Structural Insights into Drug Therapy of FAODs

Al-Walid Mohsen1,2*, PhD, Anuradha Karunanidhi1, MS, Catherine Kochersperger1, MS,

Areeg Al-Gharabawy1, MD, Bianca Seminotti1,3, PhD, Guilhian Leipnitz1,3, PhD, MSc,

Peter Wipf4, PhD, Jerry Vockley1,2, MD, PhD.

1Division of Medical Genetics, Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA, USA, 2Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA, USA, 3Department of Bioq, ICBS, UFRGS, Porto Alegre, RS, Brazil, 4 Department Chemistry, University of Pittsburgh, Pittsburgh, PA, USA

*aam27@pitt.edu, +1 412-692-6498

Mitochondrial fatty acid b-oxidation disorders (FAODs) collectively represent the most frequent metabolic disorders at a worldwide frequency of ~1/10,000 of newborns. Most patients with FAODs in the US are identified through NBS. FAO is an essential source of energy for cardiac (80% of energy requirement) and skeletal muscles and is more critical during times of fasting or physiological stress. Symptoms of long-chain FAODs include fasting or stress-related hypoketotic hypoglycemia, cardiac conduction abnormalities, arrhythmias, cardiomyopathy, muscle weakness, and stress-induced rhabdomyolysis. Current treatment protocols are focused on alleviating acute symptoms by IV glucose infusion and L-carnitine. Long-term therapy involves preventing hypoglycemia and replenishing carnitine stores. Medium-chain triglycerides (MCT) can bypass the need for the long chain FAO in some of the diseases, but patients are still at risk for symptoms including late onset cardiomyopathy. Triheptanoin is effective in treating hypoglycemia and cardiomyopathy and improves, but doesn’t eliminate, muscle symptoms, and significant morbidity and mortality persist. Thus, there is continued need for therapeutic agents to treat/prevent the heterogeneous pathological symptoms caused by FAODs. Accordingly, we have been developing a series of candidate drugs that address various aspects of the cellular pathophysiology induced by various FAODs.

Methods: Biochemical pathway analysis, molecular modeling, cell enzyme presence and activity, and mitochondrial energetics and metabolite analyses were performed to assess the potential use of various drug therapies on alleviating the phenotypes of FAODs.

Results: Drugs under development in our lab are categorized under four classes:

  1. Protein and lipid stabilizing chaperones: These include trimetazidine for the treatment of VLCAD, MCAD, LCHAD, and LCKAT deficiencies, phenylbutyrylglycerol, for the treatment of MCAD, and a cardiolipin binding peptide, for the treatment of LCHAD and TFP deficiencies.
  2. Mitochondrial-targeted ROS electron scavengers: These include JP4-039. FAODs increase intra-mitochondrial levels of reactive oxygen species (ROS) that is hypothesized to impair a variety of important mitochondrial functions including oxidative phosphorylation (OXPHOS) and induces inflammation. JP4-039 reduces ROS levels and improve OXPHOS function in cells from patients with VLCAD, LCHAD, and ACAD9 deficiencies.
  • Protein expression enhancers: Transcription activators of nuclear encoded mitochondrial genes, PPARd agonists, enhance the production of defective FAO proteins and levels of activity.
  1. Anaplerotic agents: We have designed a variety of novel anaplerotic agents that function similarly to triheptanoin but enter the TCA cycle directly. Anaplerotic compounds can potentially be therapeutic not only in long chain FAODs but for methylmalonic acidemia and propionic acidemia. Their role is meant to alleviate the tertiary deficiency of specific biochemical intermediates exhausted as a result of the enzymatic block.

Conclusion: Changes in key biochemical markers suggest that some of the damaging biochemical abnormalities in FAODs can be remedied by additional therapeutic agents. Since the severity of the disease is genotype-dependent, a personalized therapeutic regime will likely be considered. Our comprehensive approach using these novel drugs with known pharmacodynamics and showing efficacy in vitro provides the impetus to bring these drugs to clinical trials soon.

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