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Characterizing the mechanism of action for mRNA therapeutics for the treatment of propionic acidemia, methylmalonic acidemia, and phenylketonuria.
Baek, Rena; Coughlan, Kimberly; Jiang, Lei; Liang, Min; Ci, Lei; Singh, Harkewal; Zhang, Hannah; Kaushal, Neeraj; Rajlic, Ivana Liric; Van, Linh; Dimen, Rain; Cavedon, Alexander; Yin, Ling; Rice, Lisa; Frassetto, Andrea; Guey, Lin; Finn, Patrick; Martini, Paolo G V.
Afiliación
  • 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.
Nat Commun ; 15(1): 3804, 2024 May 07.
Article en En | MEDLINE | ID: mdl-38714648
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.
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Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Fenilcetonurias / ARN Mensajero / Modelos Animales de Enfermedad / Acidemia Propiónica / Errores Innatos del Metabolismo de los Aminoácidos Límite: Animals / Female / Humans / Male Idioma: En Revista: Nat Commun Asunto de la revista: BIOLOGIA / CIENCIA Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos
Texto completo
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Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Fenilcetonurias / ARN Mensajero / Modelos Animales de Enfermedad / Acidemia Propiónica / Errores Innatos del Metabolismo de los Aminoácidos Límite: Animals / Female / Humans / Male Idioma: En Revista: Nat Commun Asunto de la revista: BIOLOGIA / CIENCIA Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos