Exenatide Therapy Increases Key Frataxin Protein Levels, Study Finds

Exenatide, a drug that mimics the effects of the gut hormone GLP-1, increased the levels of frataxin — a protein involved in iron metabolism, whose deficiency leads to Friedreich’s ataxia (FA) — in a mouse model of the disease, a new study shows.

Treatment with exanatide also improved the function both of mitochondria, the powerhouses of cells, and insulin-producing beta-cells, which play an important role in regulating glucose (sugar) metabolism in the body.

The study, “Exenatide induces frataxin expression and improves mitochondrial function in Friedreich ataxia,” was published in the journal JCI Insight.

Friedreich’s ataxia is caused by a mutation in the frataxin (FXN) gene. This gene provides instructions for making a protein called frataxin, which is essential for mitochondria — the cell compartments responsible for energy production — to work properly.

Lack of frataxin in FA patients disrupts the mitochondria’s energy production, leading to the accumulation of free iron and to the production of large amounts of harmful molecules called reactive oxygen species. These reactive oxygen species damage and kill cells — a condition known as oxidative stress.

Nerve cells in the muscles and central nervous system — composed of the brain and spinal cord — are easily affected by the resulting lack of energy, which is the reason behind many manifestations of FA, such as gait instability, lack of coordination, and involuntary movements.

Further, most people with FA develop diabetes or glucose intolerance (pre-diabetes) due to the impairment in function and death of pancreatic beta-cells — cells in the pancreas responsible for the production of the hormone insulin.

Glucagon-like peptide-1 (GLP-1) is a gut hormone secreted in response to food intake, other hormones, and neurotransmitters, which are molecules involved in nerve cell communication.

GLP-1 analogs, which mimic the effects of the hormone, were developed to treat diabetes. They include exenatide, sold as Byetta by AstraZeneca for type 2 diabetes in adults, among other trade names. These analogs bind to receptors on beta-cells, stimulating the production and release of insulin, and preventing these cells from being destroyed.

Previous studies have shown that exenatide can reduce oxidative stress, as well as the death of insulin-producing beta-cells and neurons lacking frataxin cultured in a lab dish.

The aim of this study was to further assess the effects of exenatide in different animal models of FA, as well as in human patients with the disease.

To start, the investigators randomly selected mice with FA and healthy (wild-type, WT) mice to be fed for a period of 15 weeks with either a normal or a high-fat diet. High-fat diets induce metabolic stress and can cause glucose intolerance. After the first 15 weeks, the animals again were randomly assigned to receive either exenatide or an innocuous solution (control) for 12 weeks.

The results showed that exenatide did not alter insulin sensitivity — the sensitivity of cells in response to insulin — in any of the animals. However, it did improve glucose tolerance, or the cells’ ability to absorb and process glucose (sugar), in both WT and FA mice.

In addition, exenatide improved the function of beta-cells in FA mice fed with both diets — although this improvement was not found in the WT animals. Later testing of the animals’ pancreases confirmed that exenatide increased the levels and secretion (release) of insulin only in sick animals.

The researchers then assessed the effects of exenatide on the levels of frataxin in key areas of the brain commonly affected in FA — the cerebrum and cerebellum — as well as in the heart and pancreas.

Treatment with exenatide increased the levels of frataxin in the cerebrum and cerebellum of FA mice, but not in WT animals, the results showed. However, it did not have any effect in the pancreas or in the heart of any of the animals.

Following the testing in animals, the researchers examined exenatide’s effects on human cells. To that end, they first created induced pluripotent stem cells (iPSCs) — fully matured cells that can be reprogrammed back to a stem cell state, where they are able to grow into any type of cell — using skin cells from a 26-year-old FA patient.

The iPSCs were then differentiated into both beta-cells and sensory neurons. Treatment with exenatide for 72 hours (three days) led to a mild, but significant, increase in the levels of frataxin in beta-cells.

The exenatide therapy also reduced oxidative stress and increased the production of adenosine triphosphate (ATP) — a small molecule used as “fuel” (energy) by all cells in the body — in patient-derived sensory neurons. This supports its exenatide’s therapeutic effect in mitochondrial function.

Next, the researchers tested the effects of exenatide and liraglutide — another GLP-1 analog — in an open-label pilot trial. The study enrolled 16 FA patients who did not have diabetes. Participants received treatment with liraglutide or exenatide for five weeks, followed by a four-week washout period.

The main goal was to assess whether GLP-1 analogs would be able to raise the levels of frataxin in the participants’ peripheral blood mononuclear cells (PBMCs) and platelets. PBMCs are immune blood cells, namely lymphocytes, monocytes, and dendritic cells.

The trial also tested the treatments’ safety and tolerability. The secondary goal of the study was to assess changes in clinical rating scales.

As expected, the levels of frataxin, both at the RNA (the template cells use to make proteins) and protein level, were reduced in PBMCs and platelets from FA patients compared with the healthy individuals (controls).

Treatment with exenatide resulted in a modest increase in frataxin protein levels in platelets. However, in PBMCs, exenatide did not alter protein levels. It did, however, significantly increase frataxin RNA levels. Technical issues prevented the researchers from assessing the levels of frataxin in patients treated with liraglutide.

No changes in the Scale for the Assessment and Rating of Ataxia, the Inventory of Non-Ataxic Symptoms, and the Activities of Daily Living scale scores were seen following treatment with either of the GLP-1 analogs.

There were no serious side effects identified in the trial. The most frequent side effects were nausea and a reduced appetite. Further, treatment with the GLP-1 analogs resulted in an average 1.5 kg (about 3.3 pounds) weight loss, but this was regained following the washout period.

“Our preclinical and clinical data indicate that GLP-1 analogs are beneficial for frataxin-deficient β cells and neurons. They improve β cell function, reduce oxidative stress, and improve mitochondrial function of FRDA [Friedreich’s ataxia] patient sensory neurons, possibly, but not exclusively, through a frataxin-inducing effect,” the researchers said.

“These data provide a strong rationale for the design of a long-term clinical trial to assess the disease-modifying effect of GLP-1 analogs in patients with FRDA,” they concluded.