A novel small molecule approach for the treatment of propionic and methylmalonic acidemias

Propionic Acidemia (PA) and Methylmalonic Acidemia (MMA) are inborn errors of metabolism affecting the catabolism of valine, isoleucine, methionine, threonine and odd-chain fatty acids. These are multi-organ disorders caused by the enzymatic deficiency of propionyl-CoA carboxylase (PCC) or methylmal...

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Veröffentlicht in:Molecular genetics and metabolism Jg. 133; H. 1; S. 71 - 82
Hauptverfasser: Armstrong, Allison J., Collado, Maria Sol, Henke, Brad R., Olson, Matthew W., Hoang, Stephen A., Hamilton, Christin A., Pourtaheri, Taylor D., Chapman, Kimberly A., Summar, Marshall M., Johns, Brian A., Wamhoff, Brian R., Reardon, John E., Figler, Robert A.
Format: Journal Article
Sprache:Englisch
Veröffentlicht: United States Elsevier Inc 01.05.2021
Schlagworte:
Acyl Coenzyme A - metabolism
Amino Acid Metabolism, Inborn Errors - drug therapy
Amino Acid Metabolism, Inborn Errors - genetics
Amino Acid Metabolism, Inborn Errors - pathology
Carnitine - metabolism
Cell Line
Citrates - metabolism
Hepatocytes - drug effects
Humans
Methylmalonic acidemia
Methylmalonyl-CoA Decarboxylase - genetics
Methylmalonyl-CoA Mutase - deficiency
Methylmalonyl-CoA Mutase - genetics
Propionic acidemia
Propionic Acidemia - drug therapy
Propionic Acidemia - genetics
Propionic Acidemia - pathology
Small Molecule Libraries - pharmacology
Methylmalonic acidemia
Propionic acidemia
ISSN:1096-7192, 1096-7206, 1096-7206
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Zusammenfassung:Propionic Acidemia (PA) and Methylmalonic Acidemia (MMA) are inborn errors of metabolism affecting the catabolism of valine, isoleucine, methionine, threonine and odd-chain fatty acids. These are multi-organ disorders caused by the enzymatic deficiency of propionyl-CoA carboxylase (PCC) or methylmalonyl-CoA mutase (MUT), resulting in the accumulation of propionyl-coenzyme A (P-CoA) and methylmalonyl-CoA (M-CoA in MMA only). Primary metabolites of these CoA esters include 2-methylcitric acid (MCA), propionyl-carnitine (C3), and 3-hydroxypropionic acid, which are detectable in both PA and MMA, and methylmalonic acid, which is detectable in MMA patients only (Chapman et al., 2012). We deployed liver cell-based models that utilized PA and MMA patient-derived primary hepatocytes to validate a small molecule therapy for PA and MMA patients. The small molecule, HST5040, resulted in a dose-dependent reduction in the levels of P-CoA, M-CoA (in MMA) and the disease-relevant biomarkers C3, MCA, and methylmalonic acid (in MMA). A putative working model of how HST5040 reduces the P-CoA and its derived metabolites involves the conversion of HST5040 to HST5040-CoA driving the redistribution of free and conjugated CoA pools, resulting in the differential reduction of the aberrantly high P-CoA and M-CoA. The reduction of P-CoA and M-CoA, either by slowing production (due to increased demands on the free CoA (CoASH) pool) or enhancing clearance (to replenish the CoASH pool), results in a net decrease in the CoA-derived metabolites (C3, MCA and MMA (MMA only)). A Phase 2 study in PA and MMA patients will be initiated in the United States.
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A.A, S.C., B.H., M.O., B.J, B.W., J.R., R.F. designed research and discussed results. A.A. supervised the project and wrote the paper. B.H. and J.R. conceived the original idea. S.H. analyzed the data. C.H. and T.P. carried out the experiments and contributed to the interpretation of the results. K.C. and M.S. reviewed and advised the project. All authors provided critical feedback and helped shape the research, analysis and manuscript.
Author Contributions
ISSN:1096-7192
1096-7206
1096-7206
DOI:10.1016/j.ymgme.2021.03.001