Using Statins to Prevent Heart Conditions in Friedrich's Ataxia

According to new research published in PLOS One from the Perelman School of Medicine at the University of Pennsylvania (Penn), a widely-used cholesterol-lowering drug increased a precursor of high-density lipoprotein (HDL) in models that mimicked liver cells of patients with Friedrich’s ataxia (FA).

The study, “Low apolipoprotein A-I levels in Friedrich’s ataxia and in frataxin-deficient cells: Implications for therapy,” showed that decreased levels of HDL, commonly referred to as “good cholesterol,” and apoliprotein are often associated with an increased risk of death from cardiomyopathy and heart failure.

Senior author Ian Blair, PhD, a professor of Systems Pharmacology and Translational Therapeutics had been working in biomarkers when he was approached in 2014 to work as a part of a collaboration being formed between Penn and the Children’s Hospital of Philadelphia (CHOP) — The Penn Medicine/CHOP Friedrich’s Ataxia Center of Excellence.

“The elephant in the room, and the easiest thing to work on was frataxin, the protein missing in Friedrich’s ataxia,” said Blair in an interview with Rare Disease Report. “That seemed like the easiest approach; if frataxin is down, and we can make it go up, that’s obviously the best way for us to try and cure the disease.”

In individuals with FA, the frataxin protein is produced in amounts inadequate for the proper functionality of the mitochondria. This occurs because of a mutation in the FXN gene, which results in decreased expression of frataxin, which is typically found in the mitochondria of cells and is heavily involved in biochemical reactions that generate energy.

“We also found the FA patients had serum ApoA-I levels that were lower than healthy control subjects,” Blair continued. Using a highly specific and sensitive assay, Blair and David Lynch, MD, PhD, a professor of Neurology at CHOP, found a 22% decrease in ApoA-I in the blood of FA patients in comparison to blood samples from non-affected healthy individuals.

The pair found that statins could possess the ability to assist FA patients increase their naturally low ApoA-I levels, thus increasing their HDL levels and potentially preventing heart disease. Using an experimental FA cell line, they also discovered that cells without frataxin produced lower levels of ApoA-I compared to controls. The cholesterol-lowering drug simvastatin, however, increased the ApoA-I levels by 20% in these cells.

“I think that our findings provide compelling evidence for a trial of statins in FA patients to potentially reduce their cardiovascular risk,” Blair said in an article in Penn Medicine News. He did note, however, that one potential issue is that increased doses of statins are associated with myositis and rhabdomyolysis, so it would be critical to vigilantly monitor these side effects.

Additionally, co-administration of coenzyme Q10 supplement could help lower the risk of muscle-related side effects.

It was concluded in the study that the ApoA-I levels did not correlate with trinucleotide (GAA) repeat length. Therefore, it will be important in the future to evaluate frataxin levels in FA cases to determine whether there is a threshold level required for optimal ApoA-I secretion.

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