boston Children’s Hospital (CHB IDDRC – 1U54HD090255).

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Authors and Affiliations

  1. Vascular Biology Program, Boston Children’s Hospital, Harvard Medical School, Boston, MA, 02115, USA

    Victoria H. Ko, Lumeng J. Yu, Duy T. Dao, Xiaoran Li, Jordan D. Secor, Lorenzo Anez-Bustillos, Bennet S. Cho, Amy Pan, Hiroko Kishikawa & Mark Puder

  2. Department of Surgery, Boston Children’s Hospital, Harvard Medical School, 300 Longwood Ave, Fegan 3, Boston, MA, 02115, USA

    Victoria H. Ko, Lumeng J. Yu, Duy T. Dao, Xiaoran Li, Jordan D. Secor, Lorenzo Anez-Bustillos, Bennet S. Cho, Amy Pan, Hiroko Kishikawa & Mark Puder

  3. Institutional Centers for Clinical and Translational Research, Boston Children’s Hospital, Boston, MA, 02115, USA

    Paul D. Mitchell

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Correspondence to Mark Puder.

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The authors MP and DTD have submitted a patent for the use of Roxadustat in promoting lung growth.

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Ko, V.H., Yu, L.J., Dao, D.T. et al. Roxadustat (FG-4592) accelerates pulmonary growth, development, and function in a compensatory lung growth model. Angiogenesis 23, 637–649 (2020). https://doi.org/10.1007/s10456-020-09735-9

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