Biomarkers for drug development in propionic and methylmalonic acidemias. Issue 2 (26th January 2022)

• Record Type: Journal Article
• Authors: Longo, Nicola; Sass, Jörn Oliver; Jurecka, Agnieszka; Vockley, Jerry
• Is Part Of: Journal of inherited metabolic disease. Volume 45:Issue 2(2022)
• Page Start: 132
• Page End: 143
• Publication Date: 2022-01-26
• Subjects: biomarker -- clinical trials. -- methylmalonic acidemia -- pathophysiology -- propionic acidemia -- surrogate endpoint; Metabolism, Inborn errors of -- Periodicals; Metabolism -- Disorders -- Periodicals; 616.39042
• DOI: 10.1002/jimd.12478
• Languages: English
• ISSNs: 0141-8955

Abstract

Abstract: 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 13 C‐propionate (exhaled 13 CO2 ), 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. Abstract :