Another major supplement, creatine, proven ineffective in the fight against Huntington’s disease

For the second time in less than three months, a widely taken and long-studied dietary supplement envisioned as a potential treatment for Huntington’s disease has been proven ineffective, bringing a halt to a clinical trial.

Creatine, a supplement popular among body builders and readily available in health food stores, was studied in a clinical trial called CREST-E (Creatine Safety, Tolerability, and Efficacy in Huntington’s Disease), which began in 2009 and was to be completed in 2016.

On October 29, the National Center for Complementary and Alternative Medicine, part of the National Institutes of Health (NIH), announced that it was discontinuing CREST-E because a preliminary analysis of the data “showed with high confidence that it was unlikely that the study would be able to show that creatine was effective in slowing loss of function in early symptomatic Huntington’s Disease.”

The study was carried out by the Huntington Study Group (HSG) and led by Dr. Steven Hersch of Massachusetts General Hospital and Dr. Giovanni Schifitto of the University of Rochester School of Medicine.

“The entire point of the CREST-E study was to determine whether creatine slows the course of HD or not, and the answer is, no, it does not,” Martha Nance, M.D., a member of the HSG executive committee, said in an e-mail. “Although this result is disappointing, it is still important, as it gives us a definite answer to the question: ‘I have HD. Should I take creatine?’ The answer is, ‘no.’”

“I recommend that all stop taking creatine,” Dr. LaVonne Goodman, the founder of Huntington’s Disease Drug Works (HDDW), said in an e-mail.

False hopes

Huntington’s disease typically reduces people’s energy levels. Scientists thought that creatine, which cells use to store energy, might help compensate for the energy deficit in brain cells and enable them to survive.

Positive results in animal studies regarding the impact of creatine, the rise of HDDW’s “treatment now” program ten years ago, and the advent of both CREST-E and a companion study in presymptomatic individuals known as PRECREST led to much discussion about the supplement in the HD community.

Many people have taken or considered taking creatine in the hopes of avoiding or ameliorating symptoms.

I have taken creatine for about ten years, beginning with my participation in the HDDW program.

Just after receiving the news about CREST-E yesterday, I received an e-mail from an individual inquiring about where to purchase creatine and what amount to take. I responded that “it is now recommended that nobody take creatine.”

HDBuzz.net also reported on the end of CREST-E, calling the new evidence against creatine “compelling.”

Awaiting HD-specific remedies

In mid-August, the National Institute of Neurological Disorders and Stroke and the HSG stopped a clinical trial for coenzyme Q10, another widely taken supplement.

I outlined my approach to HD supplements and the pros and cons of the matter in a February article titled “To take, or not to take, unproven supplements in the fight against Huntington’s disease.” That article also reported on the hopes for PRECREST and CREST-E.

With the elimination of both coenzyme Q10 and creatine in rapid succession, the HD community is suddenly left without two potential treatments that supplied significant  hope.

However, supplements lack what researchers refer to as HD-specific approaches to treatments. They were not designed or marketed with HD in mind, whereas the new treatments currently under study will potentially attack the specific causes of Huntington’s.

Hope for effective treatments is on the rise as researchers and pharmaceutical firms gear up for new clinical trials such as the Isis Pharmaceuticals, Inc., gene-silencing approach announced for the first half of 2015.

“The important thing right now is to learn from ‘negative’ outcomes like this,” the HDBuzz article observed. “Studies like CREST-E have helped us, as a community, to get really good at designing, enrolling and running clinical trials, and understanding why particular treatments don’t work. Now we have the result of CREST-E, all that energy, enthusiasm and experience can be directed into testing other experimental treatments with a higher chance of success. One very solid benefit is that hundreds of volunteers are now freed up to sign up for other clinical trials enrolling now or in the near future.”

For the latest news on HD research and clinical trials, watch the video below for the update by Jody Corey-Bloom, M.D., Ph.D. (Note that the talk took place on October 27, before the announcement about creatine.)

2014 Huntington's Disease Research Update: A presentation by Dr. Jody Corey-Bloom from Gene Veritas on Vimeo.

The dire need for neurological treatments

I am now rethinking my approach to supplements. I have stopped taking coenzyme Q10.

I agree with the doctors’ recommendations to halt creatine. My breakfasts and dinners will no longer include a heaping teaspoon of fruit-flavored creatine dissolved in a glass of water.

Container with over-the-counter creatine (photo by Gene Veritas)

I will discard my remaining supply of creatine but keep the container as a piece of historical evidence in the quest for HD treatments.

It will also serve as a reminder of the dire need for truly effective approaches against a devastating disease that has reminded the world how the discovery of the first effective drug for any neurological disorder has continued to elude science.

To take, or not to take, unproven supplements in the fight against Huntington’s disease

Should people facing Huntington’s disease take creatine and other supplements to relieve or prevent symptoms?

I do.

I saw HD inexorably destroy my mother’s ability to walk, talk, and care for herself. She died eight years ago this month. I tested positive for HD in 1999 and since then have worried daily about when it will strike.

There is no treatment to slow HD’s devastation of the brain. So I’ve been open to taking supplements that might help.

In early 1996, just shortly after learning of my mother’s diagnosis, I started taking coenzyme Q-10 (Co-Q), a vitamin-like substance found throughout our bodies and seen by researchers as a possible way to help remedy the energy deficits suffered in HD.

In 2004, when Dr. LaVonne Goodman introduced a “treatment now” regimen and clinical trial of safe supplements that had shown promising results in animal testing, I jumped at the chance to participate. I was the only presymptomatic individual in the small, three-year study, run under the auspices of Dr. Goodman’s Huntington’s Disease Drug Works (HDDW).

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 Co-Q; two g of omega-3 oil; two g of blueberry extract; and ten g of medical-grade creatine. The trial paid for and delivered the supplements.

The trial did not show significant improvement for any of the symptomatic participants. “The only thing that appeared to be helpful was trehalose,” Dr. Goodman said in a February 9 phone interview. Today, almost a decade later, the supplements remain medically unproven to affect HD.

Nevertheless, scientists still think that trehalose, Co-Q, and creatine might still provide help in treating HD. Since the end of the HDDW, I have continued to take all of the supplements, spending about $2,000 per year. In fact, several years ago, relying on medical advice, I roughly doubled my daily intake of creatine to about 20 g.

I get semi-annual blood tests to monitor potential kidney damage, which creatine can cause. I also drink plenty of water throughout the day to prevent dehydration, which can occur at doses higher than 10 g. Creatine also can cause weight gain.

Am I wasting money and endangering my health?

I don’t think so. A few years ago, one of the doctors at the local Huntington’s disease clinic told me to stay on the supplements, observing that the combination of substances might be helping to delay my HD onset. I inherited the same degree of mutation as my mother, but, at 54, have passed the age of her onset.

The yin-yang of supplements

Whether others in the HD community should take creatine and other supplements is an individual choice ideally made in consultation with a doctor.

During our interview, the Seattle-based Dr. Goodman reviewed the pros and cons of taking creatine.

She cautioned against taking high doses of the substance, because more serious side effects occur at higher dosage, and urged people to consult a physician before starting any supplement.

She stressed that people need to understand the “yin-yang” involved in the decision to take supplements.

“Yes, you want to take care of yourself,” Dr. Goodman said. If they do nothing else, supplements can at least furnish a “very important” placebo effect and the prospect of hope, she said.

Dr. LaVonne Goodman (photo by Gene Veritas)

The placebo effect is a “real” phenomenon, she observed. “If you could bottle it, it would be great.”

However, taking supplements also reminds asymptomatic gene carriers of their risk, she added.

More importantly, people’s use of supplements could also obstruct the path to other, potentially far more promising treatments, she said.

The benefits of supplements “need to be counterbalanced with the need to test promising new drugs, or we will never have better treatments for Huntington’s,” she explained.

Interfering with clinical trials?

“There are so many competing interests here,” Dr. Goodman continued. “We all want to believe that (creatine) is helpful, because it’s available, and we can take it, so why not do it, we say. This is what I said with HDDW trials. Well, yes, but it needs to be measured. Otherwise, we’re going to know nothing more than we did.”

“It is important for people to know that if they take these things, they can’t be in clinical trials at the same time. We deplete our clinical trial participant base, which is going to impede progress for finding better treatments. There’s the yin-yang. And people need to hear both.”

However, Dr. Goodman noted that individuals could do both: to become eligible for a clinical trial, individuals could clear the supplements out of their system so that they don’t interfere with the measurement of the tested drug’s effects, then resume the supplements after completing the trial.

I would stop taking my supplements in order to qualify for a trial, although until the most recent creatine trial (see below), practically every trial has targeted only symptomatic individuals.

Dr. Goodman underscored the need to treat creatine and all other supplements as “medicines.” Supplements should meet USP (U.S. Pharmacopeial Convention) standards, she added. The HDDW website contains information on supplement safety. Further information on supplements is available at Huntington’s Disease Lighthouse Families.

(I buy my creatine from my local GNC outlet but plan to search for a better grade of the product.)

All drugs, including FDA-approved ones, produce side effects and can affect individuals differently, Dr. Goodman noted.

Regarding creatine, she concluded: “If it’s not watched closely, it may cause more harm than good.”

A historic trial

People in the HD community became excited about creatine as a potential treatment after Harvard University’s online news service on February 7 published an article titled “Nutritional supplement slows onset of Huntington’s.”

According to the article, a team of researchers based at the Harvard-affiliated Massachusetts General Hospital had finished a historic Phase II clinical trial that produced MRI scans showing evidence of the slowing of brain atrophy (shrinkage) in HD gene carriers who have yet to manifest the classic symptoms of the disorder. Sixty-four people took part.

Participants took up to 30 g of creatine per day.

According to Steven Hersch, M.D., Ph.D., the trial, called PRECREST (Creatine Safety and Tolerability in Premanifest HD), was a “huge step” for three reasons – including its impact on a separate creatine trial for symptomatic patients called CREST-E (Creatine Safety, Tolerability, and Efficacy in Huntington’s Disease)

“One, it’s the first therapeutic trial that has tried doing prevention,” Dr. Hersch, the study’s senior author and a long-time HD researcher, said in a February 11 phone interview. “Two, because we created a design that let anybody participate who’s at 50% risk, as well as those who have tested positive. And three, the imaging finding increases the probability that CREST-E will show a clinical benefit.”

Dr. Steven Hersch (photo from HDSA website)

Currently in progress and still recruiting participants, CREST-E is a phase III trial – the final step before drug approval (click here to learn how to enroll).

The PRECREST administrators recruited untested at-risk individuals who were then tested for the purposes of the trial as well as individuals who already knew that they have the HD mutation. However, those who entered the study untested did not receive their results, which were only known to the statistician. Thus, they avoided the potentially traumatic psychological aftermath and remained protected from genetic discrimination.

“The ethical challenges for those recruiting and conducting trials include how to accommodate nontested at-risk individuals while preserving a noncoercive choice regarding genetic testing,” states an editorial about PRECREST in the March 2014 issue of the prestigious journal Neurology, adding that “unequivocal changes” occur in the brain of presymptomatic individuals “15 to 20 years before conventional clinic-based diagnosis.” An article on PRECREST by Dr. Hersch, lead author Herminia D. Rosas, M.D., and nine other collaborators appears in the same issue.

For these and other reasons, 90 percent of at-risk individuals choose not to test, Dr. Hersch explained.

The MRI changes and other data from PRECREST will eventually be assessed in CREST-E, Dr. Hersch explained. CREST-E is also doing MRI imaging. With nearly 600 participants so far, it will be large enough to show whether the benefits shown in PRECREST images correspond to a significant slowing of HD.

Avoiding false hopes

As with many news articles about clinical trials and other scientific experiments, the Harvard report’s headline, which claimed the supplement slowed the onset of HD, inaccurately reflected the researchers’ results as reported in the actual scientific article.

“While slowed atrophy suggests that creatine could slow preclinical progression, the potential clinical impact of these findings on delaying the onset of HD is unknown and must be defined by an efficacy study designed to measure it,” the Neurology article states.

Nor can the public buy the high-quality creatine used in the study, as it’s prepared specially for clinical trials.

“I don’t want people to take from this study that they ought to go running out and take a bunch of creatine or take it at these doses,” said Dr. Hersch. “Even though the imaging benefit is very exciting, we don’t know what it means clinically. It doesn’t provide the evidence that would lead me to recommend that people take it. The high doses that we used should also not be used without medical supervision.”

As noted in the Neurology article, some PRECREST participants suffered stomach upset and diarrhea caused by the creatine. About a dozen people had to drop out of the study.

Regarding the study’s clinical significance, Dr. Goodman offered an assessment similar to that of Dr. Hersch.

The widely read HD research website HDBuzz.net also weighed in.

“How much hope and how my hype?” an HDBuzz article asked. While recognizing the importance of the study, it pointed out that the causes and effects of the slowed shrinkage in the brains of the PRECREST participants need further study.

“It’s possible that creatine causes HD brain cells to bulge or swell without making them healthier,” it states. “Swelling like that could produce false optimism and might even be harmful. That’s not something this trial can tell us either way, because the patients weren’t followed long enough to see whether creatine treatment delayed the onset of symptoms.”

“The participants in PRECREST who took creatine but did not have the HD mutation did not experience any brain swelling, so this is an unlikely explanation for our findings,” said Dr. Hersch. “Including and treating these subjects was very unusual. However, we did so to allow us to answer questions like this.”

Awaiting the Holy Grail

“HD researchers face a major challenge in finding a treatment for the pre-manifest,” I wrote in 2011. “It’s really the Holy Grail not only for HD, but also for other neurological diseases such as Alzheimer’s in which brain damage occurs many years before symptoms appear. Ideally, researchers want to design medications that will completely prevent these diseases.”

The Neurology editorial used the term “Holy Grail,” too, in noting how the PRESCREST study “investigates a potentially neuroprotective agent designed to delay disease onset.”

The word “potentially” is key.

As Dr. Hersch explained, the PRECREST findings about slower shrinkage “suggest” that creatine provides a benefit, but they don’t permit researchers to say anything about delayed onset of symptoms in presymptomatic individuals or a longer lifespan for patients.

It remains for the CREST-E Phase III trial to produce similar brain scan results – and an actual effect on symptoms.

“If CREST-E shows efficacy in slowing down the disease in people who are symptomatic, I would think that most people would think that you may be slowing down the disease in people who aren’t symptomatic yet as well,” he said.

Until treatments become available, presymptomatic gene carriers like me will continue to face the extremely difficult decision about whether to take supplements.

I’m grasping at creatine and other supplements in the hopes of delaying onset until researchers succeed. 

Yale’s partnership against Huntington’s disease: an alumnus reconnects and finds hope as scientists pursue ‘Viagra for the brain’ and other solutions

The revelation in 1995 that I was at risk for Huntington’s disease, followed by my positive genetic test for HD in 1999, thrust me into a role as an activist, a journey to understand the biotechnological frontier, and a fight for my life.

However, for many years, and even after “coming out” in a major speech to scientists in February 2011, HD has remained my radioactive semi-secret because of the stigma surrounding the disease and my fear of genetic discrimination.

In those early years of confronting HD, I needed to open up to someone – and to seek help for the cause. Beyond some branches of my family and my local HD support group, I turned to the people I trusted most: fellow Yale University alumni, some close friends, others within a circle of trust. Many lent a sympathetic ear, offering donations, contacts, and advice.

Above all, they helped me feel less lonely inside the terrible “Huntington’s closet.”

Dr. Martha Nance, a neurologist in Minneapolis dedicated to finding treatments for HD, became one of my closest HD confidantes. Brooklyn-based journalist Norman Oder suggested the idea for this blog. Editing nearly every article, Oder has become more than a friend: he is my Huntington’s alter ego.

Dr. Martha Nance and Gene Veritas in San Diego, 2007.

Yale’s seal, which includes the Latin phrase “Lux et Veritas” (light and truth), echoed in my choice of an HD pseudonym, “Gene Veritas,” the “truth in my genes.”

Now, in a way I would never have imagined, I have come to rely on Yale itself in my fight against HD.

At the CHDI Foundation’s Seventh Annual HD Therapeutics Conference, held February 27-March 1 at the Parker Palm Springs in Palm Springs, CA (a hotel owned by fellow alum and real estate developer Adam Glick), I heard exciting news about how scientists in the Yale School of Medicine will help prepare the way for clinical trials of potential therapies.

(Backed by a group of anonymous donors, the non-profit CHDI once stood for “cure Huntington’s disease initiative” but today simply represents the name of the foundation, which focuses exclusively on the search for HD treatments.)

In my unrelenting drive to translate HD science into understandable terms, I dubbed these compounds “Viagra for the brain,” a phrase that refers not to the salacious aspects of the famous drug but to these compounds’ biochemical similarity to Viagra.

I also decided to visit the scientists’ labs to deepen my understanding of their crucial work, to offer my assistance, and to give myself a shot of much-needed hope.

Below, watch my short introductory video of the visit.




An emotional return to New Haven

I had returned only twice to Yale – in 1983, a year after graduation, and, during a memorable cross-country trip with my wife and daughter in 2010 in my effort to enjoy life to the fullest before the inevitable symptoms of HD set in.

This time I arrived in New Haven on May 28 after a two-hour train ride from Manhattan.

That evening, walking through the Yale campus almost 30 years to the day after I graduated, I experienced a flood of memories – some painful, some hilarious, and many, many warm and wonderful.

I remembered the sacrifices my grandparents and parents had made to help me to attend one of the world’s top institutions of learning. I recalled how, as the grandson of immigrant grandfathers and the son of working-class parents, I strived to reach the top academically and then professionally.

As I peered into the darkened windows of the Yale Daily News, where I served as a reporter, I wondered whether my 12-year-old daughter, who writes well and recently sent letters to 35 U.S. Senators about my plight and the need to reverse their opposition to health care reform, might herself someday become a journalist. I imagined the two of us critiquing news articles together. She’s finishing up sixth grade this month, and she says she wants to attend Yale. I imagined her striding confidently through the offices.

It seemed almost yesterday when I walked to classes and debated and laughed with friends in the dining halls of the university’s grand gothic buildings. Once imposing, they no longer felt intimidating. Life is fast, I thought with a tinge of sadness.

My life was abruptly sidetracked by HD. My mother died in 2006, and my father, with a broken heart, followed her in 2009. I wondered: will HD prevent me from helping my daughter apply for college and begin her own path in life?

Yale has generated many of America’s leaders, and it inspires leadership in various ways. I pondered how I had to rise, along with many others, to an unexpected leadership role in the fight against the disease. And I reminded myself that I must do my part to keep the flame of leadership burning, within myself, for as long as I can; within my family; and within the HD movement.

Back in my hotel room later that evening, I prepared for the next day’s emotionally charged meetings at the School of Medicine. It was a place I didn’t go to as an undergraduate, I thought, and represented a new phase in my HD activism, in my relationship with Yale, and in my life. These scientists could help save me.

Catching the disease early

As part of a global effort to eradicate HD, the Yale scientists will play an important role in investigating some of the disorder’s mysteries and in seeking effective treatments. The university’s faculty in neuroscience, neuropharmacology, and other fields provide a supportive context for this work.

Two of the scientists, Hoby Hetherington, Ph.D., and Doug Rothman, Ph.D., are starting groundbreaking work on important facets of HD.

Dr. Hetherington will apply his knowledge of epilepsy, brain trauma, and brain scans to study an energy deficit in HD resulting from insufficient adenosine triphosphate, the basic fuel for our cells.

Using Yale’s 7 Tesla MRI scanner, one of only a few dozen in the world with ultra-powerful magnets, Dr. Hetherington will scan humans using a method called MRSI (magnetic resonance spectroscopic imaging).

Dr. Hetherington hopes to determine whether the energy deficit in HD is a cause or an effect and, in the process, to produce a clearer picture of the disease as it actually occurs.

MRSI involves the MRI machine augmented with two pieces of additional equipment – a head detector and shim insert – permitting him to track the energy deficit by obtaining clear, high-resolution images of study participants’ brains.

As Dr. Hetherington explained, the detector allows him to adjust the readouts of each scanned individual’s brain by accounting for distortions in the magnetic field caused by the presence of the head. It also accounts for the heat generated by the head. Using the detector, he can contour the magnetic field and also pick specific regions of the brain to excite.

Dr. Hetherington’s lab designed and built the first generation of the detector and continues to develop and test new versions of the device. The detector is now in commercial development for more widespread use.

Dr. Hetherington will use the detector in his planned study of gene-positive, asymptomatic HD people like me.

Dr. Hoby Hetherington places a special head detector in the 7 Tesla MRI scanner in his lab at Yale University (photo by Gene Veritas).

Dr. Hetherington explains the innards of the head detector (photo by Gene Veritas).

To compensate in yet another way for distortions in the scanner’s magnetic field, Dr. Hetherington employs the shim insert, which he also helped to design. Like a common shim used to straighten objects in woodwork or masonry, the shim insert levels out the scanner’s magnetic field. He uses the shim to do the opposite of what the head of the scanned individual does to the field. This makes the field uniform and thus easier to read.

A standard scanner shim typically can do eight adjustments, Dr. Hetherington explained. Yale’s can do about 30.

This shim will play an important part in Dr. Hetherington’s HD scans, in which he will examine areas of the brain (such as the basal ganglia) where distortions are created by the presence of the sinuses and the ear canals.

Dr. Hetherington and the shim insert (photo by Gene Veritas)

Dr. Hetherington explains an actual anatomical image of the brain obtained from the 7 Tesla scanner (photo by Gene Veritas).

“It’s catching the pathology before it’s become lethal or progressed,” Dr. Hetherington said of his lab’s technology during my visit while showing me images from an epilepsy study. “That’s the idea of trying to have an early marker of what’s going on. If the cells have died already, the structure gets small. You can see that on standard anatomical imaging, but that’s kind of too late.”

Boosting creatine

Looking ahead 50 to 100 years, Dr. Hetherington speculated that patients with brain-based disorders such as HD and epilepsy may take a common drug to correct the problems they cause in bioenergetics.

Dr. Hetherington explained that the HD study will seek to measure phosphocreatine levels in the brain. Brain cells produce phosphocreatine, which is essential in bioenergetics, from creatine, which is also created by the body and can be taken in the form of a supplement.

Beginning with my participation in the Huntington’s Disease Drug Works (HDDW) program, I have taken creatine for nearly a decade in an effort to stave off symptoms. Creatine is currently under study in an HD clinical trial. (Click here to read more about HDDW founder Dr. LaVonne Goodman's latest assessment of creatine and other supplements.)

“If you can boost the whole pool (of creatine), you’ll have more phosphocreatine around,” Dr. Hetherington said of the theory behind creatine supplementation.

Paralleling mice and humans

Supported by CHDI, Dr. Doug Rothman, Ph.D. a pioneer in the use of magnetic resonance spectroscopy (MRS) and the Director of Magnetic Resonance at Yale, will employ MRS to examine another kind of energy deficits in the mitochondria, the powerhouses of the cell, in transgenic mice.

HD patients often need a higher-than-average caloric intake.

Rothman’s work could provide important clues as to how Huntington’s kills brain cells – and what treatments might stop it. He hopes to extend the experiment to humans, beginning with a 4 Tesla scanner and perhaps later using the 7 Tesla scanner and its accessories.

“It’s really important to keep an eye on what are the relevant aspects of a mouse model,” Dr. Rothman commented, noting that transgenic animals can manifest symptoms differently than humans, and that the mitochondria are more evolved in humans than in mice. “The only way to do that is to really explore, hopefully in parallel, what’s happening with human subjects.”

Dr. Rothman at work in his office (photo by Gene Veritas)

Alleviating symptoms, strengthening the brain

Also with support from CHDI, two other Yale research groups will assess compounds that, if successful, would improve memory and cognition, arrest some of the psychiatric symptoms, and act as neurotrophins, so-called “fertilizers” for the brain. At least one of these neurotrophins (BDNF, brain-derived neurotrophic factor) is severely deficient in HD.

As noted above, I dubbed these substances, developed by Viagra producer Pfizer, “Viagra for the brain” because the substances belong to the same class of drug as Viagra, an inhibitor of an enzyme known as a phosphodiesterase (PDE).

Although targeting different PDE families than the PDE-5 targeted by Viagra, the biochemistry is very similar. Essentially, the new compounds are cousins of Viagra, aiming to inhibit other PDEs.

The Yale scientists will test these compounds in collaboration with CHDI’s “drug hunters” and Pfizer. One coordinator of the three-way partnership is Ladislav Mrzljak, M.D., Ph.D., CHDI’s director of neuropharmacology and a former postdoctoral fellow in Yale’s Department of Neurobiology.

Scientists hope that inhibition of PDEs will compensate for some of the changes occurring in HD.

With new research showing that some PDE inhibitors reverse symptoms in mice, CHDI and Pfizer recently began collaborating with the ultimate goal of taking them into clinical trials.

“There are currently no PDE inhibitors marketed for central nervous system diseases,” Christopher Schmidt, Ph.D., a senior director at Pfizer, explained. “This is new territory.”

Mihaly Hajos, Pharm.D., Ph.D., a former Pfizer scientist and neurophysiologist with a background studying schizophrenia and Alzheimer’s disease, aims to detect whether the same inefficient use of the brain’s information processing (a so-called “auditory gating deficit”) that occurs in humans with HD also occurs in mice and rats genetically engineered to have the disease. If so, Hajos will then test PDE inhibitors as a remedy.

The experiment also could validate the electrical signals as a good biomarker, or measure, of the inhibitors’ impact on people.

Dr. Mihaly Hajos (center) with assistants Elizabeth Arnold and Dr. David Nagy (photo by Gene Veritas)

Studying nonhuman primates

Another project involves the husband-wife team of Graham Williams, D.Phil., and Stacy Castner, Ph.D., neuroscientists in the Department of Psychiatry who are specialists on schizophrenia and substances known as “cognitive enhancers.” The duo will test the effects of PDE inhibitors on cognition in normal, healthy nonhuman primates. These subjects contrast sharply with the transgenic, diseased mice, rats, flies, and even sheep and pigs used in other Huntington’s research.

“We can’t be dependent on the genetic model,” Dr. Williams explained, emphasizing the need to view the disease and the effect of potential drugs from various perspectives.

If the inhibitors work, Drs. Williams and Castner will submit the animals to harmless brain scans using FDG-PET to localize areas of the brain affected. These measurements could help predict the impact of the inhibitors in humans.

Successful studies in the nonhuman primates could help to accelerate the process of getting the inhibitors into human trials and ultimately approved as drugs, a process that could take five to ten years.

The PDE inhibitor projects seek ways to intervene early in the disease, before disabling symptoms occur. The potential therapies could help prolong my life and the lives of tens of thousands of gene-positive and symptomatic individuals.

A key workshop: from animals to humans

On May 31 and June 1, I observed yet another aspect of Drs. Williams and Castner’s research by participating with them in a CHDI meeting in Manhattan titled “Translatability of Cognitive Readouts Workshop.” With some two dozen participants and organized by Dr. Allan Tobin, one of CHDI’s two chief scientific advisors, the workshop aimed to help CHDI move from testing of potential treatments in animals to human clinical trials.

Dr. Mrzljak also took part, as did Dr. Ethan Signer, CHDI’s other chief scientific advisor, Dr. David Howland, director of in vivo biology, and Dr. Beth Borowsky, director of translational medicine. Robi Blumenstein, the president of CHDI’s sister management firm, kicked off the meeting.

CHDI will release the conclusions of the workshop in the near future. Watch my short interview about the meeting with Dr. Tobin in the video below.



The workshop was quite intense and intimate, to say the least. Sitting at a table with one another for eight hours on two consecutive days, and sharing dinner and drinks in lower Manhattan the evening of May 31, we formed new friendships and professional relationships. Dr. Tobin purposely plans the workshops in this way to extract the maximum of candor and new ideas.

I was invited to the meeting as an “observer.” I thought I would quietly sit in the back and take notes.

However, to my surprise, Dr. Tobin seated me at one of the heads of the workshop table. Just before the event began at 9 a.m. on May 31, he asked if I would mind sharing my story with the scientists, and to be “interviewed” by Dr. Julie Stout, an American HD researcher based in Australia.

A number of the invitees, such as Drs. Williams and Castner, had devoted their careers to non-HD conditions and questions, so for many in the room I was a first contact with a person from an HD-affected family.

What I expected to be a few minutes of introduction to the disease turned into a 90-minute discussion about the many social ramifications of the disease. In an effort to contribute to the questions of translatability and cognition, I described such symptoms as my mother’s depression, her loss of the ability to work, her inability to interact with her granddaughter and other family members, and the ways in which our family and her physicians attempted to deal with her symptoms. I also spoke about the fear surrounding genetic testing.

Dr. Stout commented that telling my story helped the scientists understand what it’s like to live with HD. Scientists, she observed, need the collaboration of those confronting HD in the quest for solutions.

At the end of the workshop, I thanked Dr. Tobin, CHDI, and the scientists for allowing me to share my story – which, I pointed out, was just one of thousands of such stories one could hear from the HD community.

CHDI translatability workshop participants, with Gene Veritas standing in back of room (photo by Jerry Turner, CHDI)

Yale and the big picture

Together with CHDI and Pfizer, Yale scientists will furnish pieces of a very large and complex Huntington’s puzzle currently under study by researchers throughout the world in academic labs, pharmaceutical companies, and medical clinics. CHDI, as well as governments and other organizations, supports many of  those projects in producing what most scientists project as an “HD cocktail” of therapies for managing the disease and allowing those affected to lead normal and productive lives. (Scientists don’t speak of “curing” HD, because of its immense complexity and the fact that the defective gene cannot be removed from the body.)

The path, however, isn’t simple. At Yale, Drs. Hetherington and Rothman voiced concern about the potential lack of volunteers for their research involving brain scans. Indeed, stigma and other factors threaten to leave scientists with too few research participants in which to adequately test drugs for safety and efficacy. Tragically, the drive to halt Huntington’s could stall. I pledged to help spread the word of the scanning studies in the Huntington’s community.

In the quest for treatments, scientists and patients depend on each other. Likewise, the many disease communities share a mutual goal. By helping to solve Huntington’s, Yale’s scientists will also assist those fighting Alzheimer’s, Parkinson’s, and many other conditions that afflict millions – as well as the estimated tens of millions of victims of thousands of other genetic and orphan conditions, the focus of Yale’s new Center for the Study of Mendelian Disorders.

Yale, its alumni, and its scientists have lent an enormous hand in my family’s fight. I have already gained strength and support from a network of Yale ties. Someday I may take a Huntington’s drug tested in a Yale lab.

The place that ignited my intellectual passion and launched me into life once again holds one of the keys to my future. This is the American university at its best – engaging in cutting-edge drug discovery, aiding a community long beleaguered by stigma and hopelessness, and affirming life.

Are we failing to stop Huntington’s disease by ignoring ‘natural’ remedies, alternative therapies, and repurposed drugs?

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.

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.”

Robert Pacifici, Ph.D. (photo by Gene Veritas)

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.

CHDI: many 'irons in the fire' in quest for Huntington's disease therapies from Gene Veritas on Vimeo.