This article is Part 2 of a two-part series.
Because Huntington’s disease is so devastating and intractable, many affected individuals and presymptomatic gene carriers like me have chosen to take substances outside the pharmaceutical mainstream to try to forestall the inevitable onset or worsening of symptoms.
The reason: 26 years after the discovery of the huntingtin gene, despite significant progress in understanding the disease, there is no effective therapy or cure.
In Part 1 of this series, Robert Pacifici, Ph.D., the chief scientific officer for CHDI Foundation, Inc., discussed the immense progress made in HD research and the optimistic prospects for developing therapies. CHDI is the largest nonprofit effort aimed at defeating HD.
Only two drugs addressing symptoms of HD have been approved by the U.S. Food and Drug Administration (FDA) – Xenazine in 2008 and the similar, improved drug Austedo in 2017. Both treat the involuntary movements in HD (chorea) but do not attack the causes or halt progression of this fatal disorder. (Click here to read more.)
Physicians also prescribe medications – nonspecific for HD – to alleviate the difficult behavioral and psychiatric symptoms. Those drugs also have no effect on progression.
Trying supplements
My mother died of HD in 2006 at age 68. As I desperately witnessed the disease’s inexorable onslaught on her mind and body, I embarked on a controversial “treatment now” program of unproven but certainly not quackish supplements, the Huntington’s Disease Drug Works (HDDW) regimen developed by veteran HD physician LaVonne Goodman, M.D.
Starting in 2005, I introduced the supplements into my diet in steps. I worked up to a daily routine in which I took 75 grams of trehalose, a sugar that seems to help the brain clear cellular debris; 600 mg of medical-grade coenzyme Q-10 (which I had taken on and off since 1996); two g of omega-3 oil; two g of blueberry extract; and ten g of medical-grade creatine. (Click here to read more.)
For several years I participated as a subject in an HDDW online observational study, performing cognitive tests on a home computer. In this very small study, several early or midstage HD-affected people showed stabilization or improvement. Late-stage patients did less well, continuing to progress with the disease. The study was too small for its results to be applicable to the general HD population. (Click here to read more.)
I was the only presymptomatic gene carrier in the trial. Afterwards, I continued the regimen on my own, but regularly consulted with Dr. Goodman.
In 2014, I stopped coenzyme Q-10 and creatine after clinical trials proved them ineffective. Recently, in place of expensive high-grade omega-3 pills, I’m eating more fish. Annually, I’ve spent thousands of dollars on supplements – none covered by health insurance.
I have also sought to lead a healthy lifestyle, including intellectual and social enrichment. Doctors and researchers encourage this and have pointed out that it could be part of why I have long passed my mother’s age of onset, although there is no scientific proof (Click here to read more).
The HDDW program and the clinical trials for coenzyme Q-10 and creatine were the most formal testing of supplements. HD-affected individuals have tried and/or discussed a range of other substances, including injections of live fetal shark cells, the amino acid cysteine, medical marijuana, and the highly popular – but potentially harmful – marijuana and hemp extract cannabidiol (CBD), usually by drinking an oil.
Above, CBD products in a Los Angeles, CA, grocery store (photo by Deceptitom [CC BY-SA 4.0 {https://creativecommons..org/licenses/by-sa/4.0}]). Below, the supplements I have taken (photo by Gene Veritas, aka Kenneth P. Serbin)
One group of advocates has also pushed for a clinical trial of methylene blue, a dye under study as a possible way to alleviate a variety of medical conditions.
One group of advocates has also pushed for a clinical trial of methylene blue, a dye under study as a possible way to alleviate a variety of medical conditions.
In our recent interview, Dr. Pacifici and I delved into whether CHDI and the HD community are failing to defeat the disease by ignoring these types of alternative approaches, including so-called “natural” remedies and repurposed drugs. The video of our interview is posted at the end of this article.
HD-specific drugs needed
Citing the increased interest in HD in the pharmaceutical industry (discussed in Part 1), Dr. Pacifici said that CHDI would assist any company aiming to test an HD drug, as long as it’s safe, tolerable, and backed with enough resources to do a careful clinical trial.
“It’s wonderful that there’s this diversity of folks that have assets and try and come into the field, as long as they’re credible and well-thought-out,” he said.
However, because of HD’s genetic cause and complexity, CHDI has stressed that drugs for halting disease progression must be “new chemical entities” and HD-specific.
Dr. Pacifici pointed to an example: difficulties with sleep, a serious symptom of HD. The HD field must consider: “What are the things that are probably going to happen out there anyway, because there’s a big market for sleep medications versus the things that are very specific to HD, that if we don’t do them, they’re not going to get done?”
Don’t expect to win the jackpot
The need for unique HD drugs, and the overall history of drug discovery, point to the fact that so-called “natural” approaches and repurposing of other drugs will not result in effective treatments, Dr. Pacifici asserted.
The alleviation of Dr. Pacifici’s own suffering from familial Mediterranean fever (FMF, discussed in Part 1) resulted from the discovery of the drug colchicine, “a natural thing from the crocus flower” already in use to treat gout. Such a scenario is atypical, he explained.
“Obviously, I didn’t just win the Lotto,” Dr. Pacifici said. “I won the Mega Millions with the fact that I happen to be treated by an existing drug. It’s pretty rare.”
The HD community should not expect such an outcome, he said.
“Obviously the thing that’s wonderful when that does happen is that there’s no path that’s shorter from a discovery to a treatment,” he continued. “But the effect has to be pretty overwhelming.”
Indeed, colchicine “completely stopped” the recurrent abdominal pain and fever of FMF.
“You can imagine,” he said, “that observation’s a little harder to make in Huntington’s disease, given the slow progression of the disease, given the myriad of symptoms.”
Is ‘natural’ better?
The notion of “natural” products is a bit “artificial,” Dr. Pacifici pointed out.
“People, first of all, seem to think that something that’s ‘natural’ is better,” he said. “There are plenty of horrible poisons like ricin that are natural, and if you take them, they kill you. It’s ‘organic,’ and it’s ‘natural.’ That doesn’t mean it’s good for you!”
We discussed a clinical trial for an eye disease using liquid from the resin of the mastic tree from the Greek island of Chios, as reported by New York Times columnist Frank Bruni. For thousands of years, people have used the resin to address many types of health problems. The trial seeks to test whether the liquid can repair damaged nerves in the eye, with potentially positive implications for people with Alzheimer’s disease and other neurological conditions.
Dr. Pacifici said that, in such a study, scientists need to know the exact chemical makeup of the substance and, in the case of a possible HD treatment, determine whether that makeup is any different from other compounds CHDI has tested.
In the case of the mastic tree, scientists also need to ensure that weather conditions and the conditions of the tree do not alter the makeup of the resin. Also, the testing of the substance needs to be “reproducible,” he explained.
That the compound in the liquid comes from a natural source is irrelevant, he added, because scientists can produce such compounds in a lab.
Clinical trials are expensive, costing hundreds of millions of dollars, Dr. Pacific observed. Ultimately, CHDI and HD researchers need to avoid “taking empty shots on goal that we could have predicted up front had no chance of working.”
Millions of experiments
Not long after its founding in 2003, CHDI did a project to ensure that the HD field did not miss a possible remedy among existing drugs and other substances, some of them natural. According to Dr. Pacifici, the foundation worked with a small firm that had a library of all FDA-approved drugs and also substances such as vitamins and other generally safe items, including some shown to be safe and tolerable in Phase 1 clinical trials.
“We tested all of those,” Dr. Pacifici recalled, referring to the entire library. “In fact, we tested all of those at multiple concentrations. In fact, we tested all of those at multiple concentrations with each other, in pairwise fashion [two drugs at a time].”
Carried out in cells, the tests ran into the millions, he said.
“But we found nothing that suggested, ‘Yeah, there’s the Mega Millions hit or combination of things that should go forward,'” he said.
The massive experiment confirmed the need for a unique, HD-specific type of medicine that could be delivered to the brain safely over a long period of time, thus attacking the specific problems caused by the disease, Dr. Pacifici observed.
Through Enroll-HD, the CHDI-sponsored global study of HD-affected individuals and their families, CHDI tracks unusual data from visits to HD clinics that might suggest follow-up to discover further clues for developing drugs.
The CBD ‘craze’
As a September 29 CNN documentary reported, in the United States production and use of CBD for health reasons has boomed in the last six years. The unregulated proliferation of CBD-containing products such as tinctures, foods, and oils has left the public with little reliable information on the risks, including items with harmful impurities.
“The CBD craze that we’re in, I think, is unprecedented really in the history of medicine,” Donald Abrams, M.D., a leading cannabis researcher, said in the broadcast. “It’s a compound that has gotten way ahead of any research to support the claims that are being made.”
Dr. Pacifici, who’s studied the issue closely, echoed these concerns. Tetrahydrocannabinol (THC), CBD, and other marijuana-based compounds are “enjoying their moment in the sun” because of legalization for recreational and medical use in some states, although not federally, he observed. “It’s kind of the flavor of the month, if you will.”
Only one approved CBD drug
CBD is a “real compound,” he explained.
However, there is only one FDA-approved drug made from CBD, Epidiolex, manufactured by the British firm GW Pharmaceuticals. Epidiolex was shown to be safe and efficacious in the treatment of two types of childhood epilepsy.
GW Pharmaceuticals had to run “through the same paces as any other drug substance,” Dr. Pacifici remarked. “They happened to get it out of the marijuana plant. That’s fine. I don’t care where it comes from. But it’s highly purified and highly quantified so that they know exactly what’s in there and what’s not in there and the purity of it.”
No other CBD product has been tested in a clinical trial.
In Dr. Pacifici’s view, because of the lack of quality control and regulatory approval in the making of CBD products, a critical question remains: “Are people who are experimenting with it actually getting real, pure CBD?” In some cases, the products do not even contain CBD, or have an incorrect concentration.
CBD not yet tested for HD
Could CBD potentially treat Huntington’s disease?
“The short answer is, we don’t know,” he asserted. “I can’t tell you of the number of fantastic ideas that I’ve had. Wonderful ideas, that I sit down, I think, ‘I’ve had this eureka moment.’ Until you test it, and you find out that biology is more complicated than you thought.”
Scientists, he said, know about CBD’s “pharmacology” – its function, effects, and where it gets into the body. “Is it something that could potentially have a beneficial effect? Sure. But has it been properly tested, especially in HD? Absolutely not.”
Many researchers are currently focusing on CBD for HD, and they have developed some very reasonable hypotheses, he said.
“To my mind, none of them, yet, have reached a level of evidence where somebody wants to go spend a hundred million dollars or more on a trial to see if it’s actually efficacious,” he said. “Maybe they will.”
Insufficient evidence on methylene blue
Regarding methylene blue, Dr. Pacifici observed that research is currently insufficient, “so I don’t think any of us can say definitively that it will work or it won’t work.”
“Isolated examples” show that it might be efficacious, but that’s not enough “evidence to actually run a full-blown human clinical trial,” he explained.
Produced by HD community members in 2016, The Blue Solution video suggests that families can consult their doctors about methylene blue.
However, Dr. Pacifici cautioned against this approach.
“A lot of times people have said things like, ‘Well, as long as it doesn’t do anything bad, why not take it,’” he remarked. “I think that’s a little bit dangerous. First of all, you never really know whether or not something is safe and well-tolerated until it’s tested.
“There are examples of opportunity costs. There are people who were on Co-Q 10 who were not allowed to participate in other, real trials because they were loaded up with Co-Q 10. So, the idea that ‘it’s probably safe, and I’ll take it in case it is good,’ I wouldn’t certainly advise somebody to go just based on that limited amount of evidence.”
Diet and lifestyle
I asked Dr. Pacifici why so little research has focused on HD and diet and whether it should.
“It doesn’t surprise me that people are curious about this,” he said, citing the example of Lorenzo’s Oil, a nutrition-based treatment developed for adrenoleukodystrophy, a deadly genetic brain disorder rarer than HD.
“In fact, we’re very careful,” he said of CHDI’s mission. “One of the reasons we say that we’re trying to accelerate ‘therapies’ for HD – we don’t say accelerate ‘drugs’ – is because we don’t know what shape that therapy could take. We want to be deliberately inclusive. In fact, I wouldn’t even limit it to diet. I would say ‘lifestyle.’”
He recalled the research of Jenny Morton, Ph.D., who works with transgenic HD mice and sheep. Dr. Morton observed in an experiment that HD mice had erratic sleep schedules – as do HD-affected people. She placed them with normal mice, giving them sleeping and wakeup pills, and gave them things only at night, a mouse’s normal time for activity.
“She was able to show that those mice now absolutely were back to their regular rhythm – they had no choice – and actually it was very beneficial for them,” Dr. Pacifici noted. “They actually even lived longer.”
Keeping our eye on the ball
With the advent of historic clinical trials such as the Roche Phase 3 gene-silencing program, “we’re at a stage now where there are some unbelievably compelling drug candidates,” Dr. Pacifici remarked.
“I guess the question we have to ask ourselves is: how much do we want to take our eye off the ball?” he asked. “Imagine how tragic it would be if there was something that collectively we, with CHDI’s involvement, could do to make those things successful and we were distracted with something else that had much lower probability of success.”
The HD community needs to “discipline” itself to focus on the “very best” possibilities for treatments and avoid “diluting our efforts the way we did in the old days” and “detracting resources.”
For a disease as complex and devasting as Huntington’s, there are no easy answers. The HD community – affected families, scientists, advocacy organizations, foundations, and our supporters – must continue the hard but brave march towards therapies.
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