Understanding molecular mechanisms in propionic acidemia and investigated therapeutic strategies

作者：Richard Eva; Perez Belen; Perez Cerda Celia; Desviat Lourdes R

来源：Expert Opinion on Orphan Drugs, 2015, 3(12): 1427-1438.

DOI：10.1517/21678707.2015.1092380

• anaplerotic therapy
• antioxidants
• antisense oligonucleotides
• ataluren
• propionic acidemia
• readthrough drugs
• RNA therapies

Introduction: Propionic acidemia (PA), one of the most frequent, life-threatening organic acidemias, is caused by mutations in either the PCCA or PCCB genes, encoding both subunits of the mitochondrial propionyl-CoA carboxylase (PCC) enzyme. PCC catalyzes a key step in the catabolism of several amino acids, cholesterol side chain and odd-chain fatty acids. Advances in supportive treatment based on dietary restriction and carnitine supplementation have allowed patients to live beyond the neonatal period. However, natural progression of PA leads to intellectual deficits, and increased risk for neurological, gastrointestinal and cardiac complications. Secondary mitochondrial dysfunction and associated oxidative stress potentially contribute to the pathophysiology.Areas covered: Important issues in gene therapy approaches must be addressed before translation into the clinic. The observed favorable response to antioxidant agents in patients' fibroblasts opens the possibility of antioxidant treatment in PA. Investigational therapies targeting specific mutation types (readthrough drugs, antisense oligonucleotides and chaperones) hold promise but are still in the preclinical stage.Expert opinion: Progression into the clinical stage of mutation-specific therapies is limited by lack of adequate cellular/animal models, sensitive biomarkers and drug testing methods as well as by the low number of patients amenable to be treated with each drug.

• 出版日期2015-12-2