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Biomarkers for drug development in propionic and methylmalonic acidemias

  • There is an unmet need for the development and validation of biomarkers and surrogate endpoints for clinical trials in propionic acidemia (PA) and methylmalonic acidemia (MMA). This review examines the pathophysiology and clinical consequences of PA and MMA that could form the basis for potential biomarkers and surrogate endpoints. Changes in primary metabolites such as methylcitric acid (MCA), MCA:citric acid ratio, oxidation of 13C-propionate (exhaled 13CO2), and propionylcarnitine (C3) have demonstrated clinical relevance in patients with PA or MMA. Methylmalonic acid, another primary metabolite, is a potential biomarker, but only in patients with MMA. Other potential biomarkers in patients with either PA and MMA include secondary metabolites, such as ammonium, or the mitochondrial disease marker, fibroblast growth factor 21. Additional research is needed to validate these biomarkers as surrogate endpoints, and to determine whether other metabolites or markers of organ damage could also be useful biomarkers for clinical trials of investigational drug treatments in patients with PA or MMA. This review examines the evidence supporting a variety of possible biomarkers for drug development in propionic and methylmalonic acidemias.

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Document Type:Article
Author:Nicola Longo, Jörn Oliver Sass, Agnieszka Jurecka, Jerry Vockley
Parent Title (English):Journal of Inherited Metabolic Disease
First Page:132
Last Page:143
Publishing Institution:Hochschule Bonn-Rhein-Sieg
Date of first publication:2022/01/17
Copyright:© 2022 BridgeBio. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License.
Funding:Jonathan Latham of PharmaScribe, LLC received a grant from CoA Therapeutics to provide medical writing support. JV was supported in part by NIH grant R01 DK.109907.
Keyword:biomarker; clinical trials; methylmalonic acidemia; pathophysiology; propionic acidemia; surrogate endpoint
Departments, institutes and facilities:Fachbereich Angewandte Naturwissenschaften
Institut für funktionale Gen-Analytik (IFGA)
Dewey Decimal Classification (DDC):6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Entry in this database:2022/01/26
Licence (German):License LogoCreative Commons - CC BY-NC - Namensnennung - Nicht kommerziell 4.0 International