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INDIGO’s new MitoVir platform provides novel approach to evaluating mitochondrial toxicity
STATE COLLEGE, Pa.—Various clinical studies involving antiviral compounds have recently been paused or ended because of mitochondrial toxicity, such as that which led to the observation of hepatotoxicity during clinical trials of the antiviral drug candidate fialuridine aimed at hepatitis B. According to INDIGO Biosciences, some of these efforts might have fared better if the companies had been able to use its MitoVir Platform, a series of assays to evaluate mitochondrial toxicity by examining inhibition of the ribonucleoside triphosphates that are substrates for the human mitochondrial RNA polymerase (POLRMT).
The platform's origins come out of research conducted by Dr. Jamie Arnold, Dr. Craig Cameron and their colleagues at Pennsylvania State University, demonstrating that antiviral drugs may not only enter into viral RNA, but also into healthy mitochondrial RNA.
After nucleoside reverse transcriptase inhibitors (NRTIs) enter a cell, for example, the NRTIs and their phosphorylated metabolites partition between the cytoplasm and mitochondria facilitated by nucleoside and nucleotide transporters, INDIGO notes. In mitochondria, many triphosphorylated NRTIs serve as substrates for the mitochondrial DNA polymerase gamma.
"The cellular mitochondria that are responsible for making ATP are affected by these compounds, which is why we see adverse side effects," Cameron said, noting that some individuals are more sensitive to the effects of antiviral drugs. "We hope this method will prevent adverse events in the clinic, at least until prescreening of patients to identify those with mitochondrial diseases becomes a part of the process."
The use of MitoVir was discussed in a journal article for which Arnold served as lead, which was titled "Sensitivity of Mitochondrial Transcription and Resistance of RNA Polymerase II Dependent Nuclear Transcription to Antiviral Ribonucleosides" and appeared in the Nov. 15, 2012, issue of in the journal PLOS Pathogens.
As noted in the article, maintenance, replication and expression of the mitochondrial genome (mtDNA) is absolutely essential for cell function because mtDNA encodes 13 proteins required for oxidative phosphorylation, as well as the tRNAs and rRNAs essential to their production.
"However, cells have far more mtDNA than required to support oxidative phosphorylation; therefore, a substantial reduction in mtDNA copy number is required for manifestation of a clinically apparent phenotype," the authors noted. "Therefore, adverse effects of drugs that interfere with replication and/or expression of mtDNA may not be readily apparent in mammalian cells or animal models on the timescale of preclinical testing. In addition, because mammalian cell lines are often grown in high concentrations of glucose, oxidative phosphorylation is not necessarily required for ATP production in cells, the so called Crabtree effect."
Under these conditions, according to the authors, even severe mitochondrial dysfunction would have little to no impact on intracellular ATP levels.
The MitoVir Platform includes three assays: ATP production, mitochondrial RNA production and POLRMT activity, and INDIGO President and CEO Jack Vanden Heuvel says of them, "We now have a method of predicting adverse side effects to antiviral drugs in the safety of a laboratory setting, rather than in clinical trials where patients may be placed at risk. We're certain this will be a significant advance in the development of this important class of antiviral compounds."