Along with promising clinical findings from a Phase 2 clinical trial (NCT03917225), the results support the use of leriglitazone, and the general strategy of activating PPAR gamma, as a treatment for FA.
FA is a progressive disease in which reduced levels of the mitochondrial protein frataxin result in defects in iron metabolism and abnormalities in mitochondria, the powerhouses of cells.
PPAR gamma is a transcription factor that regulates the expression of multiple genes in cells. Among other functions, it is a regulator of mitochondrial signaling and functioning. As such, “using [PPAR gamma activators] may be an appealing therapeutic approach [for FA]” the researchers wrote.
Leriglitazone, also known as MIN-102, is a selective activator of PPAR gamma that is orally available and able to pass through the blood-brain barrier — the semi-permeable barrier separating the brain from harmful substances circulating in the blood — and enter into the central nervous system.
Now, researchers at Minoryx and elsewhere have tested the investigational compound in various cell and animal models of FA. Also, two of the researchers have filed a patent application for the use of the investigational compound as described in the study.
In rat neurons engineered to express low amounts of frataxin, treatment with leriglitazone significantly increased frataxin levels, by 48%. The treatment also increased survival of these cells by 44% and decreased signs of neuronal problems, such as loss of nerve filaments. Mitochondrial function was better after leriglitazone treatment.
Notably, similar increases in frataxin levels were not observed in cardiomyocytes, or heart muscle cells, lacking the protein, suggesting that “the effect of leriglitazone on frataxin levels was cell-type dependent,” the researchers wrote.
But the treatment led to other improvements in cardiomyocytes, the team noted. While heart muscle cells lacking frataxin had an abnormal accumulation of lipid droplets, a type of cellular structure where fat molecules (lipids) are stored, leriglitazone reduced the accumulation of these droplets by 42%.
The researchers then tested leriglitazone treatment on an established mouse model of FA. Mice were given the compound in their food at a concentration of 0.06% (equivalent to 50 mg/kg/day). Other mice, serving as controls, were untreated.
These animals normally exhibit progressive motor deficits, but leriglitazone significantly improved the mice’s performance on a balance test.
On two other tests of motor function — the rotarod test and the pole test — leriglitazone had no significant impact. However, when the researchers calculated an overall motor score based on a combination of all three tests, leriglitazone treatment significantly improved motor function.
The researchers also used leriglitazone to treat human skin cells (fibroblasts) from people with and without FA. Regardless of disease status, the treatment increased frataxin levels significantly, and it also increased levels of several proteins known to promote mitochondrial function, such as PGC-1α.
“In the present study we have demonstrated that across several models leriglitazone rescues cellular, biochemical and behavioural features of frataxin deficiency,” the investigators concluded. “Given the widely varying features of these models, these results confirm that leriglitazone represents a potential therapeutic agent.”
Leriglitazone is being evaluated in people with FA in the FRAMES Phase 2 clinical trial, which already has shown the treatment can increase frataxin levels, reduce iron overload in nerve cells, improve mitochondrial function and energy metabolism, and prevent disease progression in FA patients.
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