Sustained release Exendin-4 Reduces Neurodegeneration in Parkinson’s Rat Model, Study Shows
The study, “Post-treatment with PT302, a long-acting Exendin-4 sustained release formulation, reduces dopaminergic neurodegeneration in a 6-Hydroxydopamine rat model of Parkinson’s disease,” was published in Scientific Reports.
Parkinson’s disease is a chronic and progressive neurodegenerative disorder, mainly caused by the gradual loss of dopaminergic neurons in the substantia nigra, a region of the brain responsible for movement control.
Exendin-4, a peptide that activates the glucagon-like peptide-1 (GLP-1) receptor, is a hormone originally discovered in the saliva of the Gila monster. Previous studies have already shown that pre-treatment with exendin-4 significantly reduced dopaminergic neurodegeneration.
These promising results led researchers to propose GLP-1 receptor agonists as a new treatment option for several neurodegenerative diseases, including Parkinson’s, Alzheimer’s, Huntington’s, traumatic brain injury, stroke, and peripheral neuropathy.
However, the use of exendin-4 to treat patients with Parkinson’s has been severely hampered by the medication’s short half-life.
As a result, investigators at Peptron developed a new sustained release formulation of exenatide (marketed as Byetta and Bydureon) — a synthetic version of exendin-4 — called PT302, that extends the medication’s lifetime in the body.
“We are proud to apply our decades of experience in developing sustained-release therapeutics to the great unmet medical need of millions of people around the world who suffer from Parkinson’s disease,” Ho-Il Choi, PhD, CEO and director of Peptron, said in a press release.
In this preclinical study, researchers tested the effectiveness of PT302 in a rat model of Parkinson’s disease. First, they observed that a single under-the-skin administration of PT302 was able to sustain the levels of exendin-4 in the plasma of adult rats for more than 20 days.
Then, to determine a clinically relevant dose within this range, rats received PT302 once every two weeks, either before or following a lesion performed on one side of the brain. Remarkably, pre- and post-treatment with PT302 successfully reduced methamphetamine-induced rotation, a measure of brain lesion severity, after lesioning.
Post-lesion treatment with PT302 significantly increased brain tyrosine hydroxylase immunoreactivity (TH-IR) — a readout of dopaminergic neurons’ activity — in the substantia nigra and striatum on the lesioned side of the brain. Moreover, researchers found a direct correlation between the levels of exendin-4 in the plasma and TH-IR in the lesioned substantia nigra and striatum.
These findings indicate that post-treatment with PT302 sustains the levels of exendin-4 for longer periods of time and reduces neurodegeneration of dopaminergic neurons in a rat model of Parkinson’s disease at a clinically relevant dose.
“The peer-review and publication of this data is an important step in confirming the ability of our novel SR-exenatide drug to cross the blood-brain barrier and deliver long-acting therapeutic effects of the neuroprotective peptide. We are looking forward to beginning our Phase 2 clinical trial in Parkinson’s disease and advancing a novel therapeutic that could fight neurodegeneration,” Choi said.