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

Autor: Baek R; Moderna, Inc., 200 Technology Square, Cambridge, MA, 02139, USA., Coughlan K; Moderna, Inc., 200 Technology Square, Cambridge, MA, 02139, USA., Jiang L; Moderna, Inc., 200 Technology Square, Cambridge, MA, 02139, USA., Liang M; Moderna, Inc., 200 Technology Square, Cambridge, MA, 02139, USA., Ci L; Moderna, Inc., 200 Technology Square, Cambridge, MA, 02139, USA., Singh H; Moderna, Inc., 200 Technology Square, Cambridge, MA, 02139, USA., Zhang H; Moderna, Inc., 200 Technology Square, Cambridge, MA, 02139, USA., Kaushal N; Moderna, Inc., 200 Technology Square, Cambridge, MA, 02139, USA., Rajlic IL; Moderna, Inc., 200 Technology Square, Cambridge, MA, 02139, USA., Van L; Moderna, Inc., 200 Technology Square, Cambridge, MA, 02139, USA., Dimen R; Moderna, Inc., 200 Technology Square, Cambridge, MA, 02139, USA., Cavedon A; Moderna, Inc., 200 Technology Square, Cambridge, MA, 02139, USA., Yin L; Moderna, Inc., 200 Technology Square, Cambridge, MA, 02139, USA., Rice L; Moderna, Inc., 200 Technology Square, Cambridge, MA, 02139, USA., Frassetto A; Moderna, Inc., 200 Technology Square, Cambridge, MA, 02139, USA., Guey L; Moderna, Inc., 200 Technology Square, Cambridge, MA, 02139, USA. Lin.Guey@modernatx.com., Finn P; Moderna, Inc., 200 Technology Square, Cambridge, MA, 02139, USA. Patrick.Finn@modernatx.com., Martini PGV; Moderna, Inc., 200 Technology Square, Cambridge, MA, 02139, USA. Paolo.Martini@modernatx.com.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2024 May 07; Vol. 15 (1), pp. 3804. Date of Electronic Publication: 2024 May 07.
DOI: 10.1038/s41467-024-47460-9
Abstrakt: 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.
(© 2024. The Author(s).)
Databáze: MEDLINE
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