Exenatide increased frataxin protein in mouse brains, patient-derived neurons, and modestly in a pilot human trial, showing promise for this untreatable neurodegenerative disease.
3 evidence levelsmouse, iPSC, and human pilot data all showing exenatide increases frataxin — the missing protein in Friedreich ataxia
What the researchers found
The study tested exenatide across three levels of evidence:
In frataxin-deficient mice, exenatide improved glucose handling through enhanced insulin content and secretion. More importantly, it induced frataxin protein and iron-sulfur cluster-containing proteins in both pancreatic beta cells and brain tissue. It was also protective to sensory neurons in dorsal root ganglia, the neurons that die in Friedreich ataxia.
In patient-derived induced pluripotent stem cells (iPSCs) differentiated into beta cells and sensory neurons, GLP-1 analogs induced frataxin expression, reduced oxidative stress, and improved mitochondrial function.
In a pilot human trial, Friedreich ataxia patients treated with exenatide for 5 weeks showed modest frataxin induction in platelets. While modest, this is the first demonstration that a GLP-1 drug can increase frataxin in actual patients.
The mechanism involves GLP-1 receptor (incretin receptor) activation, identifying this receptor as a new therapeutic target for Friedreich ataxia.
Why it matters
Friedreich ataxia has no treatment to slow disease progression. It affects about 1 in 50,000 people and causes progressive loss of coordination, heart disease, and diabetes. Finding that an already-approved drug (exenatide) can increase the deficient protein (frataxin) and improve the fundamental cellular defect (mitochondrial dysfunction) is a significant breakthrough that could lead to clinical trials.
The numbers in context
Frataxin induced in brain and beta cells; oxidative stress reduced in iPSC neurons; modest platelet frataxin increase in 5-week pilot; JCI Insight
How the study worked
Multi-level study: frataxin-deficient mouse models (in vivo), patient iPSC-derived beta cells and sensory neurons (in vitro), and a pilot clinical trial in Friedreich ataxia patients (5 weeks of exenatide treatment with platelet frataxin measurements). Published in JCI Insight.
Who was studied
Frataxin-deficient mice; patient iPSC-derived neurons and beta cells; Friedreich ataxia patients (pilot trial)
What this study cannot tell us
The pilot trial was very small and short (5 weeks). Platelet frataxin is a surrogate marker that may not reflect brain frataxin levels. The frataxin induction in patients was described as "modest." Mouse models of Friedreich ataxia do not perfectly replicate human disease. Whether the frataxin increase is sufficient to slow neurodegeneration is unknown.
How to read the evidence
Moderate evidence. Consistent findings across mouse, cell, and human studies, though the pilot trial was very small and short with modest results.
When this study was published
Published in 2020 in JCI Insight. Larger clinical trials of GLP-1 drugs in Friedreich ataxia may be underway.
The bigger picture
Friedreich ataxia has no disease-modifying treatment. Finding that an already-approved drug (exenatide) can boost the deficient protein across multiple evidence levels accelerates the path to clinical trials significantly compared to developing a new drug from scratch.
Questions still open
- Would longer exenatide treatment produce larger frataxin increases?
- Do platelet frataxin levels reliably reflect brain frataxin changes?
- Could higher GLP-1 drug doses achieve more clinically meaningful frataxin induction?
Common questions
What is Friedreich ataxia?
Could someone with Friedreich ataxia take exenatide now?
Read the original research
Exenatide induces frataxin expression and improves mitochondrial function in Friedreich ataxia.
JCI insight, 5(2)
Citation
Igoillo-Esteve, Mariana; Oliveira, Ana F; Cosentino, Cristina; Fantuzzi, Federica; Demarez, Céline; Toivonen, Sanna; Hu, Amélie; Chintawar, Satyan; Lopes, Miguel; Pachera, Nathalie; Cai, Ying; Abdulkarim, Baroj; Rai, Myriam; Marselli, Lorella; Marchetti, Piero; Tariq, Mohammad; Jonas, Jean-Christophe; Boscolo, Marina; Pandolfo, Massimo; Eizirik, Décio L; Cnop, Miriam. (2020). Exenatide induces frataxin expression and improves mitochondrial function in Friedreich ataxia.. JCI insight, 5(2). https://doi.org/10.1172/jci.insight.134221