Novel Drug Therapies of Mitochondrial Fatty Acid β-Oxidation Disorders: Current Focus and Hope

Al-Walid Mohsen^1,2, Peter Wipf³, Jerry Vockley^1,2
¹Division Medical Genetics, Department Pediatrics, University of Pittsburgh, Pittsburgh, PA, USA; ²Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA, USA; ³Department of Chemistry, University of Pittsburgh, Pittsburgh, PA, USA

Fatty acid β-oxidation (FAO) is the major source of energy during times of physiologic stress and is especially critical for heart and skeletal muscle. FAO disorders are a major cause of human disease causing mitochondrial dysfunction and collectively represent the most frequent metabolic disorders in newborns worldwide. Deficiencies of FAO enzymes are often lethal, if diagnosis and treatment are delayed. Symptoms include hypoketotic hypoglycemia, Reye-like syndrome, arrhythmias, cardiomyopathy, and/or rhabdomyolysis. Current treatment protocols are inadequate, and patients are still at risk for cardiomyopathy and muscular symptoms, with significant morbidity and mortality. Therefore, we are developing a series of novel therapies to address the biochemical abnormalities. We present results of our FAOD therapies in development, and discuss prospects of implementation into clinical practice.
Drugs under development can be categorized as follows:
Chaperones for stabilizing protein and lipid. These include trimetazidine (TMZ) to treat of VLCAD, MCAD, LCHAD, and LCKAT deficiencies, phenylbutyrate to treat MCADD, and a cardiolipin stabilizing peptide to treat LCHAD and TFP deficiencies.
Mitochondrial-targeted ROS electron scavengers. These include JP4-039 and XJB-5-131. FAODs increase mitochondrial ROS levels that apparently impair a variety of mitochondrial functions including OXPHOS, as well as inducing inflammation. Both drugs reduce ROS levels and improve OXPHOS function in cells from patients with VLCAD, LCHAD, or ACAD9 deficiencies.
Protein expression enhancers. PPARδ agonists enhance the production of defective FAO proteins and their levels of activity. Our preliminary data show that a TMZ/PPARδ combination treatment has a superior effect compared to treatment with either alone.
Anaplerotic agents. We have designed a variety of novel anaplerotic agents that enter the TCA cycle directly and improve energy production in long chain FAODs. These agents would additionally provide benefit for methylmalonic or propionic acidemias. Their role is to alleviate the tertiary deficiency of biochemical intermediates exhausted as a result of the enzymatic block.
Conclusion: Changes in key biochemical markers suggest that damaging biochemical abnormalities in FAODs can be remedied by additional therapies. Our novel drugs with known pharmacodynamics have proven in vitro efficacy, and so provide the impetus to bring them to clinical trials expediently.

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