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Translational Pharmacokinetic/Pharmacodynamic Model for mRNA-3927, an Investigational Therapeutic for the Treatment of Propionic Acidemia.
| Content Provider | Europe PMC |
|---|---|
| Author | Attarwala, Husain Lumley, Matthew Liang, Min Ivaturi, Vijay Senn, Joe |
| Copyright Year | 2023 |
| Abstract | Propionic acidemia (PA) is an ultrarare disorder caused by deficiency of the mitochondrial enzyme, propionyl-CoA carboxylase (PCC), composed of PCCA and PCCB subunits. An enzyme replacement therapy is being developed using dual messenger RNA (mRNA) therapy composed of lipid nanoparticles (LNPs) encapsulating mRNAs encoding PCCA and PCCB subunits of the PCC enzyme. We herein report on development of a translational semimechanistic pharmacokinetic (PK) and PK/pharmacodynamic (PD) model to quantify the relationship between the mRNA components of mRNA-3927 (an LNP encapsulating PCCA and PCCB mRNAs) and dose levels; PCCA/B mRNA PK and PD responses were assessed as circulating levels of primary disease markers 2-methyl citrate, 3-hydroxypropionate, and propionyl carnitine normalized to acetyl carnitine (C3/C2 ratio) to inform the first-in-human dose range and regimen selection. The translational PK/PD model was developed using preclinical data available in mice with PA, Sprague Dawley rats, and cynomolgus monkeys at dose levels ranging from 0.2 to 9 mg/kg. PCCA/B mRNA PK in mice, rats, and monkeys was adequately described using allometric scaling of volume and clearance parameters. The interspecies preclinical model was scaled allometrically to humans to predict the dose–response relationship in adult and pediatric patients with PA to guide selection of dose range and regimen for the Phase 1 clinical trial (ClinicalTrials.gov Identifier NCT04159103). |
| Related Links | https://europepmc.org/backend/ptpmcrender.fcgi?accid=PMC10066765&blobtype=pdf |
| Page Count | 7 |
| ISSN | 21593337 |
| Volume Number | 33 |
| DOI | 10.1089/nat.2022.0036 |
| PubMed Central reference number | PMC10066765 |
| Issue Number | 2 |
| PubMed reference number | 36577040 |
| Journal | Nucleic Acid Therapeutics [Nucleic Acid Ther] |
| e-ISSN | 21593345 |
| Language | English |
| Publisher | Mary Ann Liebert, Inc., publishers |
| Publisher Date | 2022-12-27 |
| Publisher Place | USA |
| Access Restriction | Open |
| Rights License | This Open Access article is distributed under the terms of the Creative Commons License [CC-BY] (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © Husain Attarwala et al., 2023; Published by Mary Ann Liebert, Inc. |
| Subject Keyword | propionic acidemia propionyl-CoA carboxylase mRNA therapy lipid nanoparticles |
| Content Type | Text |
| Resource Type | Article |
| Subject | Genetics Drug Discovery Molecular Biology Biochemistry Molecular Medicine |
