‘Striving for a cure’: highlights from the 19th Annual Huntington’s Disease Therapeutics Conference

 

Progress towards effective treatments for Huntington’s disease relies on the affected families’ collaboration with researchers exploring the frontiers of science.

 

The potentially pathbreaking findings featured at the recently completed 19th Annual HD Therapeutics Conference, sponsored by the nonprofit CHDI Foundation, Inc., led CHDI Chief Scientific Officer Robert Pacifici, Ph.D., to declare that the community will achieve therapies.

 

In this article I highlight the scientists’ work with a photo essay on their conference presentations and some of their key observations.

 

I cover most of the presentations. For detailed reports on the conference, see the articles in HDBuzz by clicking here, here, and here. Later CHDI will post videos of the presentations on its website. It is also preparing a video “postcard” of the event.

 

In recent decades, Huntington’s breakthroughs have resulted from the increasing amount of human data, which Dr. Pacifici and other scientists say is the best way to study the disease and develop potential therapies. The presentations at this conference especially reflected this trend. Researchers such as Matthew Baffuto, B.S., of the Heintz Lab at The Rockefeller University (in the photo above), recognized the importance of postmortem donations of HD-affected individuals’ brains and other human samples for their research. Baffuto’s final slide included a dedication: “To the HD patients and families who make this human research possible and for whom we continue to strive for a cure.” (All photos by Gene Veritas, aka Kenneth P. Serbin) (Click on an image to make it larger.)

 

The first wave of attempts by pharmaceutical companies to defeat Huntington’s has involved attempts to lower the amount of the abnormal huntingtin protein (HTT) in patients’ brains. In many of these approaches, this also means lowering the amount of normal HTT. The lab of Jeff Carroll, Ph.D., a scientist at the University of Washington and a HD gene expansion carrier like me, has extensively studied huntingtin lowering in mice. Normal huntingtin is necessary for adult mice to function, Dr. Carroll observed. Huntingtin lowering is not a “bad idea, just that there’s a floor between 50 percent and zero percent HTT,” he said.

 

Tony Reiner, Ph.D., of the University of Tennessee Health Science Center, presented the latest findings of his work comparing HD mouse brains to human tissue from deceased HD-affected individuals. He also focuses on how HD affects the various regions of the brain differently. This photo illustrates how Dr. Reiner uses antibodies to measure the complications that arise in HD mouse brains.

 

Sarah Tabrizi, M.D., Ph.D., of University College London, discussed her lab’s research on somatic expansion, the tendency of the abnormal huntingtin gene to expand with time and become more harmful to the brain. She presented data on developing drugs to interact with modifier genes, which can impact somatic expansion and therefore the age of disease onset. Dr. Tabrizi focused on the modifier gene MSH3 as an ideal therapeutic target. For this research, the Tabrizi lab has utilized stem cells, CRISPR gene editing techniques, and antisense oligonucleotides, used in huntingtin lowering drug programs and other HD research projects.

 

Ricardo Mouro Pinto, Ph.D., of Harvard University Medical School, presented his lab’s work on genetic modifiers of somatic expansion. Dr. Pinto has implicated the so-called DNA mismatch repair pathway as a critical driver of somatic expansion. His lab is also developing CRISPR-based strategies as potential therapies. Dr. Pinto’s team was recently awarded a grant from the Hereditary Disease Foundation to continue the search for therapies.

 

Mark D. Bevan, Ph.D., of Northwestern University, spoke on his lab’s latest findings in HD mice, in particular the dysregulation and rescue of subthalamic nucleus, involved in the suppression of movement. Dr. Bevan highlighted the need for both huntingin-lowering and somatic expansion therapies to have widespread delivery into the brain.

 

Osama Al-Dalahmah, M.D., Ph.D., of the Columbia University Irving Medical Center, discussed the major role of astrocytes in HD. There are over 100 different brain cell types. Astrocytes are cells that provide physical and chemical support to other cells such as neurons, key in the brain. As a neuropathologist, Dr. Al-Dalahmah analyzes post-mortem brain tissues. Among other observations, he noted that astrocytes can be neuroprotective. His lab is working on ways to protect neurons in HD.

 

Scientist Baffuto’s wide-ranging presentation focused on specifying cell types in unraveling both the molecular mechanisms underlying somatic expansion and also the path of the disease. The Rockefeller team developed what it describes as an “innovative methodology” for deep profiling of cellular processes in the brain. The technique is fluorescence-activated nuclear sorting (FANS). As shown in one of Baffuto’s slides, they used FANS to detail the disease process in key areas of postmortem HD-afflicted brains: the striatum, cortex, thalamus, hippocampus, amygdala, and cerebellum.

 

Scientists continue to debate exactly what triggers Huntington’s. Assessing the impact of somatic expansion, the Harvard University Medical School team studying HD proposed a new model for how somatic expansion contributes to HD pathology. Bob Handsaker, B.S., explained that, until recently, scientists thought that the DNA triplet repeat creates a toxic protein whenever the CAG repeat length is greater than 40 and that HD pathology arises from lifelong exposure to this toxic protein, similar to how smoking damages the lungs. (The abnormally repeated DNA word CAG is the genetic root of HD.)

 

New research has challenged this idea in three important ways: First, there is much more somatic expansion than had been appreciated, with affected neurons expanding to reach over 400 CAG repeats. Second, this somatic repeat expansion starts slowly and then accelerates over time, like a "slowly ticking DNA clock” in each individual neuron. Third, the evidence suggests that modest somatic expansion, up to a repeat length of 150 CAGs, does not create a protein that is toxic - the toxic effect in each individual neuron only begins above this longer repeat-length threshold. Along with other research presented, this finding underscored that there may be a longer window of opportunity than had previously been appreciated for any therapeutic interventions that act to slow or block somatic expansion. This is because in the first few decades of life in a person with HD, the DNA in most neurons has typically not expanded to reach this toxic threshold.

 

Darren G. Monckton, Ph.D., of the University of Glasgow, presented his new research on biomarkers, signs of a disease and indicators of whether a drug has efficacy. Dr. Monckton focused on biomarkers in areas of the body outside the brain such as blood, in particular regarding the degree of somatic expansion and measuring it over time.

 

Carlos Bustamente, Ph.D., a Venezuelan American geneticist and the founder and CEO of Galatea Bio, Inc., advocated for enabling precision medicine around the globe. Dr. Bustamante observed that new technological advances have made it faster and less expensive to understand human genomes but most of such resources have gone to understanding predominantly northern European communities. He pointed out the need to expand the genetic dataset to other parts of the globe. Dr. Bustamante also explained how genetic differences in the global population have contributed to differences in the geographic prevalence of Huntington's.

 

David Margolin, M.D., Ph.D., the vice president for clinical development at uniQure, presented an update on the early-stage (Phase 1/2) clinical trial of the company’s gene therapy drug, AMT-130, involving 39 trial volunteers in the U.S. and Europe. Dr. Margolin reported that, relative to baseline, volunteers treated with AMT-130 showed evidence of preserved neurological function. So far, the drug has proved to be safe.

 

Amy-Lee Bredlau, M.D., the senior medical director at PTC Therapeutics, presented interim safety and biomarker data for the company’s huntingtin-lowering pill, PTC-518, in PIVOT-HD, a Phase 2 trial. At this stage, the drug has been shown to be safe and has achieved a lowering of huntingtin in the blood – although data do not yet show whether the lowering is also occurring in the brain.

 

From left to right, Roche researchers Jonas Dorn, Ph.D., Peter McColgan, M.D., Ph.D., and Marcelo Boareto, Ph.D., reanalyzed the data from the firm’s first attempt at a Phase 3 huntingtin-lowering trial program, which in 2021 ended without the drug tominersen showing the necessary efficacy for approval as a drug. The scientists discussed ways to improve clinical trial design, including for GENERATION HD2, a less ambitious, Phase 2 trial of tominersen in a smaller number of volunteers. GENERATION HD2 is in progress.

Tough news for Huntington’s, other neurological disease patients: Roche halts dosing in historic clinical trial on signs of inefficacy

 

Calling it “tough news to share” and “even more difficult to receive,” pharmaceutical giant Roche announced on March 22 that it has halted dosing in the firm’s historic Phase 3 Huntington's disease clinical trial of its gene silencing drug tominersen, GENERATION HD1, because of unfavorable efficacy data, as seen by an independent review committee.

 

“The committee recently met for a pre-planned review of the latest safety and efficacy data from GENERATION HD1 and made a recommendation about the investigational therapy’s potential benefit/risk profile,” wrote David West, Roche’s senior director, for Global Patient Partnership, in a letter addressed to the international HD community. “Based on the committee’s recommendation, we will permanently stop dosing with tominersen and placebo in the GENERATION HD1 study.”

 

GENERATION HD1 began in early 2019, paused for several months to recalibrate dosing, and became fully enrolled in April 2020. Volunteers were to receive the drug over 25 months, and Roche had expected to finish the trial and report results in 2022. Tominersen developer Ionis Pharmaceuticals, Inc., Roche’s partner, had completed a Phase 1/2a trial of the drug (testing for mainly safety and tolerability) in 2017. That trial was so successful that Roche skipped a full-blown Phase 2 and went directly to Phase 3, GENERATION HD1.

 

West noted that the review committee’s recommendations resulted not from “any new emergent safety concern, but on a broad assessment of the benefit/risk” for those receiving the drug as compared to those getting the placebo.

 

This means that the drug demonstrated an “unfavorable efficacy trend,” an official of U.S. Roche’s subsidiary Genentech wrote me in an e-mail. If successful, the trial would have demonstrated that tominersen could slow, halt, or even reverse HD symptoms.

 

“This is brutal and I am absolutely devastated for our patients and families,” Jody Corey-Bloom, M.D., Ph.D., the director of the Huntington’s Disease Society of America (HDSA) Center of Excellence at the University of California, San Diego, wrote me.

 

Trial participants in Dr. Corey-Bloom’s clinic were among those taking part in GENERATION HD1. “I am glad that Roche will continue following patients for safety and clinical outcomes,” she added.

 

Veteran HD physician LaVonne Goodman expressed a similar sentiment. “Hope has been so very high for this drug; our community will feel not just disappointment, but real grief,” Dr. Goodman wrote me. “However, we’re accustomed to grief, and are resilient.  I think part of the community message should be that supporting each other is vitally important now.”

 

HDSA Chief Scientific Officer George Yohrling, Ph.D., called the news “devastating.” “HD families around the world had their hopes held high that this experimental drug could one day soon become an effective therapy for HD,” Dr. Yohrling stated. “While this is clearly not the news we wanted to hear, I am confident that in the coming weeks the Generation HD1 data will help the scientific community understand why tominersen did not meet its desired outcome.”

 

Robert Pacifici, Ph.D., the chief scientific officer for CHDI Foundation, Inc., the nonprofit virtual biotech dedicated to discovering HD therapies and a collaborator of Roche and Ionis, also commented on the development.

 

“Roche’s decision to discontinue dosing in most of its Huntington’s disease studies based on a recommendation from the unblinded [with access to data] Independent Data Monitoring Committee that periodically reviews study data is a very disappointing outcome,” Dr. Pacifici wrote. “However, knowing our colleagues at Roche we are confident that this decision has been made in good faith with the best interests of study participants uppermost in mind.”

 

 

No new safety concern caused the halt

 

The stop to the Roche trial underscores the fact that an effective treatment still eludes not only HD scientists, but also researchers of Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis (ALS), and other neurological conditions.

 

The reviewers who recommended the halt to GENERATION HD1 work separately from Roche. The committee has not yet shared its specific reasoning or data with Roche.

 

“It is important to note that the recommendation is not based on any new emergent safety concern,” West’s letter stated.

 

Roche has notified the clinical trial sites in the 18 participating countries of the halt. The sites are contacting the 791 symptomatic volunteers who had enrolled in the program.

 

The participants were receiving intrathecal (spinal) injections of tominersen or a placebo. Participants in GEN-EXTEND (an extension study for participants coming from any Roche HD study) will also no longer receive doses.

 

“It is our intention to provide as much information as we can to the community, which at this time is limited until we have accessed and analyzed full data,” West’s letter explained.

 

West acknowledged “the tremendous contribution of the families who are participating in these studies, as well as the broader Huntington’s community for their collaboration.”

 

Next steps depend on the data

 

Although Roche has stopped giving tominersen to the volunteers, the trial has not yet ended.

 

“The studies will remain ongoing (without further dosing in GENERATION HD1 and GEN-EXTEND) and it is intended that study participants will be followed by their physicians for safety and clinical outcomes,” West stated. Roche has not provided a timeline for the remainder of the work to be completed.

 

A Q&A appended to West’s letter states that “Roche remains committed to the HD space and our studies are continuing,” and data from GENERATION HD1 “will advance our understanding of tominersen and inform research for other disease modifying treatments.” It adds: “In addition to tominersen, the Roche family of companies is investigating gene therapy approaches to treating Huntington’s disease.”

 

The conclusions about GENERATION HD1 – and possible next steps by Roche and Ionis­­ – will depend on the analysis of the independent reviewers’ explanations and all of the massive data from the Phase 3 trial.

 

As Dr. Pacifici noted, only when data from the independent review committee has been “shared with the wider HD community” will it become possible to “form a scientific opinion” about the halting of the trial.

 

A perplexing result

 

Ionis held a public conference call on March 22 to answer questions about the Roche announcement.

 

“This is the largest Huntington’s trial ever conducted,” stated Ionis CEO Brett Monia, Ph.D. “It was conducted on a wealth of information.”

 

Monia stated that, “while we are saddened by today’s outcome, we are committed to the HD community and focused on delivering treatments for this and other devastating neurological diseases.”

 

Monia added, “Although this is a disappointing setback for Ionis and the HD community, we are confident in the potential of our technology platform to address many neurological diseases.”

 

Various questioners on the call asked Dr. Monia and Ionis scientists to speculate about the reasons for the halt and future potential approaches using the company’s technology (antisense oligonucleotides, or ASOs), but the Ionis officials emphasized that answers are premature without access to the data.

 

“We are still strong believers in the ASO approach,” Dr. Monia asserted.

 

However, Ionis Chief Scientific Officer Frank Bennett, Ph.D., the long-time coordinator of the firm’s HD program, added that the news of the potential ineffectiveness of using an ASO to reduce the amount of huntingtin protein in patients was “perplexing and disappointing to us,” leaving many unanswered questions.

 

Eric Swayze, Ph.D., Ionis’s executive vice president for research and one of the developers of the ASO, reminded the participants on the call of a fundamental reality of HD: “It’s a complex disease.”

 

Dr. Monia added that “one silver lining” in the halt to GENERATION HD1 was that it did not, as noted above, result from a concern about safety.

 

Diversification necessary

 

Although the pioneering Roche-Ionis program had electrified the HD world with the hope of the first effective treatment, the HD research community has also deliberately diversified the approaches to treating HD.

 

Thus, companies like Triplet Therapeutics, Inc. have leveraged publicly available knowledge gained from the Roche/Ionis program and others to plan their own, unique drug development strategies.

 

Triplet aims to start a clinical trial in the second half of this year for a potential drug targeted at stopping the mutant huntingtin gene’s tendency for continued expansion with age. That expansion compromises brain cells and triggers disease. In this respect, HD is known as a repeat expansion disorder (RED), with the triplets of the genetic code CAG recurring too many times and thus causing disease.

 

As a Triplet scientist explained last year, the Roche/Ionis approach is like “putting a brake” on the disease, whereas Triplet’s ASO will target the expansion of the gene and therefore seek to “remove the foot on the gas.” (Click here to read more).

 

Using the same mechanism, in addition to HD, Triplet hopes to develop transformative treatments for many of the more than 50 other REDs. For REDs of the central nervous system, it would use the same drug as for Huntington’s.

 

Although unavailable for comment on the Roche announcement, Triplet executives offered encouragement in an e-mail to me: “Triplet’s thoughts are with the HD community, and our clinical development plans in HD and other repeat expansion disorders remain on track and unchanged.”

 

As one scientist wrote me (and as I also felt), the Roche announcement was like a punch to the gut. However, I am also heartened by the potential of other clinical trials like Triplet’s. (I will further explore the implications of the Roche trial halt in upcoming articles.)

 

To echo Dr. Goodman’s words, our community and its scientists are indeed resilient.

 

(For more on the Roche announcement, see the article in HDBuzz).

 

(Disclosure: I hold a symbolic amount of Ionis shares.)

I’m a Huntington’s disease gene carrier at age 60, so why haven’t I developed symptoms yet?

Huntington’s disease struck my mother in her late 40s, turned her into a debilitated, mere shadow of herself by her late 50s, and took her life at 68. I inherited from her the same degree of genetic mutation. Last December, I turned 60. So, doomed to suffer this inevitable and untreatable disease, why don’t I have any apparent symptoms yet?

Of course, I am thrilled to have avoided the dreadful scenario I imagined for myself after my mother’s diagnosis in 1995 and my positive test for the mutated, expanded gene in 1999. I did not believe that, by age 60, I would still be able to work, write, and not become a burden for my family. Indeed, in January, I marked fifteen years as a Huntington’s disease blogger.

I have written about my broad range of strategies for keeping healthy, including swimming, neurobics  (exercising the brain) and blogging, and taking supplements, some of which were ultimately proved ineffective. I stretch daily to keep limber, and I eat a healthy diet (no alcohol, sodas, or red meat; minimal processed foods; and lots of fish and fresh fruits, vegetables, and salads). I also consult a psychotherapist, meditate, and practice spirituality. 

I also have the benefit of a stable, solid-paying job and a close relationship with my wife and daughter. I cannot be sure whether any of these things help avoid HD, but they generally bolster health.

As Robert Pacifici, Ph.D., the chief scientific officer for the nonprofit, HD-focused CHDI Foundation, Inc., pointed out in a major interview last year, “lifestyle” is potentially very important. Evidence from at least one animal study suggests this, he said, although no scientific data yet prove this for HD in humans (click here to read more).

However, extensive, pathbreaking research based on humans has provided a new understanding of the genetics of Huntington’s and why people with the same size of gene mutation – the same CAG count, as explained below – can experience widely different ages of onset. A Huntington’s Disease Society of America (HDSA) webinar, presented by James Gusella, Ph.D., on November 19, 2019, explained the main points of this research and its relevance for HD families.

“You can relatively easily find people who’ve developed symptoms maybe 20 or more years later than you’d expect from the average, or 20 or more years earlier than you’d expect, and you can find people all along that range,” said Dr. Gusella, who titled his presentation “New Insights on Huntington’s Disease Age of Onset from Genetic Studies of HD Families.”

Dr. Gusella is the Bullard Professor of Neurogenetics at Harvard Medical School and the director of the Center for Human Genetic Research at Massachusetts General Hospital. He helped lead the efforts that narrowed the search for the huntingtin gene to chromosome 4 in 1983 and the discovery of the gene in 1993 (click here to read more). Since then, he and his collaborators have continued to make important discoveries about HD.

Above, Dr. James Gusella (left) during an interview with Gene Veritas (aka Kenneth P. Serbin) at the 7th Annual Huntington's Disease Therapeutics Conference, sponsored by CHDI,  in 2012. Below, a slide from Dr. Gusella's HDSA webinar presentation illustrating the average age of HD onset correlated with the CAG count.

The CAG count

Focusing on the discovery of so-called “modifier genes” for HD, Dr. Gusella delved into the reasons for the wide variations in onset – and the potential this research has for producing HD treatments.

As Dr. Gusella explained in the webinar, the human genome has 3 billion “letters,” or base pairs, which make up our DNA. The four letters that make up the bases of DNA are A (for adenine), C (cytosine), G (guanine), and T (thymine).

Like all genes, the huntingtin gene is made of a string of “three-letter words,” sequences from those four letters. Within the gene is a segment in which the word “CAG” is repeated a number of times. Normal genes have 10-25 CAG repeats. Repeat lengths of 26-34 do not ordinarily cause HD, but the repeat number can increase as the gene is passed to a child, leading to HD in the offspring. HD can occur in people with 35-39 repeats, and genes with 39 or more repeats “almost always” cause the disease, Dr. Gusella stated.

“CAG repeats” is the lingo of the HD community. Tested gene carriers like me usually know our repeats, and those of our affected parent and relatives. I have 40, as did my mother.

The “CAG count,” as it’s also known, became critical in my wife’s and my decision to conceive, especially because males (we were told) had a greater tendency to pass on a larger number of repeats. What if our child had a few more repeats or even more?

The CAG count has long factored heavily in genetic counseling and even in people’s decisions about moral dilemmas like abortion.

In general, the more repeats, the earlier the onset, leading even to juvenile HD – although, as Dr. Gusella emphasized, the age of onset varies widely.

New thinking about HD genetics

Since the discovery of the HD gene, scientists have published thousands of papers on HD, many of them based on studies in non-human organisms such as flies, mice, sheep, and primates – some of these organisms genetically modified (before birth) to later develop HD-like symptoms. However, because HD occurs only in humans, ultimately our species provides the best model for understanding and treating the disease, scientists say.

Scientific advances and the advent of clinical trials have made deeper research in humans more widespread and easier to carry out.

“We’re firm believers that, if you’re going to study a human disease, you’re best to study it first in people, rather than in trying to recreate it in other animals,” Dr. Gusella stated. “People really give you the information for what the disease is.”

Assessing genetic data collected over decades in more than 9,000 people affected by HD, Dr. Gusella and the Genetic Modifiers of HD (GeM-HD) Consortium have made discoveries that have changed standard thinking about Huntington’s genetics.

This type of broad-ranging study is known as GWAS, genome-wide association study. 

As Dr. Pacifici stated in 2015, human data are “precious” because they enable Huntington’s drug hunters to design and run better clinical trials, which are crucial for developing treatments.

Dr. Robert Pacifici (photo by Gene Veritas)

Explaining onset

In the webinar, Dr. Gusella detailed the research on CAG repeats and onset. A correlation definitely exists, he stated. However, other key factors come in into play.

“The inherited CAG length accounts for about 60 percent or so of the variation in age of onset, but there is a lot of variation” at each CAG count, he said.

“Just measuring the CAG repeat doesn’t give you an accurate prediction of when any given individual is going to have onset,” he emphasized. Research in thousands of people produces an average, “but it really doesn’t tell you much specifically about a given individual that would be useful diagnostically.”

However, the mass CAG data can help scientists explain why individuals diverge from the average, he stated.

Forty percent of the reason for onset must be due to factors other than the CAG count, Dr. Gusella continued. From their research, the GeM-HD Consortium concluded that 20 percent is due to other genes, that is, modifier genes “that are influencing when you have onset.”

Environmental factors ‘hard to study’

“The other 20 percent remains unexplained,” Dr. Gusella said. “It could be anything. It could be chance. It could be environmental factors.”

Environmental factors “are very hard to figure out and study,” he added. In answer to a webinar question about environment, diet, and exercise, Dr. Gusella could point to no study on the topic, although he noted that such research falls outside his expertise.

Indeed, in my more than two decades as an HD advocate and participant in numerous research studies, I’ve not been aware of any such study for presymptomatic gene carriers like me. The closest was PREDICT-HD, which collected samples of blood, urine, saliva, and cerebrospinal fluid from presymptomatic gene carriers. It also had them undergo a motor coordination exam and brain MRI scan and perform a battery of cognitive and mood tests. (Click here to read more).

Dr. Gusella added that the unexplained factors could also include “simply the diagnostic uncertainty, because you’re dealing with a motor onset.”

Motor onset marks the start of the involuntary movements typical in HD. Doctors have long used it as the standard way of diagnosing the disease, as opposed to other, initially often more subtle symptoms such as depression or cognitive difficulties.

However, as Dr. Gusella noted, diagnosing motor onset can be “a little bit subjective” on the part of the patient, the family, and the physicians. They all might also lack certainty about the exact time of onset.

Modifier genes influence age of onset

For the 20 percent of onset determined by modifier genes, the GeM-HD Consortium has hard evidence from the genetic studies of the 9,000-plus individuals.

It is “clear” that genetic variations “account for the differences” in age of onset for people with the same CAG count, Dr. Gusella said.

Everybody has genetic differences such as hair and eye color, and the overall number of differences among people is very large, he explained. By studying thousands of people, and using two methods of analysis, the scientists have detected 23 genes that influence the onset of HD.

Modifiers can come from both the affected and non-affected parent, Dr. Gusella pointed out.

As with many other genes, researchers have assigned these modifiers with very long, scientific names, which they have abbreviated to terms like FAN1. Delay in onset from the average varied from one to 20 years. FAN1 and most of the other modifiers are involved in the maintenance and repair of DNA, which, in general, helps cells remain healthy, he noted.

A slide from Dr. Gusella's presentation illustrating the location on the chromosomes of some of the currently identified Huntington's disease modifier genes

Dr. Gusella stressed that the GeM-HD research had not yet resulted in new types of genetic tests for individuals to discover whether they have favorable or unfavorable modifier genes. The research correlates to observations in thousands of people, but does not allow for prediction of age of onset in any given individual. 

The GeM-HD findings have shed light on other genetic aspects of the disease critical for families and family planning. When an affected parent passes on an abnormal CAG repeat, the count can increase or decrease, usually by one to three repeats, with a slight tendency to go up, and with a greater tendency for increases in CAG count when the gene is passed on by males, Dr. Gusella stated.

However, because of the action of modifier genes and the larger overall variation in onset, any attempt to “to predict onset from relatives” could “easily be wrong.”

So, Dr. Gusella asked, if such findings cannot directly inform individuals and their families, what are they good for?

Researchers can seek to investigate the “mechanism” by which the modifiers affect the “disease process” and then, based on that knowledge, design treatments to influence that process “in a much, much stronger fashion” than any of the modifiers does individually.

“Imagine if we had a drug that could delay onset of motor symptoms by 40 years!” Dr. Pacifici exclaimed, commenting on the discovery of the modifier genes. “My gosh, that would be fantastic. Nature’s kind of done that experiment for us. It’s told us that it is possible to modulate the disease.”

A slide from Dr. Gusella's presentation illustrating how age of disease onset is influenced by modifier genes, as shown in the different curves

The defective protein

Another key finding of the GeM-HD studies has also changed standard thinking in the HD field. This discovery involves the protein made by the huntingtin gene, also called huntingtin.

Each 3-letter “word” in the DNA encodes an amino acid to put into the protein the cell is making.  There are 20 different amino acids; proteins are made of long chains of hundreds or thousands of amino acids, which are then folded, linked, or otherwise modified to create the final product. Dr. Gusella described proteins as the “workers in the cell.” Cells are assisted in this process by RNA, which acts as a messenger to carry instructions from the DNA in the making of proteins.

In the case of huntingtin, there is a particular location in the gene where the word CAG appears many times in a row, as noted above. This leads to the creation of a protein that includes the amino acid glutamine many times in a row.

Since the discovery of the gene, scientists have assumed that HD onset occurred because of too many glutamines in the protein, supposedly resulting in cumulative damage to brain cells by the faulty protein, Dr. Gusella observed.

“This assumption is actually not correct,” he reported.

The gene drives onset

The GeM-HD researchers found that, after the string of CAG repeats in the gene, there is usually the “word” CAA and then another CAG, Dr. Gusella explained. The DNA “words” CAG and CAA both mean “glutamine” to the cell’s protein-making apparatus.  

“The vast, vast majority of Huntington’s disease individuals have that structure,” he continued.

However, in less than one percent of people with HD, there is no extra CAA-CAG – or there are two CAA-CAG combinations.

These genetic differences affect the measurement of the CAG count, making the actual section of the gene shorter or longer than the laboratory would measure using usual test methods, Dr. Gusella explained. Detecting these very small variations in DNA sequence in a small number of patients is difficult and costly. Also, as with modifier genes, getting tested for these differences would not benefit HD patients in any way, he added.

However, these uncommon variants in the DNA sequence permitted researchers to do something very important: to distinguish the effect of the CAG from the effect of the glutamine.

“It’s not glutamine that’s driving the time of onset,” Dr. Gusella explained. “It’s some property of the CAG repeat itself, some property of the DNA where the consecutive CAG that’s not interrupted by anything is determining roughly the time of onset.”

Here is an example: a typical person with HD might have a huntingtin gene with 42 CAGs followed by a CAA and another CAG. Because both CAA and CAG lead to glutamine, the gene test would say that he had 44 CAG repeats, and his huntingtin protein would have 44 glutamines in a row. But the testing in Dr. Gusella’s laboratory would show that there were only 42 CAG repeats before the CAA “interruption.” Another person might have 44 CAG repeats without a CAA interruption. Her gene test would show that she has 44 CAG repeats, the special test would show 44 repeats, and the protein would have 44 glutamines in a row. The first patient, however, who has a smaller actual number of CAG repeats before the interruption, would have a later onset age than the second patient.

This finding “makes a big difference for how you think about the disease and how you might go about trying to intervene in it,” Dr. Gusella concluded.

Dr. Gusella with long-time collaborator Marcy MacDonald, Ph.D., a member of the GeM-HD team (HSDA photo)

The CAG can expand over time

Another “special property” of the expanded CAG repeat is that the longer it starts out, the more likely it is to increase in size over time, Dr. Gusella said.

According to Dr. Pacifici, this so-called somatic expansion could be related to the appearance of symptoms. In this theory, brain cell damage and death occurs as CAG repeat lengths within the cell increase from 40-50 to 100 or more.

Several of the 23 modifier genes identified by the GeM-HD team appear to influence somatic expansion of the CAG; some modifiers seem to make it go faster, leading to early symptom onset, while others seem to slow somatic expansion, leading to a later onset of symptoms.

Onset (start of the disease) is different from progression (how the disease worsens over time).

Dr. Gusella cautiously answered a question from a webinar participant about whether a later onset could slow or hasten “progression” of the disease. He observed that the HD field has not yet established a clear definition of progression, with much debate on the matter. Clearly, as the GeM-HD data demonstrate, there’s a “lesser influence” of the CAG count on the changes in symptoms “than there was on getting there in the first place, of starting to have them.”

Implications for potential treatments

Taken together, the GeM-HD findings have helped to specify – over a large number of people – a number of genetic factors determining HD onset, and to show that it’s not a “cumulative damage as a result of the huntingtin protein,” Dr. Gusella summarized.

“The mechanism of toxicity is uncertain – it might involve huntingtin protein or might act by another mechanism involving the DNA or RNA of the HD gene,” he said.

The search for other modifier genes continues in the quest to clarify how the cells are being harmed, he said. Researchers are also examining how rapidly certain measures of health change before onset, how the disease changes after onset, and the differences in how the disease develops in people with very similar CAG length.

Dr. Gusella addressed the potential implications of the GeM-HD research for clinical trials in progress that seek actually to reduce the amount of the huntingtin protein in brain cells. Run by Roche, the first of these so-called huntingtin-lowering trials, GENERATION HD1, entered a critical and final Phase 3 in early 2019 (click here for the latest update on the trial).

“Those therapies are being applied at a point in time where you’re right around onset or after onset, which means that the expansion of the repeat that is leading to damage has gotten to the point where enough cells are damaged that you are close to or showing symptoms,” Dr. Gusella said. “If you now knock down the huntingtin [protein], if the huntingtin is the mechanism by which the expanded repeat ultimately kills the cell, then it should work. If it’s the RNA, it may work, depending on what the effect of the treatment is on the RNA level.”

However, Dr. Gusella emphasized that the GeM-HD findings do not address when a huntingtin lowering therapy should be given, or whether or how they work.

“I certainly hope that it does,” he added.

Other paths to drugs

Dr. Gusella addressed other ways in which the new understanding of HD genetics might help in the search for treatments. One possibility would be to interfere with the characteristic of the CAG repeat that is seen as driving onset, he said. Another approach could involve the modifiers engaged in DNA maintenance and repair – by manipulating them with drugs, suppressing them, or by activating them.

Yet another way would be to block the somatic expansion of the huntingtin gene, Dr. Gusella continued. Researchers could also use the new techniques developed for manipulating DNA and perhaps even change the number of repeats. Also, huntingtin-lowering drugs (if and when they are developed) could be used in combination with as yet undiscovered modifiers, he said.

Would more genetic information be helpful?

In addition to the Dr. Gusella’s 2019 webinar – his first such presentation for HDSA – I’ve also watched talks at scientific conferences by him, his long-time collaborator Marcy MacDonald, Ph.D., and Jong-Min Lee, Ph.D. According to Dr. Gusella, Dr. Lee “in particular has helped drive these studies.”

People in the HD community often speculate as to what “triggers” the disease. The GeM-HD research provides a partial but important answer with its discovery of modifier genes and other genetic factors that influence the age of onset.

Dr. Jong-Min Lee at the 2015 HD Therapeutics Conference (photo by Gene Veritas)

For many years, I have speculated about my age of onset, almost always referencing my mother’s situation. However, as the GeM-HD research now shows, that is not very helpful because of the great variation in age of onset.

Thus, as I’ve watched the research progress, I have wondered: could one or more modifier genes inherited from my parents have acted to delay my HD onset well beyond my mother’s?

I’ve also thought about somatic expansion: perhaps my mother’s 40 CAG repeats expanded to a much higher number more quickly than mine. Perhaps the other genetic factors outlined by Dr. Gusella have had an impact.

For now, at least, I can’t be tested for the modifier genes or these other factors. As Dr. Gusella indicated, even if I could, it’s not clear how predictive they would be, nor how helpful such knowledge would be.

From 1995 to 2000, my family went through three CAG tests: my mother’s, mine, and our daughter’s. Luckily, our daughter tested negative in the womb, but my wife and I waited for three agonizing months to learn her status.

After those difficult experiences, would I really want to go through more tests? If I could know my genetics to a more precise level, including moment of onset and how the disease would develop, would I really want such information?

Because of the lack of an effective treatment, most at-risk untested individuals decline testing for the CAG count. As Gene Veritas – the person who wanted to know the “truth in his genes” – I’m an outlier.

However, I cannot predict my feelings about further genetic testing until actually facing that possibility. I would only know at the moment they became available.

HD in the vanguard, but still highly complex

A decision to get tested again and my feelings about it would also depend on the availability of effective treatments. With the potential success of the Roche drug and others, doctors and HD clinics are preparing for the likely boom in testing for the CAG mutation, as people seek to learn their status before taking a drug.

As Dr. Gusella pointed out, HD stands in the vanguard of the attempt to apply protein-lowering and other cutting-edge techniques because, unlike the other major neurological disorders, it is monogenetic: it has a single genetic cause.

The critical GeM-HD discoveries could perhaps bolster the effectiveness of these other approaches or even result in unique medicines.

However, the new genetic research also underscores another reality of HD. Despite its monogenetic status, it is complex and features subtle genetic nuances. Huge challenges remain in developing treatments.

For HD-impacted individuals and their families, in the near term much will remain a mystery.

(For further background on the GeM-HD research, click here for the 2019 CHDI presentation “Genetic Modifiers” by Dr. MacDonald. Click here for the 2015 CHDI presentation by Dr. Lee.)