‘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.

What’s in a name? How Huntington’s disease gene carriers are seen by themselves and by others

In 1999 I received the results of a genetic test that showed I had 40 CAG repeats on the huntingtin gene inherited from my mother, who died of Huntington’s disease in 2006 after a two-decade struggle with the disorder.

Everybody has this gene, which first appeared 800 million years ago in a species of amoebae. Huntingtin helps our cells function properly.

The gene’s CAG repeats refer to the sequence of three nucleotide bases – cytosine, adenine, and guanine, all building blocks of DNA – on the DNA molecule. Most people have 27 or fewer repeats. The gene I inherited from my father had fewer than 20.

My mother’s high CAG count caused her to start experiencing HD symptoms – typically manifested as emotional distress, cognitive loss, and involuntary movements – in her late forties.

The term “CAG repeats” and my mother’s count of 40 were two of the very first facts I learned about HD after receiving news of her diagnosis in late 1995.

The geneticist used the same terminology when he revealed my test results.

However, as he told me and many other recipients of HD test results, “a positive test result is not a diagnosis.” While everybody with 40 or more repeats will develop HD in his or her lifetime, scientists cannot yet predict the exact moment and type of disease onset.

According to John Warner, Ph.D., the director of biostatistics for CHDI Management, Inc., which carries out the day-to-day mission of the non-profit, HD drug-discovery biotech CHDI Foundation, Inc., 95 percent of those individuals with 40 CAG repeats will experience disease onset between the ages of 50 and 74. (A future article will explore the statistical meaning of the CAG count in greater detail.)

With an ominous test result at age 39 but no symptoms, I needed to construct a definition of my genetic predicament for both myself and for others.

As I said recently in an interview, unlike treatments for certain kinds of cancer, I cannot irradiate my defective huntingtin gene to destroy it. It’s part of me, literally residing in every cell.

Because of its genetic nature, HD also requires a far more nuanced kind of diagnosis. Subtle symptoms can exist for years before the more noticeable symptoms commence.

'Gene-positive'

For many years, I referred to myself as “gene-positive for Huntington’s disease,” a term I heard often in HD family and scientific circles. I also used phrases such as “tested positive for HD.”

“Gene-positive” echoed the term “HIV-positive” used by the AIDS community. It meant not only that I had tested positive for a condition, but that I inevitably faced its dire consequences.

Thus, “gene-positive” resonated with the deep stigma, discrimination, and alienation suffered by members of both the AIDS and HD communities.

“Gene-positive” further implied an activist stance. As with the early years of the fight against AIDS, we in the HD community needed to tell the world we needed treatments and the resources to find them.

I experienced all of these feelings in the late 1990s and early 2000s, as I immersed myself in advocacy work for the Huntington’s Disease Society of America.

They remain with me today as we still await the discovery of an effective treatment.

Changing perceptions

As my knowledge about HD increased, and as I came into ever closer contact with HD researchers in labs and at events such as the annual CHDI-sponsored HD Therapeutics Conference, both my perceptions of HD and the terms I used to describe my situation changed.

As I learned to my first visit to CHDI in 2009, many scientists see gene-positive individuals as genetically and, at least at the cellular level, even functionally compromised from birth.

I started to hear scientists used the word “premanifest” to describe asymptomatic, gene-positive individuals.

Soon I would be introduced to “prodrome” and “prodromal”. A precursor or forerunner to the disease, prodrome refers to the period before onset.

However, I could never imagine using such a technical term to describe myself to others.

Scientists and physicians also used “asymptomatic” and especially “presymptomatic” to describe people like me. I have frequently used the former to indicate to people that I face the danger of HD but am fine for now.

Other phrases I have used or heard include: HD gene carrier; HD gene mutation carrier; asymptomatic HD gene carrier; disease-gene carrier; tested positive for the genetic defect that causes Huntington’s disease; and carry the gene for Huntington’s disease.

Living with the ‘phantom gene’

At the World Congress on Huntington’s Disease in Rio de Janeiro last September, HD activist, historian, and author Alice Wexler, Ph.D., noted that much recent scientific discussion has focused on defining when HD actually begins.

During a panel on coping with HD, Dr. Wexler asked how global HD advocate Charles Sabine and I – both gene-positive but asymptomatic – viewed ourselves as individuals living with the “phantom gene” and in what circumstances would consider ourselves as having HD.

“It changes for me depending on where I am,” I replied. “If I’m at a conference like this: ‘Oh, my God! I have HD.’ Because I see all these studies and brain scans and searches for biomarkers … and references to me as prodromal…. There’s a tendency of the scientific community to see gene carriers as diseased from Day One.”

In settings such as my doctor’s office, I felt different, I said. “My doctor’s telling me: this time you got a clean bill of health.”

Charles, agreeing with my outlook and saying that he “treasured” his current good health, answered the question in a “wider, more metaphysical sense.”

“We are not just someone who’s had a bit of bad luck,” Charles said about having inherited the HD mutation. “We are a part of history. I have absolutely not a single shred of doubt in my mind that, whether it’s 20, 50, or a 100 years [off], that this disease will be managed just like HIV-AIDS can be now.”

You can watch the entire exchange in the video below.

Living with a 'Phantom Gene': Two Huntington's Disease Gene Carriers Discuss Their Perceptions from Gene Veritas on Vimeo.

A new shorthand

The latest conception emerged at the CHDI-sponsored HD therapeutics conference in Palm Springs, CA, last month, where Andrea Varrone, M.D., Ph.D., of the Karolinska Institutet (Sweden) gave a presentation whose title included the phrase “Huntington’s disease gene expansion carriers.”

That phrase very accurately describes someone like me, because it specifically identifies the cause of the disease: an expansion of the huntingtin gene. However, the term does not by itself identify whether a person is symptomatic or asymptomatic.

Nevertheless, it’s good shorthand for the concept of expanded CAG repeats.

However, both the phrase and its acronym, HDGEC, are a mouthful! They might not resonate with the community, and even less so with the general public, which is more familiar with the idea of a “mutated gene” than with the term “expanded gene.”

‘You don’t look like an HD person’

The abundance of terms to describe asymptomatic HD gene carriers reminds me that those of us in this predicament are undergoing “the new and harrowing human experience of living in the gray zone between a genetic test result and the onset of a disease foretold.”

Scientists have demonstrated that changes in the brain occur ten and even 20 years before onset – meaning that my brain may already be seriously compromised, even though I function just fine.

Inexorably, perniciously, but silently, HD attacks the brain.

However, it’s not discernible from the outside.

“You don’t look like a person who has Huntington’s disease,” a health professional told me recently as I contemplated him writhing with pain and discomfort from a knee operation that forced him to wear a brace and use crutches.

There is no particular way for a premanifest person to look! Moreover, no “crutch” yet exists to help the presymptomatic HD brain recover from the initial assault on the cells.

As an HD gene carrier and advocate for this orphan neurological disorder, I continually face the challenge of explaining the seriousness of the disease and its many social implications.

Along with other neurological disease communities, we in the HD community are still searching for the right formula to project the urgency and significance of our predicament.

A temporary escape

Often those of us in the gray zone prefer not to deal with HD. Unlike others in the community, we don’t yet face the minute-by-minute struggle with symptoms.

At the local HD support group meeting this week, I was the only at-risk individual to appear. Even so, the facilitator and her replacement-in-training for the at-risk section (which normally includes both tested and untested asymptomatic individuals) held a session with me. I wanted to help bring the new person up to speed on the history of the support group and the needs of the at-risk section.

We noted that the support group’s caregiver section is usually the largest of the three subdivisions, followed by the section for those already affected.

The at-risk is usually the smallest – even though at-risk individuals outnumber affected individuals nationally by a ratio of at least five to one.

I sympathize completely with the occasional need to “escape” from HD, so I understand why other at-risk people didn’t attend the meeting. However, I am hyper-aware of the need for more individuals to participate in research studies and clinical trials to create effective treatments.

The transition to patient status

The facilitators and I also discussed the difficult choice individuals and facilitators must make in transitioning newly affected individuals out of the at-risk section and into the affected section.

I’ve witnessed this transition for a number of people. I can’t imagine how hard it is.

Once the symptoms begin, the terminological ambiguity ends. They are now “affected” or “symptomatic” individuals. They are “HD patients.”

I anxiously await the moment when an effective treatment would not only ameliorate these and other patients’ symptoms, but also prevent onset in asymptomatic gene carriers.