A medical researcher in Colorado who has spent much of his career studying treatments for Parkinson’s disease believes he has a drug therapy that could halt Parkinson’s in its tracks.
Over a decade ago, Dr. Curt Freed and his team came to focus on a class of existing drugs called HDAC inhibitors after research identified a gene mutation that in rare cases triggers Parkinson's.
Freed bet that increasing the expression of the gene might protect brain cells, and tests on a variety of those drugs turned up phenylbutyrate as one that spurs the gene’s expression. Freed and his colleague Wenbo Zhou then developed a set of mice genetically programed to develop a Parkinson’s-like disease, and the team treated half of the mice with phenylbutyrate.
The treatment brought the advance of Parkinson’s to a halt.
“I think phenylbutyrate has a good chance of stopping the progression of Parkinson’s disease in humans,” said Freed, who heads the Division of Clinical Pharmacology and Toxicology at CU Health Sciences Center at Anschutz in Aurora.
Researchers began adding phenylbutyrate to the water of half the mice in their first year of life. In the second year, untreated mice showed progressive deterioration in movement much like the disease causes in human patients. But in the treated mice, the disease didn’t progress.
With that to work from, the CU team obtained a grant from the Michael J. Fox Foundation and carried out two short-term tests on humans to prove they could tolerate the drug. The short-term tests are usually followed by a yearlong “double-blind” study of a hundred Parkinson’s patients, where one group would receive phenylbutyrate and a second would get a placebo, to prove whether the drug stops the progress of Parkinson’s in humans.
It’s now been eight years since that short-term trial, and Freed has yet to secure the $10 million it would take to conduct the clinical study.
That’s not for want of trying.
Freed sought a grant through the National Institute of Neurological Disorders and Stroke. Although phenylbutyrate is already approved by the Food and Drug Administration (used to treat children with urea cycle disorder), the approval process involved reviews by separate National Institutes of Health entities that Freed says were daunting, and in 2020 he gave up on government funding.
Another route is a private foundation. The Michael J. Fox Foundation, which funded the earlier trials, hasn’t agreed to more. Responding to a query from The Denver Gazette, a spokeswoman said the foundation reviews over a thousand requests yearly and added that it holds Freed “in utmost respect.” She declined to detail why the foundation hadn't offered more funding.
Other foundations, pharmaceutical companies and venture capital groups have also taken a pass. Freed said double-blind studies are a difficult hurdle for a new drug.
“Phase II trials,” he said, “are called the Valley of Death because they’re where most Phase I trials go to die.”
Drugs targeted at neurological disorders are historically in the bottom quarter of all success rates and approval times, according to a study by the biotech trade association BIO. Freed doubts any company will fund a trial before a double-blind trial proves that phenylbutyrate actually halts Parkinson’s.
But Freed has little doubt that if successful, phenylbutyrate would be picked up by a pharmaceutical company for broader tests and would head to market. That would prove revolutionary for patients and their families, says Freed.
Close to a million Americans battle Parkinson’s disease — more than are afflicted with muscular dystrophy, multiple sclerosis and Lou Gehrig's disease combined. The progressive disorder first described by English surgeon James Parkinson in 1817 had no effective treatment whatsoever until levodopa was introduced in 1961. Sixty years later, levodopa is still the core Parkinson’s remedy, one that gradually loses potency. Dosages are increased as patients become more immobile, accompanied by waves of dyskinesia, or uncontrolled muscle movement, caused by fluctuations in the drug itself.
There’s a double irony in the hiatus of the new drug’s development. Unlike many potential treatments, phenylbutyrate is already FDA-certified for patients, saving a series of expensive, time-consuming tests. And it is already available as a consumable liquid, with much about its dosing already understood.
But there’s a Catch-22. The downside of being FDA-approved is that it has already been patented, and pharmaceutical investors like the added profitability of holding a patent.
“Big pharma companies would most like to develop a drug they already have a patent on,” said Freed — allowing them to tweak new variations.
Freed is a veteran researcher with plenty of experience working with the National Institutes of Health and the scientific review that accompanies medical advances. During the 1990s, he led a major effort at CU to test whether embryonic fetal tissues could be injected into the small, motor nerve center of the brain where Parkinson’s destroys nerve cells, to see if new neurons could replace those that were lost.
After early tests at CU and elsewhere were promising, Freed and neurosurgeon Robert Breeze led a trial surgery in 1994 on 61 patients with advanced Parkinson’s, including 40 who were part of a federally funded double-blind study. Half of those received actual cell implants, while the rest received a placebo surgery. Neither group knew which surgery they had received.
In 2001, The New York Times ran a front page story on early results from the trial, suggesting that patients who had received the actual injections were failing to report improvements, and that some were showing dyskinesia similar to what the levodopa drug sometimes creates in advanced patients.
The reaction to the story, Freed said, largely shut down research into cell transplants to treat Parkinson’s, although his team and other researchers continue to explore possibilities using new stem-cell technology and microsurgery. Bayer AG, Freed said, is testing a new cell line developed at Memorial Sloan Kettering Hospital in New York, specifically for transplants.
Although not an actual Parkinson’s “cure” in that it wouldn’t fix damage already done to motor functions, Freed said that if and when phenylbutyrate has a successful trial, patients who might begin using it early in their diagnosis could have dramatically improved outcomes as years advance. There is, he adds, no guarantee it would stop all of Parkinson’s degenerative effects, including ones unrelated to motor functions.