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)

At HDF symposium, a Huntington’s disease ‘hero’ who prays for scientists to find a cure

 

Recognizing the invaluable input from people living with Huntington’s disease, the Hereditary Disease Foundation (HDF) featured a conversation with Michael, a 62-year-old HD-affected Boston man, at its biennial conference of scientists seeking therapies for this incurable disorder.

 

Michael was interviewed about his HD symptoms by neurologist Diana Rosas, M.D., of Harvard University and Massachusetts General Hospital.

 

Titled “Living with Huntington’s Disease: Family Perspectives,” this HDF tradition of focusing on an HD-affected person took place on August 8 during HD2024: Milton Wexler Biennial Symposium. Convening some 300 researchers, biopharma officials, and advocates, the event ran August 7-10 at the Royal Sonesta Boston Hotel in Cambridge, MA.

 

HD usually impedes speech. I saw that affecting my mother. She died of the disorder at 68 in 2006, after two decades of symptoms, and I carry the HD gene.

 

Michael struggled but persistently formed words and sentences. “I pray for everybody,” Michael said, referring to the quest for therapies, during the Q&A after the interview.

 

Michael’s former wife attended in support of his advocacy, as did his two sons, both in their 20s.

 

Michael (left), who has Huntington's disease, and his physician, Diana Rosas, M.D. (photo by Gene Veritas, aka Kenneth P. Serbin)

 

A diagnosis in 2017

 

Born in Chicago, Michael grew up in Princeton, NJ. As a young adult he moved to Boston, where he studied to become a French chef. He spent a year traveling through France to master his profession. He worked in several restaurants in Boston and also at Gillette Stadium for the NFL’s New England Patriots.

 

Michael believes his father had HD, although he was never formally diagnosed, due to the limited knowledge about the disease as Michael grew up in the 1970s. His father was also an alcoholic. Michael’s aunt also suffered from HD and went into a care home.

 

Michael was diagnosed with HD in 2017.

 

It became ‘too dangerous and messy’ to cook

 

Dr. Rosas is Michael’s physician. As she noted, many lab researchers have little contact with HD-affected individuals. The interview aimed to inform them of the complex triad of symptoms and many psychosocial challenges posed by HD.

 

Dr. Rosas asked Michael to address questions about the first type of symptoms: movement disorders, including involuntary movements.

 

These symptoms, Michael explained, caused him to stop cooking: it had become “too dangerous and messy.” It also became harder to dress himself.

 

Typical of HD patients (including my mother), Michael has suffered several serious falls, leading to a broken wrist, ribs, neck, a punctured lung, and a subdural hematoma (a serious injury to the head). Though he had participated in research conducted by Dr. Rosas, the hematoma has prevented him from participating in clinical trials, because of a restriction by pharmaceutical companies.

 

“I like helping out however I can,” he said of his participation in research.

 

Michael, who lives alone, does have a chocolate labrador retriever that he walks.

 

Michael used to drink alcohol daily and smoke heavily. The drinking caused one of his falls, he said. He quit both habits. Alcohol was a “big part” of his life, he recalled, adding that he doesn’t “miss the days of drinking.”

 

A greatly modified daily routine

 

Dr. Rosas brought up another part of the HD triad: cognitive loss, executive dysfunction, and failing memory.

 

Michael observed that his loss of executive function prevented him from cooking, which had required preparing items and “lots of multitasking.”

 

Though he “can remember my bank card number,” he has ongoing difficulties with memory. He pays his cable and phone bills but has an accountant to assist with his overall finances. He still cares for two salt-water fish tanks, an activity he took up in his 20s.

 

Michael arises at 6 a.m., when he takes his medications: risperidone, an antipsychotic, twice daily; deluxotine for depression; and a multi-vitamin. He also takes medical marijuana.

 

After some small accidents, Michael stopped driving, now relying on Uber.

 

Overcoming impulsiveness and depression

 

Regarding the third part of the triad, psychiatric and mood disorders, Dr. Rosas observed that HD-affected individuals can become fixated or impulsive.

 

Michael agreed that this has affected him, recalling that his drinking also led him to be “very impulsive.” He also suffers from depression. Many HD-affected people become angry when faced with unexpected changes in their daily routine. Michael has also experienced this type of anger. Getting over the anger can take time, he added.

 

Like many of the affected, Michael also has difficulties sleeping. His drinking had exacerbated this problem.

 

“It’s like your mind and body are always on with HD,” he observed.

 

Indeed, HD-affected individuals burn lots of calories. Dr. Rosas recommends five meals per day, although Michael said he eats three to four. 

 

Dr. Rosas interviews Michael about his HD symptoms (photo by Gene Veritas).

 

‘You are a hero!”

 

In the Q&A following the interview, Michael expanded on aspects of his life.

 

One has involved his relationship with his ex-wife and sons. Michael said that the divorce occurred around the time of his diagnosis and was “probably” the result of it.

 

Michael saluted his former spouse as “one of my huge supporters. I haven’t had a girlfriend after my divorce. We were married for 24 years.”

 

He said that he has “two great kids” who are “successful and happy.”

 

Michael also socializes with friends, some of them also divorced.

 

Asked about the work of the researchers, Michael said, “I love them to death.” He added that he is looking forward to new advances.

 

Dr. Rosas asked what most worries Michael about HD.

 

“I suppose going to a home, going to an assisted living situation,” he said.

 

His capacity to manage on his own prompted praise. “You are a hero!” declared Tacie Fox, a family advocate and co-trustee of The Fox Family Foundation (which supports HD research), leading the audience to applaud enthusiastically.

 

“It feels like you have somehow navigated in a way that brings you joy in your life,” she added. “We’re struggling with that with my little sister. She watches a lot of TV. I’m in awe that you, living on your own, have marshaled that inner strength.”

 

The key role of modifier genes

 

At 64, I have been extremely fortunate to have not been diagnosed with HD. It is likely that I have benefited from modifier genes and other factors.

 

Like the rest of the audience, I was deeply moved by Michael’s courage and perseverance in living with HD.

 

I hope that when the inevitable symptoms arrive, I will have the same strength as Michael.

 

Stay tuned for upcoming articles on the conference proceedings, including deep discussion of the key role of modifier genes in the search for therapies.

 

Disclosure: the Hereditary Disease Foundation covered my travel expenses.

Exploring the unique qualities of INGREZZA, the newest FDA-approved drug for Huntington’s disease chorea

 

After the news last year that the U.S. Food and Drug Administration (FDA) had approved INGREZZA to treat chorea associated with Huntington’s disease, a debilitating movement disorder, I wanted to better understand the development of this drug and the unique qualities claimed by its creator.

 

On November 17 I interviewed company officials at Neurocrine Biosciences, Inc., which fashioned valbenazine – the chemical name for INGREZZA – in the early 2000s. In 2017, INGREZZA was approved by the FDA for the treatment of tardive dyskinesia, an irreversible involuntary movement disorder unrelated to HD. Neurocrine is in San Diego, one of the world’s leading biotech hubs and where I reside.

 

In an initial report on INGREZZA, including a Zoom interview with three Neurocrine officials, I noted the drug’s advantages over the two other FDA-approved chorea remedies, Xenazine (tetrabenazine) and Austedo (deutetrabenazine).

 

INGREZZA is easier to take, requiring just one daily dose in capsule form. Xenaxine and Austedo have long required multiple daily doses, although in May the FDA approved once-daily extended-release tablets for Austedo. Unlike the other drugs, INGREZZA also does not require titration, that is, slowly increasing the dosage over weeks. INGREZZA is always just one pill.

 

 

In contrast with the other drugs aimed at chorea, INGREZZA is a capsule – not a tablet – and is taken once daily even without an extended-release formulation. These characteristics potentially provide physicians and patients greater flexibility in dosing, because INGREZZA can be crushed and is available in three effective doses. As a result, Neurocrine’s drug, while indicated for oral administration, can also be crushed and mixed with food or provided through a feeding tube – often necessities for late-stage HD patients.

 

In April the FDA approved INGREZZA SPRINKLE capsules, a new formulation of the drug, in oral granules. Neurocrine developed this version of the drug for those with HD or tardive dyskinesia who experience difficulties in swallowing. It can be sprinkled on soft food. INGREZZA SPRINKLE offers the same three simple and effective dosing options (40 mg, 60 mg and 80 mg) as INGREZZA.

 

In last year’s interview, recognizing that INGREZZA only treats chorea, the Neurocrine officials stated that they plan to seek potential disease-modifying remedies that could potentially slow, halt, or reverse the progression of debilitating neurological conditions, which might include HD.

 

A substantial reduction in chorea

 

According to a Neurocrine press release (and also a June 2023 scholarly article in Lancet Neurology), INGREZZA decreased chorea severity three times better than a placebo.

 

So far researchers have not done a head-to-head study of Xenazine, Austedo, and INGREZZA. All three are VMAT2 inhibitors, designed to reduce involuntary movements of chorea. VMAT2 inhibitors help regulate dopamine, a chemical messenger in the brain that affects movements.

 

As my above-mentioned article stated, Dietrich Haubenberger, M.D., the executive medical director at Neurocrine and clinical lead for the firm on the successful Phase 3 KINECT-HD clinical trial leading to INGREZZA’s approval, called valbenazine a “unique molecule.”

 

Comparing INGREZZA with competitors

 

In 2015 I reported on the key differences between tetrabenazine (Xenazine) and its derivative deutetrabenazine (Austedo), which was also developed in San Diego.

 

During my November 2023 interview with Dr. Haubenberger and other Neurocrine scientists, I sought to better understand INGREZZA’s uniqueness and its benefits for HD-affected individuals. How does valbenazine contrast with tetrabenazine and its derivative deutetrabenazine?

 

The basics were described by Dimitri Grigoriadis, Ph.D., a pioneer of valbenazine and today a semi-retired distinguished scholar at Neurocrine. A neuropharmacologist by training, Dr. Grigoriadis started with the firm at its inception in 1993 and previously served as chief research officer.

 

Understanding the chemistry

 

Dr. Grigoriadis explained how INGREZZA works in the brain.

 

The “unique part of INGREZZA,” he said, is that it gets broken down by the body, then produces a single “isomer” that is a key metabolite of tetrabenazine. A metabolite results from the breaking down of a chemical.

 

“That is the chemical that binds to VMAT2, the protein, and blocks the entrance of dopamine” into relevant parts of brain cells, Dr. Grigoriadis added.

 

The drug discovery that Neurocrine did for valbenazine involved a drug profile that was highly selective for the VMAT2 protein, Dr. Grigoriadis recalled. “And through our research, we were able to identify a molecule that provides only the high affinity, very selective isomer of [the metabolites] of tetrabenazine.”

 

Comparing hands

 

Dr. Grigoriadis illustrated the concept of an isomer by noting how left and right hands resemble each other but are positioned differently.

 

“An isomer is a molecule that is exactly the same, has the same structural components,” he said. “So, it's an identical molecule, but it's left-handed, right-handed orientation. Your hands are four fingers and a thumb. They're identical, but they are in a different orientation.”

 

Isomers work in a similar way, he continued.

 

“They fit differently,” he said. “Functionally, they are different, even though they look exactly the same. You could have two isomers of the same molecule, a left hand and a right hand, that fit into different proteins, that fit into different spaces because they are in a different orientation.”

 

As a result, the various qualities of a drug “could be different,” he continued, resulting in a “slightly different” way in which the chemicals produced by INGREZZA “function.”

 

Dimitri Grigoriadis, Ph.D. (left), Dietrich Haubenberger, M.D., and Gene Veritas (aka Kenneth P. Serbin) discuss INGREZZA at the Neurocrine offices (photo by Aimee White, Director, Corporate Communications, Neurocrine). (Click on an image to make it larger.)

 

Building on tetrabenazine

 

At the time of valbenazine’s discovery, Neurocrine did not know whether it could help patients with diseases like tardive dyskinesia or HD, because the research on valbenazine had not been done, emphasized Eiry Roberts, M.D., Neurocrine’s chief medical officer. No drug had been developed for tardive dyskinesia before valbenazine.

 

“So this was a totally new research project,” Dr. Roberts continued. “There were learnings from experience with tetrabenazine that made it important to find out how valbenazine could be a safe and effective treatment for patients with conditions not sufficiently addressed by other medications available at the time.” The company also did extensive research to prove valbenazine’s safety, she added.

 

In addition, Neurocrine determined that, besides showing promise in the lab and efficacy in clinical trials for the treatment of tardive dyskinesia and chorea associated with Huntington’s disease, valbenazine could be mass-produced, Dr. Grigoriadis said.

 

Benefits for patients

 

Dr. Haubenberger stressed that INGREZZA is unique because  it involves just “one capsule, once daily with no complex dose adjustments to get to an effective dose.”

 

The once-a-day quality results from valbenazine’s “very long half-life of its effectiveness” (the time it remains in the body), explained Grace Liang, M.D., a movement disorders neurologist and Neurocrine’s vice president of clinical development in neurology.

 

“We know that the long half-life is important not only for the convenience this provides, but it allows patients to take it consistently without forgetting a dose,” said Dr. Liang. “Everybody has a life to live.” The “long duration” in the body and the selectivity – that it doesn’t act on other receptors of the brain that may cause other effects – make INGREZZA “special” for patients, she added.

 

INGREZZA “gives that nice, smooth, and steady coverage,” in contrast with the other chorea drugs, which have multiple daily doses and a shorter half-life, Dr. Liang continued.

 

INGREZZA also takes effect faster than Xenazine and Austedo, Dr. Haubenberger pointed out. He added that “with the first dose and as early as at two weeks of treatment, the clinical trial showed a greater reduction of chorea in patients on valbenazine compared to placebo.”

 

Unlike medicines that purposely have a material on their capsule to cause an extended release, valbenazine needs no such modification to achieve its “inherent,” smooth, once-daily effect, Dr. Roberts added.

 

Looking to the HD community

 

The FDA approved INGREZZA for use in adults with HD chorea. Neurocrine has no plans for a clinical trial of the drug in juvenile HD patients.

 

“We do recommend that people just use INGREZZA as it's labeled,” Dr. Liang said. “Obviously the care providers, the physicians would need to evaluate what the best treatment options are for those children, and we're hopeful that future developments can also support their needs as well.”

 

“Data is still being collected,” said Dr. Haubenberger, referring to an ongoing three-year study of more than 150 adults with HD taking INGREZZA. “There's lots more to learn about the compound itself and that's really where we want to invest in, where we can even learn more, share that with the community and even learn from that to inspire future avenues of research in HD and also other conditions.”

 

In these studies that reflect more “real-life settings, there’s much that can be learned from a broader data set than what could feasibly be done in a controlled clinical trial,” added Dr. Liang.

 

Other valbenazine projects

 

Previously, a Neurocrine clinical trial program of valbenazine for Tourette’s disorder did not show efficacy, Dr. Roberts said.

 

Neurocrine currently has a Phase 3 program for “valbenazine as an adjunctive treatment for schizophrenia, adjunctive to the antipsychotics that those patients take right now,” Dr. Roberts said. The drug is also in a Phase 3 study for the “commonest movement disorder in children, dyskinetic cerebral palsy,” she added.

 

In March Neurocrine announced the start of a Phase 1 clinical trial with their next-generation VMAT2 inhibitor, NBI-1065890, to study the safety and tolerability in healthy volunteers.

 

“We’re excited to bring this next-generation, internally discovered, highly potent, oral, selective VMAT2 inhibitor into the clinic with the hope of providing differentiated benefit in treating certain neurological and neuropsychiatric conditions,” Dr. Roberts stated in a press release. 

 

Gene Veritas (left) with Eiry Roberts, M.D., Chief Medical Officer, Neurocrine (photo by Aimee White, Neurocrine)

 

Aiming for disease-modifying therapies

 

Our November interview concluded with Dr. Roberts’ reflections on Neurocrine’s commitment to seek disease-modifying therapies for neurological conditions such as HD, including its new partnership with Voyager Therapeutics, a key player in the development of next-generation gene therapies. Voyager has experience in HD research.

 

“While symptomatic treatments are incredibly important for patients living with the diseases that we're seeking to serve, like Huntington's, for us to be a true innovator as well in this field, we need to be focused on understanding disease modification and cures,” Dr. Roberts said. “And so the collaboration with Voyager is one that gets us into the gene therapy space for potential curative or disease-modifying treatments. And we have other efforts that are very early in our research to look at different ways of coming upon disease modification.”

 

“It's really a focus area for us as we look at some of these novel platforms that we're coming forward with,” Dr. Roberts concluded.

 

Those research platforms are getting a boost: Neurocrine is moving to a new, state-of-the art 535,000-square-foot research campus. The lab space is scheduled for completion by year’s end.

 

Neurocrine's new research campus (photo courtesy of Neurocrine).