1. A novel small molecule approach for the treatment of propionic and methylmalonic acidemias.
- Author
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Armstrong AJ, Collado MS, Henke BR, Olson MW, Hoang SA, Hamilton CA, Pourtaheri TD, Chapman KA, Summar MM, Johns BA, Wamhoff BR, Reardon JE, and Figler RA
- Subjects
- Acyl Coenzyme A metabolism, Amino Acid Metabolism, Inborn Errors genetics, Amino Acid Metabolism, Inborn Errors pathology, Carnitine metabolism, Cell Line, Citrates metabolism, Hepatocytes drug effects, Humans, Methylmalonyl-CoA Mutase deficiency, Propionic Acidemia genetics, Propionic Acidemia pathology, Amino Acid Metabolism, Inborn Errors drug therapy, Methylmalonyl-CoA Decarboxylase genetics, Methylmalonyl-CoA Mutase genetics, Propionic Acidemia drug therapy, Small Molecule Libraries pharmacology
- Abstract
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., Competing Interests: Conflict of interest The following authors have units of ownership in HemoShear Therapeutics, Inc.: Allison J Armstrong, Maria Sol Collado, Matthew W Olson, Stephen A Hoang, Christin A Hamilton, Brian A Johns, Brian R Wamhoff, John E Reardon, and Robert A Figler. Author, Kimberly A Chapman, is the PI on the HemoShear Therapeutics' sponsored HERO (Helping Reduce Organic Acids) Clinical Trial at Children's National Medical Center, Washington DC., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2021
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