2. Academic Validation
  3. Revolutionizing Heart Failure Therapy: Harnessing IVT mRNA and Fusion Protein Technology to Prolong rhBNP Half-Life

Revolutionizing Heart Failure Therapy: Harnessing IVT mRNA and Fusion Protein Technology to Prolong rhBNP Half-Life

  • Pharm Res. 2025 Jan;42(1):137-149. doi: 10.1007/s11095-024-03807-x.
Yingyu Guo 1 2,  Tianhan Sun 2 3,  Mengyao Li 2,  Ziwei Chen 1 2 4,  Ye Liu 2 4,  Xuanmei Luo 2 4,  Yuan Chen 2 4,  Yayu Li 2 4,  Lu Kuai 2 4,  Xue Yu 5,  Lihui Zou 6 7
Affiliations

Affiliations

  • 1 Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
  • 2 The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology of National Health Commission, No.1 Dahua Road, Dongdan, Beijing, 100730, P.R. China.
  • 3 Department of General Surgery, Department of Hepato-Bilio-Pancreatic Surgery, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, P.R. China.
  • 4 Clinical Biobank, Beijing Hospital, National Center of Gerontology, National Health Commission, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China.
  • 5 Department of Cardiology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, No.1 Dahua Road, Dongdan, Beijing, 100730, PR China. yuxue2652@bjhmoh.cn.
  • 6 Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China. zoulihui4371@bjhmoh.cn.
  • 7 The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology of National Health Commission, No.1 Dahua Road, Dongdan, Beijing, 100730, P.R. China. zoulihui4371@bjhmoh.cn.
PMID: 39806211 DOI: 10.1007/s11095-024-03807-x
Abstract

Purpose: Recombinant human B-type natriuretic peptide (rhBNP) has been extensively proven to be an effective mean of heart failure (HF) therapy, but its clinical application is limited by its very short half-life. This study aims to combine in vitro transcribed mRNA (IVT mRNA) and fusion protein technology to develop a rhBNP-Fc mRNA drug with long half-life, high efficiency and few side effects to treat HF.

Methods: The rhBNP-Fc fusion mRNA with IgG4-Fc sequence was produced by IVT technology. rhBNP-Fc mRNA was transfected into HEK293T cells to examine the expression in vitro. rhBNP-Fc mRNA encapsulated in LNP was injected into normal mice to detect the translation efficiency, half-life and negative effects in vivo. Finally, it was injected into doxorubicin-induced HF mice to screen the cardiac protective effect.

Results: The rhBNP-Fc fusion mRNA extended the half-life of rhBNP, showing sustained expression in cell line for at least one day. rhBNP-Fc mRNA translation showed dose-dependent levels, and was still detectable 5 d after injection in vivo. In the HF mouse model, a single administration of rhBNP-Fc mRNA-LNP improved cardiac function, including improving heart ejection and reducing HF biomarkers expression. Additionally, rhBNP-Fc mRNA-LNP treatment mitigated myocardial damage, normalized cardiomyocyte structure, and reduced the levels of pro-inflammatory cytokines.

Conclusion: The rhBNP-Fc mRNA has the potential to serve as an alternative to traditional protein therapies, thereby reducing clinical dosages, injection frequencies, and treatment costs. Our findings offer new insights into the development and application of mRNA drugs, emphasizing their therapeutic potential in long-acting drugs.

Keywords

in vitro transcribed mRNA; B-type natriuretic peptide; fusion protein; heart failure; protein replacement therapy.

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