Exendin-4: From lizard to laboratory...and beyond
Throughout history, the natural world has served as a rich resource for compounds to treat human disease. For example, clay tablets from Mesopotamia dating from 2600 B.C.—humanity’s earliest written records—describe the healing powers of several plant species, including licorice, myrrh, and poppy capsule latex. More recently, penicillin and other lifesaving antibiotics have been developed from fungi, anti-cancer drugs paclitaxel and camptothecin have been derived from tree bark, and the powerful painkiller ziconotide has been synthesized from the venom of the sea-dwelling magical cone snail.
To this diverse catalog of natural sources for modern therapeutics we can add the unassuming Gila monster (Heloderma suspectum), a poisonous lizard found in New Mexico and Arizona. H. suspectum is long-lived but shy, spending up to 95 percent of its life underground. Encountering a Gila monster above ground can prove unpleasant. When it bites, its venom can cause pain and weakness but is rarely fatal to adult humans. And now, NIA scientists are using part of that same venom to develop promising new treatments for Alzheimer’s disease, diabetes, and other diseases common to older age.
The component of the Gila monster’s venom of greatest scientific interest is a peptide known as exendin-4. With the help of researchers in the NIA Intramural Research Program, investigators developed a synthetic form of the component—exenantide—which is now used to treat type 2 diabetes. Under the trade name Byetta®, exenatide is commonly prescribed to boost the effectiveness of patients’ primary diabetes treatment. (It is not prescribed for the less common type 1 diabetes, an autoimmune disease.) Today, scientists are testing exenatide as a possible intervention for Alzheimer’s disease.
Looking at lizards
Exendin-4 was uncovered in 1990 by endocrinologist Dr. John Eng at the Veterans Administration Center in the Bronx, NY. Dr. Eng was using chemical assays to identify new hormones and was intrigued by earlier NIH research showing that venom from certain snakes and lizards, including the Gila monster, caused enlargement of the pancreas, where insulin is synthesized. That research suggested that the compounds were somehow overstimulating the pancreas.
Dr. Eng’s interest was sparked when he learned that the Gila monster, after long periods of not eating, is able to slow down its metabolism and maintain constant blood sugar levels without affecting its health. He assayed the venom and discovered a peptide he called exendin that triggers synthesis and release of insulin from beta cells in the pancreas.
To his surprise, Dr. Eng found that exendin-4 was similar in both structure and function to GLP-1, a hormone found in the human pancreas that stimulates insulin production in the pancreas, but only when glucose production is high—for example, immediately after a meal. GLP-1 remains active in the body for about 2 minutes, but exendin-4 remains active for hours, suggesting that it could be a long-acting, effective diabetes treatment.
Examining a drug for another use
In the 1990s, NIA researcher Dr. Josephine Egan and colleagues teamed with Amylin Pharmaceuticals to begin preclinical testing of exendin-4. By 1999, they reported that a single daily injection of exendin-4 given to diabetic mice was sufficient to normalize blood glucose concentration, with benefits evident by the end of the first week of treatment. Dr. Egan and her collaborators later found that exendin-4 increased insulin production and protected the insulin-producing cells against damage in humans, and that its effects lasted for hours. After further clinical testing, it was deemed to be safe and effective, and it received FDA approval in 2005.
But the story doesn’t end there. While studying the effects of exendin-4 on the pancreas, Dr. Egan and her colleagues found that it also seemed to have beneficial effects on the brain. Specifically, GLP-1 stimulates the growth of neurites (developing neurons) in cell culture, and both GLP-1 and exendin-4 protect mature neurons against cell death. In fact, research increasingly suggests that there may be a link between some neurodegenerative disorders and metabolic dysfunction. The hope is that drugs, such as exendin-4, that enhance metabolic function may also be useful in the treatment of neurologic disease.
Building on these findings, Dr. Egan and others in the NIA Intramural Research Program have tested exendin-4 in cellular and mouse models of several neurodegenerative diseases. The results are promising. For example, using a mouse model of Huntington’s disease, they found that exendin-4 reduces the accumulation of the mutant huntingtin protein, which is implicated in the disease’s onset and progression. The treatment also improved motor function and extended the survival time of the Huntington's disease mice.
In other studies, investigators found that exendin-4 significantly reduced levels of amyloid beta protein (a hallmark of Alzheimer’s disease) and its precursor molecule in mice models of the disorder. It also proved beneficial in cellular and animal models of another neurodegenerative disorder, amyotrophic lateral sclerosis (ALS), or Lou Gehrig’s disease.
Alzheimer’s clinical trial now recruiting
NIA is now recruiting volunteers for a clinical trial of exendin-4 among older adults with either early-stage Alzheimer’s disease or mild cognitive impairment (MCI), which often leads to Alzheimer’s. Participants must be age 65 or older, have memory complaints, and live in the Baltimore area.
“We’re very excited about this study,” says lead investigator Dr. Dimitrios Kapogiannis. “The unexpected finding that exendin-4 has neuroprotective effects in animal models of various neurodegenerative diseases opens the door to testing this drug as a treatment for a number of devastating human diseases, such as Alzheimer’s.”
“I think the fact that we have been able to take this substance found in nature and consider applying it in such incredibly diverse ways—to treat diabetes, to possibly treat neurological disease—adds to the growing body of support for a link between the endocrine and nervous systems,” adds Dr. Egan. “This research also demonstrates a new way to think about therapeutics. Instead of ‘one drug, one disease,’ we should think of designing drugs that impact multiple diseases.”