At Harvard-MGH’s Mouro Pinto Lab, deploying CRISPR in the quest to cure Huntington’s disease

 

With a $1 million grant from the Hereditary Disease Foundation (HDF), a team of top researchers led by Ricardo Mouro Pinto, Ph.D., of Harvard Medical School, is deploying CRISPR to target genetic modifiers of Huntington’s disease.

 

In brain cells, these modifiers accelerate or slow so-called somatic expansions in HD.

 

The Mouro Pinto Lab at Harvard-affiliated Massachusetts General Hospital (MGH) specializes in research on these expansions. Scientists describe this process as the tendency of the mutant, expanded, disease-causing huntingtin gene to keep expanding abnormally. This causes the dysfunction – and possibly also death – of brain cells, leading to HD symptoms  (click here to read more). As scientists now see somatic expansion as a key driver of HD, research on this process has burgeoned.

 

Investigators have identified the modifier genes affecting expansion through deep research in human data. In speeding or slowing somatic expansion, those genes can hasten or delay disease onset. Many academic and biopharma groups, including the Mouro Pinto Lab, are investigating modifiers as potential drug targets.

 

The Mouro Pinto Lab is focusing on how one modifier gene, MLH3, acts harmfully as a “scissors” in HD. (By convention, human MLH3 gene is always capitalized and italicized; in contrast, the non-human gene is rendered as Mlh3.)

 

In an August 7 interview at his lab, Dr. Mouro Pinto described an experimental drug his team is testing in mice to deactivate the MLH3 scissors, a potential first step in seeking a treatment in people.

 

“I'm extremely optimistic about our approach,” Dr. Mouro Pinto said. “We can see what our drug does to somatic expansions. Can it slow it down? And our preliminary data is very encouraging in the sense that we can do that.”

 

On August 10, Dr. Mouro Pinto provided an update on the project at HDF’s HD2024: Milton Wexler Biennial Symposium. Announced in October 2023, the foundation’s two-year Transformative Research Award supports his team’s research of “therapeutic targeting of somatic CAG expansions with CRISPR base editing.” A group of anonymous donors funds the award.

 

 

Above, at the HDF symposium, Dr. Mouro Pinto displays a slide demonstrating how his lab’s experimental drug slowed somatic expansion in the striatum of mouse brains. In humans, the striatum is one of the areas most affected by HD. Below, a Mouro Pinto slide illustrates how a drug could impact somatic expansion and therefore prevent or delay HD onset, or slow progression of the disease in humans (photo of Dr. Mouro Pinto by Gene Veritas, aka Kenneth P. Serbin, image of slide courtesy of Dr. Mouro Pinto). (To make it larger, click on an image.)

 

Innovative collaborators

 

Seven innovative labs are collaborating with the Mouro Pinto team.

 

James Gusella, Ph.D., whose Harvard lab discovered the huntingtin gene in 1993, is one of three co-investigators on the project.

 

Gusella’s team has developed the human cell line that “allows us to model somatic instability so we can test the drugs,” Dr. Mouro Pinto explained.  That cell line has the expansions of the segment of the DNA code CAG (cytosine, adenine, and guanine), identified in 1993 as the underlying cause of HD.

 

At the symposium the HDF awarded Gusella the Leslie Gehry Prize for Innovation in Science, including $100,000 for research and a plaque with a small sculpture by the renowned architect Frank Gehry.

 

Specialists in somatic expansion

 

A native of Porto, Portugal, Dr. Mouro Pinto received his Ph.D. in molecular genetics at Brunel University in England in 2010, focusing on Friedreich’s ataxia, a debilitating genetic neuromuscular disorder. Along with HD, Friedreich’s is one of more than 50 repeat expansion disorders. In Friedreich’s and others, somatic expansion also plays a role. Scientists also refer to this process as somatic instability.

 

From 2010-2015, Dr. Mouro Pinto worked as a postdoctoral fellow in the lab of Vanessa Wheeler, Ph.D., an associate professor of neurology at Harvard, MGH researcher, and pioneer in the study of somatic instability. The Wheeler lab is collaborating with the Mouro Pinto group on the HDF project.

 

For Portuguese-speaking advocates, in 2022 I interviewed Dr. Mouro Pinto in his native tongue, discussing his work and outlook for HD therapies. We spoke at the 17th HD Therapeutics Conference, sponsored by CHDI Foundation, Inc., the largest private funder of HD research and a backer of the Mouro Pinto Lab.

 

On August 6, the HDF and MGH co-hosted a tour of the Mouro Pinto Lab for about 20 HDF officials, donors, and HD family members. Dr. Wheeler participated, too. I took part at the invitation of the HDF. At the start, Dr. Mouro Pinto presented an overview of the HDF project.

 

 

Above, before the tour of his lab, Dr. Mouro Pinto presents a slide demonstrating the path of his scientific studies. Below, Dr. Mouro Pinto explains the purpose of a PCR (polymerase chain reaction) workstation, where they isolate and make billions of copies of the CAG repeat so they can study it in more detail (photos by Gene Veritas). 

 

 A key task: measuring the expansion

 

In 2016 Dr. Mouro Pinto won the first Berman-Topper Family HD Career Development Fellowship from the Huntington’s Disease Society of America. That funding allowed him to conduct research demonstrating that modifier genes can speed or slow somatic expansion in mice, he said.

 

According to Dr. Mouro Pinto, his lab’s more recent examination of postmortem tissue from HD patients revealed that somatic expansion had occurred in about 30 different brain regions. In all, 50 different tissues were examined, showing different rates of somatic expansion in the liver, muscle, kidney, and others. Some of the fastest expansion was in the brain, he added.

 

To measure a drug’s effect in a clinical trial, brain biopsies are currently not an option, Dr. Mouro Pinto pointed out. However, measuring somatic expansion in blood, liver, and cerebrospinal fluid, which bathes the brain, could serve as biomarkers. A biomarker is a sign of a disease or effect of a drug. He noted that other researchers are already investigating somatic expansion in the blood.

 

“What is the right tissue, bio fluid to obtain from the patient?” Dr. Mouro Pinto asked. “And then what is the right test to be sensitive and accurate? So those two things are actually other aspects of research in our lab that we're trying to develop.”

 

Having those biomarkers will be crucial if the potential CRISPR drug reaches a human clinical trial, he observed.

 

CRISPR: a one-time, permanent edit of the gene

 

CRISPR stands for “clustered regularly interspaced short palindromic repeats,” a strand of RNA that, when activated by an enzyme, can edit DNA. Bacteria evolved this technique to defend against viruses.

 

Jennifer Doudna, Ph.D., and Emmanuelle Charpentier, Ph.D., won the 2020 Nobel Prize in Chemistry for their work in identifying and understanding CRISPR. Click here to read more about CRISPR, its potential for treating HD, and its powerful implications for the future of humanity.

 

Scientists have now used CRISPR to edit human genes in labs and in clinical trials that have resulted in drugs approved by the U.S. Food and Drug Administration (FDA). In December 2023 the FDA approved two CRISPR drugs for sickle cell disease, an inherited disorder that primarily affects people of African descent.

 

This first wave of CRISPR clinical trials has started with the “lowest-hanging fruit,” diseases that “affect the liver or the eye or the ear,” Dr. Mouro Pinto pointed out. The brain is far more difficult to research, so it has been challenging to address brain diseases with CRISPR drugs, he said.

 

“You're doing it at the level of the DNA and that causes a permanent change,” he emphasized. “Once you treat and you introduce the change you made, that will stay in that cell forever.”

 

A CRISPR clinical trial “will look, essentially, the same as any other HD trial,” he explained. “You'll need to collect samples. And you'll need to conduct a battery of physical tests, cognitive tests and behavioral tests. It will still be evaluated exactly by the same standards as any other clinical trial.”

 

In contrast with most other HD drug approaches, CRISPR has a key, beneficial difference. “It’s a one-time treatment,” Dr. Mouro Pinto said.

 

An ‘amazing toolbox’

 

Dr. Mouro Pinto underscored that in addition to serving as a drug, CRISPR has provided an “amazing toolbox” for less costly and more efficient and precise lab research.

 

In contrast with the old, very expensive process of breeding large numbers of mice over years, CRISPR “has accelerated the rate of research tremendously” and dramatically reduced the numbers needed, he said. With CRISPR, they can much more quickly pursue tasks such as making mutations in mice or screening a large number of genes to see which might modify somatic expansion, he said. The lab’s paper on this topic will be published in Nature Genetics.

 

The lab also can deliver a CRISPR reagent to a young mouse, transforming it into a model for study and producing results in a few weeks.

 

A unique ‘humanized Mlh3 mouse’

 

Use of CRISPR enabled a “really critical” step in the HDF project: creation of what Dr. Mouro Pinto described as a “humanized Mlh3 mouse,” a unique research step. To prepare the potential CRISPR drug for testing in mice for efficacy against HD and safety, the lab introduced into the animals a small sequence of human DNA from the MLH3 gene.

 

The scientists have crossed these mice with engineered HD mice. After a few generations downstream, this will result in mice with the expanded and the humanized modifier gene, which will be tested with the CRISPR reagent to see if it stops somatic expansion, Dr. Mouro Pinto continued.

 

The crossing was also necessary to assure that the humanized segment of DNA itself does indeed experience somatic instability, because the goal of the research is to stop instability, he added.

 

Another key step will involve measuring the CRISPR reagent’s impact on somatic expansion, irregular movements, and behavioral symptoms in the mice, Dr. Mouro Pinto said. For this stage, the lab will have the key assistance of the “extremely experienced” Cathleen Lutz, Ph.D., M.B.A., vice president of  The Jackson Laboratory Rare Disease Translational Center, he noted.

 

‘Promoting the flavor without the scissors’

 

As it develops greater precision, the Mouro Pinto Lab has found that one of two MLH3 variants has the scissors that cause harmful genetic cutting. That gets closer to solving the HD puzzle.

 

In a February HDF webinar about the project, Dr. Mouro Pinto explained that in people without HD, the MLH3 variant without scissors – the good variant – is present.

 

He said that he is confident that promoting expression (activation) of the good variant over the bad would be better tolerated as a treatment than simply turning off the bad. He described this approach as “promoting the flavor without the scissors, as opposed to completely getting rid of the protein” that results from the gene.

 

“In a mouse that doesn’t have the scissors, you completely stabilize the repeat,” Dr. Mouro Pinto stated in the webinar. “We know that the scissors component of this protein is essential for promoting CAG expansions.”

 

Furthermore, in human HD cells the team not only reduced but eliminated the bad version of MLH3.

 

They achieved this using a technique known as base editing.

 

Dr. Mouro Pinto noted that with standard CRISPR editing, a sequence of DNA can be broken up, potentially causing unwanted effects. In contrast, in base editing, no breakage occurs, because scientists edit the DNA by simply changing a letter of the genetic code, for example, from A (adenine) to G (guanine), or C (cytosine) to T (thymine).

 

Significantly, his team edited both copies of the MLH3 gene and completely shifted expression from the “bad” version towards only making the “good” “scissor-less” version of MLH3 protein. As a result, the experiment completely stabilized the CAG repeat (i.e. the CAG stopped expanding in edited cells), Dr. Mouro Pinto stressed.

 

There are two bases because, as Dr. Mouro Pinto reminded, every cell has two copies of each gene – a copy from each parent.

 

Partnering on more precise gene editing

 

Only a few projects have started exploring base editing for HD, and most are happening in research labs such as his, Dr. Mouro Pinto said.

 

To maximize the benefits for HD patients, the HDF project will seek to improve on this editing.

 

Recognizing the many other labs are examining directly targeting the CAG expansion, Dr. Mouro Pinto believes that, instead, deactivating a modifier gene such as the MLH3 scissors is a safer and easier strategy.

 

On this aspect, the Mouro Pinto Lab will partner with co-investigator David Liu, Ph.D., of both Harvard and the Massachusetts Institute of Technology (MIT). Dr. Liu invented both base editing and prime editing.

 

As Dr. Mouro Pinto pointed out in our interview, base editing allows for more “precise base changes.” In the HDF webinar, he noted that this method prevents breaking up of the DNA.

 

Harvard’s Benjamin Kleinstiver, Ph.D., another innovative co-investigator, has engineered CRISPR enzymes that “literally can go anywhere in the genome,” Dr. Mouro Pinto added. This enables the team to target any sequence of DNA it needs to, he said.

 

The lab continues to seek improvements in its enzyme to “achieve highest specificity and maximum efficacy,” he said.

 

The potential path to a clinical trial

 

“It's too early” to gauge whether the experimental CRISPR reagent can undergo testing in humans and have a “therapeutic impact,” Dr. Mouro Pinto told me, noting that four key questions must be answered in mice first. The lab aims to answer them in the coming months.

 

He described the outcome needed in the series of mouse experiments: “Did we change the DNA? Yes. Okay. Did we change which version of MLH3 is made? Yes. Okay. Next. Did we reduce the CAG instability? Yes. And then do we have any impact on HD symptoms?”

 

Currently the lab is working on the first step, with “promising” indications so far, Dr. Mouro Pinto said.

 

If the project proves successful, other, distinct projects testing the reagent in other animals, such as nonhuman primates, would follow, Dr. Mouro Pinto explained. The HDF grant does not include funds for those steps.

 

Emphasizing safety, avoiding unwanted edits

 

Dr. Mouro Pinto underscored that the team strives to find the safest CRISPR drug possible.

 

In line with more stringent FDA standards and bioethical concerns regarding gene editing, the project must carry out “due diligence” to avoid “very serious adversity.” That includes so-called off-target effects of gene editing, in which a gene such as one for cancer is accidentally activated or turned off, Dr. Mouro Pinto cautioned.

 

“It is not uncommon for these drugs to have some activity in unwanted regions of the genome,” he explained.  “We need to spend a lot of time looking for unwanted modifications.”

 

The CRISPR agent is “not yet ready for the clinic,” Dr. Mouro Pinto added.

 

He noted that the project is not doing edits in the sex cells; offspring therefore cannot inherit any genetic changes.

 

 

Finding the best way to deliver the cargo

 

The lab has no name yet for the experimental reagent, that is, its CRISPR enzyme.

 

“This is still an experimental reagent,” Dr. Mouro Pinto stressed. “I don't want to create false expectations. We are primarily putting effort into making sure that our cargo is good, that it's really doing what we want.”

 

The “cargo,” the potential drug, needs to be delivered safely and effectively into the brain and to the right cells, Dr. Mouro Pinto said. A common strategy in gene therapy is using a virus, specifically, an adeno-associated virus (AAV).

 

The Mouro Pinto Lab is using an AAV that works well in mice but not possible for humans, he said. As part of the HDF project, the team is searching for the ideal delivery system, which could be an AAV, a lipid nanoparticle, or extracellular vesicle, he continued. All three are tiny.

 

“There are many people now working on AAVs that you inject systemically,” Dr. Mouro Pinto said. “You give it into a vein, they go everywhere in your body including crossing the blood-brain barrier and entering the brain.” They can reach “almost every single neuron in the brain,” he added.

 

The blood-brain barrier is a membrane that protects the brain from harmful substances and germs.

 

Another project collaborator, Benjamin Deverman, Ph.D., of Vector Engineering and Harvard and MIT, has greatly improved the ability of AAVs to cross the blood-brain barrier in humans. In May, these critical findings for solving brain disorders were published in Science magazine.

 

“It's going to unlock this sort of roadblock that we have with delivery,” Dr. Mouro Pinto said of this breakthrough.

 

Lipid nanoparticles also can be injected into the blood. Some researchers are exploring oral administration of extracellular vesicles.

 

These vehicles pose less burden on clinical trial participants and patients in comparison with other methods, such as spinal taps or direct injection into the brain, a “complex surgical procedure,” Dr. Mouro Pinto observed.

 

“We're a little bit agnostic to the delivery strategy,” Dr. Mouro Pinto said, noting that the science of these delivery methods is evolving rapidly. By the time the project concludes in October 2025, “there might be a variety of different delivery options that we may want to consider.”

 

“Synergizing” with other HDF awardees

 

Dr. Mouro Pinto sees “opportunities to synergize” with the team that also received a 2023 Transformative Research Award, under the leadership of Beverly Davidson, Ph.D., of the University of Pennsylvania and Jang-Ho Cha, M.D., Ph.D., the chief scientific officer of Latus Biosciences. Latus focuses on precision delivery of gene therapy. An expert in AAVs, Dr. Davidson presented the team’s work at the HDF symposium.

 

Titled “Advancing gene therapies for HD” and focusing on AAVs, that project could potentially provide a delivery system for the CRISPR reagent, Dr. Mouro Pinto said.

 

 

Dr. Beverly Davidson presenting her team’s work on AAVs at the 2024 HDF symposium (photo by Gene Veritas).

 

Getting to market, looking beyond HD

 

In the event of the CRISPR reagent’s success in the lab, MGH will assist in commercializing it, Dr. Mouro Pinto said.

 

The hospital could license the technology to a biopharma company or, as in the case of the Davidson-Cha project, to start a company like Latus to bring the drug through a clinical trial and to market.

 

“We're open to those conversations and we've been fortunate to have a very collaborative interaction with industry partners so far,” Dr. Mouro Pinto told me.

 

The problem of somatic expansion “is shared across a large number of repeat expansion diseases,” he observed. “Individually, they're rare diseases. Collectively, they're not a rare disease. They actually affect a large number of patients around the world.”

 

“If our hypothesis is correct, the therapeutic benefit will not be limited to HD patients,” he concluded.

 

Disclosure: the Hereditary Disease Foundation covered my travel expenses to tour the Mouro Pinto Lab and attend the 2024 symposium.

 

Sadly, Michael McCabe, a 62-year-old Boston HD man who told his story at this year’s HDF symposium, died suddenly on September 12. Donations in Michael’s memory are suggested to the Huntington’s Disease Society of America.

 

 

Gene Veritas (left) and Dr. Mouro Pinto in the MGH lab (personal photo)

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.