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Characterizing the mechanism of action for mRNA therapeutics for the treatment of propionic acidemia, methylmalonic acidemia, and phenylketonuria

Author

Listed:
  • Rena Baek

    (Inc.)

  • Kimberly Coughlan

    (Inc.)

  • Lei Jiang

    (Inc.)

  • Min Liang

    (Inc.)

  • Lei Ci

    (Inc.)

  • Harkewal Singh

    (Inc.)

  • Hannah Zhang

    (Inc.)

  • Neeraj Kaushal

    (Inc.)

  • Ivana Liric Rajlic

    (Inc.)

  • Linh Van

    (Inc.)

  • Rain Dimen

    (Inc.)

  • Alexander Cavedon

    (Inc.)

  • Ling Yin

    (Inc.)

  • Lisa Rice

    (Inc.)

  • Andrea Frassetto

    (Inc.)

  • Lin Guey

    (Inc.)

  • Patrick Finn

    (Inc.)

  • Paolo G. V. Martini

    (Inc.)

Abstract

Messenger RNA (mRNA) therapeutics delivered via lipid nanoparticles hold the potential to treat metabolic diseases caused by protein deficiency, including propionic acidemia (PA), methylmalonic acidemia (MMA), and phenylketonuria (PKU). Herein we report results from multiple independent preclinical studies of mRNA-3927 (an investigational treatment for PA), mRNA-3705 (an investigational treatment for MMA), and mRNA-3210 (an investigational treatment for PKU) in murine models of each disease. All 3 mRNA therapeutics exhibited pharmacokinetic/pharmacodynamic (PK/PD) responses in their respective murine model by driving mRNA, protein, and/or protein activity responses, as well as by decreasing levels of the relevant biomarker(s) when compared to control-treated animals. These preclinical data were then used to develop translational PK/PD models, which were scaled allometrically to humans to predict starting doses for first-in-human clinical studies for each disease. The predicted first-in-human doses for mRNA-3927, mRNA-3705, and mRNA-3210 were determined to be 0.3, 0.1, and 0.4 mg/kg, respectively.

Suggested Citation

  • Rena Baek & Kimberly Coughlan & Lei Jiang & Min Liang & Lei Ci & Harkewal Singh & Hannah Zhang & Neeraj Kaushal & Ivana Liric Rajlic & Linh Van & Rain Dimen & Alexander Cavedon & Ling Yin & Lisa Rice , 2024. "Characterizing the mechanism of action for mRNA therapeutics for the treatment of propionic acidemia, methylmalonic acidemia, and phenylketonuria," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-47460-9
    DOI: 10.1038/s41467-024-47460-9
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    References listed on IDEAS

    as
    1. Lei Jiang & Ji-Sun Park & Ling Yin & Rodrigo Laureano & Eric Jacquinet & Jinsong Yang & Shi Liang & Andrea Frassetto & Jenny Zhuo & Xinhua Yan & Xuling Zhu & Steven Fortucci & Kara Hoar & Cosmin Mihai, 2020. "Dual mRNA therapy restores metabolic function in long-term studies in mice with propionic acidemia," Nature Communications, Nature, vol. 11(1), pages 1-10, December.
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