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VEGFA mRNA for regenerative treatment of heart failure

Nature Reviews Drug Discovery volume 21, pages 79–80 (2022)Cite this article

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The recent successful development of COVID-19 vaccines using mRNA technology clearly shows the great potential for this novel modality. In addition to prophylactic mRNA vaccines for infectious diseases and therapeutic mRNA vaccines for cancer, there is substantial interest in mRNA therapeutics. The first potential ‘secreted protein’ mRNA drug — designed to deliver vascular endothelial growth factor A (VEGF-A) to induce regenerative angiogenesis in patients with cardiovascular disease — was advanced into phase I trials in 2016 (NCT02935712) (Mullard, A. mRNA-based drug approaches phase I milestone. Nat. Rev. Drug Discov. 15, 595 (2016))1. Here, we highlight the history and clinical development of this agent (known as AZD8601), with the aim of providing insights that may be useful for the further development of mRNA therapeutics.

VEGF-A has long been recognized as a potential vascular and proliferative regenerative therapeutic in patients with ischaemic heart disease2,3. However, unlocking its therapeutic potential has been confounded by the challenges of the relatively short half-life of the systemically administrated protein, side effects from chronic long-term exposure and the delivery challenges to the intact heart in vivo to achieve the desired therapeutic threshold.

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Fig. 1: Development timeline for VEGFA mRNA.

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Authors and Affiliations

  1. Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden

    Anna Collén, Leif Carlsson, Li-Ming Gan & Regina Fritsche-Danielson

  2. Alliance Management, Business Development, BioPharmaceuticals R&D, AstraZeneca, Boston, MA, USA

    Nils Bergenhem

  3. Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden

    Kenneth R. Chien

  4. Moderna Inc., Cambridge, MA, USA

    Stephen Hoge

  5. Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden

    Li-Ming Gan

  6. Department of Cardiology, Sahlgrenska University Hospital, Gothenburg, Sweden

    Li-Ming Gan

Authors
  1. Anna Collén
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  2. Nils Bergenhem
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  3. Leif Carlsson
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  4. Kenneth R. Chien
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  5. Stephen Hoge
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  6. Li-Ming Gan
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  7. Regina Fritsche-Danielson
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Corresponding author

Correspondence to Anna Collén.

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Competing interests

A.C., N.B., L.-M.G. and R.F.-D. are employees of AstraZeneca and may own stock or stock options. S.H. is an employee of Moderna, Inc. and holds stock or stock options. K.R.C. is an advisor and chair of the External Science Panel for AstraZeneca and a member of the Karolinska Institutet/AstraZeneca Integrated Cardio Metabolic Center in Huddinge, and receives support for these services, as well as research support through the Karolinska Institutet Center. He is also a co-founder and equity holder of Moderna, Inc.

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Collén, A., Bergenhem, N., Carlsson, L. et al. VEGFA mRNA for regenerative treatment of heart failure. Nat Rev Drug Discov 21, 79–80 (2022). https://doi.org/10.1038/s41573-021-00355-6

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