Pharmacological screening in a fly cardiac model of Friedreich’s ataxia (FA) identified 11 potentially protective compounds. The two most promising are the anti-inflammatory Azulfidine (sulfasalazine) and the antidepressant Luvox (fluvoxamine), according to the researchers.
The study “Identification of cardioprotective drugs by medium-scale in vivo pharmacological screening on a Drosophila cardiac model of Friedreich’s ataxia” was published in the journal Disease Models & Mechanisms.
Several compounds have been or currently are being tested for FA treatment, including antioxidants, iron chelators (which bind to iron) and molecules that increase frataxin protein levels, which typically are reduced in FA patients. However, to date, no therapeutic strategy has shown sustained clinical improvement.
Cardiomyopathy, or heart muscle disease, is the leading cause of death in FA. It involves left ventricular (LV) hypertrophy (enlargement), diffuse fibrosis, or scarring, and cell death in the heart muscle, which may develop into systolic dysfunction (referring to impaired ventricular contraction).
Prior pharmacological screens of treatment candidates have used mouse and yeast cells, revealing diverse active compounds on the function of mitochondria (cells’ power plants). Of note, frataxin is a mitochondrial protein, where its deficiency leads to impaired energy production and hypersensitivity to oxidative stress.
However, assessing the ability of new compounds to improve cardiac function in FA would benefit from animal models for in vivo screening. Although the muscle creatine kinase (MCK) mouse model of FA has enabled the evaluation of potential therapies, it does not allow for the testing of a large number of molecules. Such screening is possible in fly models, which generally consist in lower expression of the fh gene, which encodes the fly frataxin.
The team from Université Paris Diderot, in France, previously developed a fly FA cardiac model, with specific fh inactivation in the heart. This model shows heart dilatation and impaired systolic function (similar to FA patients), both successfully treated by administration with human frataxin.
Using these flies, the investigators screened 1,280 small molecules, all approved by the U.S. Food and Drug Administration (FDA), European Medicines Agency (EMA) or other agencies, and with known bioavailability — the proportion of a compound reaching the circulation and able to have an effect — and safety in humans.
The results showed that 11 compounds significantly reduced cardiac dilatation (as assessed by cardiac imaging), three of which with known effects on the cardiovascular system. In turn, five worsened (increased) cardiac dilatation and were specific to frataxin deficiency as they did not induce alterations in control flies.
The compound providing the strongest protection was paclitaxel, a chemotherapy medication known as Taxol, which also improved the heart’s contractility. Paclitaxel, a compound that stabilizes microtubules — hollow rods responsible for cellular shape and transport within cells — has been tested in studies of myocardial infarction and neurodegenerative diseases, the researchers observed.
Also, the researchers noted that both paclitaxel and methylene blue (MB) — a compound known for its protective effect on cardiac dysfunction — eased structural defects in cardiomyocytes (the heart muscle’s cells).
Given paclitaxel’s toxicity, the team does not regard it as a treatment candidate for FA. However, it provides valuable information of mechanisms involved in FA cardiomyopathy, the investigators said.
Though with smaller effects than paclitaxel and MB, the two compounds with greater potential for future investigations in FA are the anti-inflammatory Azulfidine, used for rheumatoid arthritis, ulcerative colitis and Crohn’s disease, and Luvox, an antidepressant that eases mitochondrial dysfunction, the researchers considered.
“This study may, in the future, lead to therapeutic applications and improves our knowledge of the mechanisms involved in cardiac dysfunction associated with FA,” the team wrote. “This type of approach could therefore be extended in the future to a wide panel of cardiac diseases,” the scientists added.