Tuesday, March 31, 2020

Giving back during the COVID-19 pandemic


Many advocates for Huntington’s and other rare diseases work passionately and selflessly for their causes.

Now, as the coronavirus pandemic rages, more and more people around the globe want to give back. 

We are all witnessing the testimonies of the doctors, nurses, and other healthcare workers who offer front-line care for the patients hit with COVID-19, the disease caused by the virus.

As a Huntington’s gene carrier who lost his mother to the malady, I, too, want to help – in part because the crisis has postponed or forced online so many aspects of the HD cause (more on this in an upcoming article).

HD activists can and should do their part to help alleviate this crisis!

Preparing for a surge of patients

Worried about the flood of reports about shortages of personal protective equipment (PPE), I reached out to Yale University class of 1982 colleague and freshman roommate Peter S. Kieffer, M.D., an emergency room pediatrician, to see if I could help, perhaps by organizing an online campaign to support him and his institution. Dr. Kieffer works at HSHS St. John’s Hospital in Springfield, IL. An assistant professor at the Southern Illinois University School of Medicine, he also advocates for the chronically mentally ill through Independence Center

In 2014, after decades out of touch, Dr. Kieffer wrote in an e-mail that he had discovered this blog and my family’s struggle against HD.

“My heart goes out to you and your family as I have been long aware of the challenges of Huntington's disease, its genetic transmission, and the implications of early testing but have never known anyone personally with the diagnosis,” Dr. Kieffer wrote.

Since then, he and his family have donated generously to the Serbin Family Team in the annual Hope Walk of the San Diego Chapter of the Huntington’s Disease Society of America (HDSA). Several years ago, they visited us during their vacation in the area.

In his response to my March 28 e-mail, Dr. Kieffer explained that “physicians in rural Illinois have had more time to prepare for COVID-19 than our colleagues in big cities.”

“Numbers were small, now cases are becoming more frequent, and we are preparing for a surge in the next few weeks which could very easily surpass the ICU bed and ventilator capacity of our two hospitals,” he wrote. “However, Governor [J. B.] Pritzker's early shutdown may help blunt that curve. Although COVID-19 typically sickens children with less severity, they could still pass it to a white-haired pediatrician like myself! Fortunately, we still have enough PPE for what we need.”

So far, Dr. Kieffer has treated a young child who was a “Patient Under Investigation,” although tests have not yet confirmed COVID-19 in any of his patients, he wrote in an e-mail today.

Dr. Kieffer agreed to contact me should his institution need aid. I know that I personally cannot send PPE or medical equipment, but raising awareness about the local predicament and raising funds could be a way to assist.


Peter S. Kieffer, M.D. (photo by Southern Illinois University School of Medicine)

Donating critically needed blood

There are other ways I - and you - can help now.

After seeing an American Red Cross blood drive appeal on TV a couple weeks ago, I scheduled a donation for March 30. 

Last week, I suspended my minimal meat diet to raise the iron levels in my blood, as recommended by a Red Cross employee, who set me up for a “power red” donation (double the number of red blood cells).

That employee also told me of a critical shortage of blood, as reported by the Red Cross and in the media (click here to read more).

At the donation center, an employee took my temperature at the door, to make sure I had no fever and, therefore, possible COVID-19 symptoms. Donors were spaced about eight feet apart, to avoid contamination, and the nurses and other workers wore not only the typical gloves, but also masks.

Unfortunately, in a pre-donation pin-prick blood test, I fell just shy of the necessary iron level for a power red.

However, I was able to make a simple “whole blood” donation.


Gene Veritas, aka Kenneth P. Serbin, at an American Red Cross blood donation center in San Diego (photo by Gene Veritas)

Running risks for the common good

On the way home I thought: in any public place, we all run the potential risk of contracting the coronavirus, even at a facility like the Red Cross. 

I washed my hands very thoroughly, twice at the facility, then again at home. None of the donors, nor I, wore a mask. However, I may on future trips to public places, given the increasing number of reports about their effectiveness in blocking droplets that might contain the virus.

Like so many other HD gene carriers, I’ve spent many moments monitoring myself for symptoms. Now, I’ve started doing that for the virus.

However, physicians like Dr. Kieffer, first responders, grocery store workers, and so many others risk their health daily for the common good.

We all need to embrace the spirit of Dr. Kieffer’s words to me, echoing one of the signs at the Red Cross: “Thanks so much for your life-giving donation!”


Above, Gene Veritas' blood pack, and below, Gene Veritas in a donor chair at the American Red Cross (photos by Gene Veritas)



Sunday, March 15, 2020

In times of crisis, Huntington’s and other chronic disease communities provide examples of fortitude


For individuals and families facing Huntington’s and other chronic diseases, daily living often seems like nonstop crisis. These communities, including selfless caregivers, have demonstrated great fortitude.

The current coronavirus pandemic adds another giant, unknown layer to the kind of challenges and suffering many in these communities are already accustomed to.

The country’s reaction to the pandemic and the shutdown of daily routines starkly reminded me of the national climate in the months following the September 11, 2001, terrorist attacks on New York City and Washington, D.C. Resulting in 3,000 deaths, 9/11 led to a temporary grounding of all domestic flights, the fear of subsequent attacks (including nuclear), and panic regarding other, unrelated terrorist threats such as the deliberate spread of highly dangerous anthrax bacteria. The economy also suffered serious long-term effects.

Members of the San Diego Chapter of the Huntington’s Disease Society of America (HDSA), in the bewildering days after 9/11, held a previously planned fundraiser and got ready to hold its first Celebration of Hope Gala.

With so many other, urgent demands on potential donors, we feared people might not remember our needs.

Later that fall, in an editorial in Conquest, our chapter newsletter, I wrote the following:

On September 20, less than two weeks after the crisis, members of the public and local organizations participated in the Third Annual Indy Go-Kart Challenge to raise funds for the cure of HD. Then, on October 11, the one-month anniversary of the attack, several hundred San Diegans took part in the Celebration of Hope Dinner to assist the Center of Excellence for Family Services and Research at the University of California, San Diego. We raised tens of thousands of dollars at these events. Elsewhere in the country other HDSA events went on as planned.

In this manner HDSA and its supporters have sent a resounding message that generosity and compassion are far stronger than the hateful politics of terror. We will move ahead, no matter what the odds are against us. This is the American spirit.

Unprecedented impact on daily life

So far, the coronavirus pandemic has had an unprecedented impact on the United States, with schools, universities, and many other institutions closing or switching to remote, online operations. As of March 15, at least 65 people had died in the U.S., with worst-case scenarios projecting 200,000 to 1.7 million deaths.

The pandemic has changed my workplace unlike any earlier tragedy. After 9/11, no classes were cancelled by my employer, the University of San Diego (USD). In 2003, the devastating Cedar Fire in San Diego County left 15 dead, destroyed 2,820 buildings, and charred more than 280,000 acres. In response, USD shut down for just two weeks and finished the semester normally, with everybody back on campus.

Now, because of the virus, USD has cancelled classes this week and will finish the semester (eight more weeks, plus final exams) online. The University of Pennsylvania, where my HD-free daughter Bianca studies, will do the same. My wife and I are worried that Bianca will not be able to make it home in time before potential travel restrictions.

Each hour, we learn of more victims of the virus and further curtailment of life as we know it.

Impact on the HD community

The global crisis has also impacted the mission of HDSA and individual HD families.

On March 13, HDSA CEO Louise Vetter sent an e-mail to “friends of HDSA” announcing that the organization “holds the well-being of our families, volunteers and staff as our top priority” and will therefore postpone “ALL local HDSA events (educational & fundraising) nationwide” until April 30. That complies with public health recommendations to curtail public gatherings to slow the spread of the coronavirus.

According to Vetter, HDSA still plans to hold its 35th Annual Convention in New Orleans, June 4-6, but will continue to follow the guidance from the Centers for Disease Control, World Health Organization, and state and local health agencies.

HDSA’s national headquarters in New York City is closed. However, the entire staff is working remotely and has the resources “to continue the uninterrupted support of our mission during this time,” Vetter assured.

The Huntington’s Disease Youth Organization postponed its May 2020 international congress in Glasgow, Scotland, to March 2021.

I have accepted an invitation to deliver the keynote address at the 37th National Conference of the Huntington Society of Canada in November, but have been told to hold off on reserving flights until the pandemic’s long-term effects become clear.

Visiting the afflicted

For one HD community member and blogger, Mandi, 33, the pandemic meant that on March 12 she could not visit her 58-year-old HD-stricken father, Danny, at the Missouri nursing home where he resides.

“They are locking all doors for the safety of people there,” wrote Mandi, a dedicated caregiver and herself at risk, but untested, for HD. “Was my first reaction sad I couldn’t see my dad? Sure, but I immediately checked myself. I realized my own selfish want to see my dad was tiny in comparison to keeping the people in the nursing home safe because who knew if I was a carrier since you can have it for over a week and not show symptoms.”

Mandi pointed out how the nursing home’s restriction is “terrifying for those of us with possibilities of losing family.” She wants “to do everything in my power to protect him as I always have.”

However, she concluded: “Until we really know what we are dealing with let’s just take the precautions seriously.”


Danny (left) and Mandi (family photo)

Especially resilient

With the coronavirus pandemic, the world can learn from the example of the HD community and our generous supporters.

We in the HD community, and other neurological disease groups, face relentless adversity. HD grinds down the brain, leaving the affected like my late mother unable to walk, talk, or care for themselves. Caregivers like Mandi and my late father are true “HD warriors.” 

However, because of this, we have developed a very realistic view of life.

“We are all in a race to death, but people at risk for life-shortening diseases know that their time to the finish line is painfully fast and troubled,” I wrote in 2009 in an article titled “HD: hurtling towards death.”

At the same time, we also have a special appreciation for the “preciousness of life.”

Confronting HD makes us especially resilient. I am hopeful that the HD community will successfully meet the challenges of the coronavirus pandemic and, as in facing past challenges, become even stronger.

Monday, March 02, 2020

CHDI head scientist Pacifici: ‘hang on in the learning roller coaster ride of Huntington’s disease clinical trials’


With historic clinical trials now aiming for the first effective treatments for Huntington’s disease, affected individuals and their families need to clearly understand the news about these efforts and their implications.

That critical recommendation was offered by Robert Pacifici, Ph.D., the chief scientific officer of the nonprofit HD-treatment-seeking CHDI Foundation, Inc., during an interview on the last day of the organization’s 15th Annual HD Therapeutics Conference, held February 24-27 in Palm Springs, CA.

“Getting to this stage – which we’ve all so been hoping for – is still a bit of a roller coaster ride,” Dr. Pacifici told me. “You have to be able stay in our seats and weather the ups and downs. I think we’re well-poised for some great news, as some of these trials hopefully report out. Even a whisper of efficacy would be just amazing.”

However, there will also be “disappointments, where, despite our best attempts, some of the things that showed so much promise didn’t end up meeting their endpoints,” he cautioned. “But it’s going to be a learning roller coaster. So hang in there. Don’t lose hope.”

The HD-affected (and their caregivers) should keep informed about the trials by consulting their physicians, attending meetings of patient organizations such as the Huntington’s Disease Society of America (HDSA), and keeping abreast of developments in such sources as HDBuzz.net and this blog, Dr. Pacifici advised.

Become knowledgeable, he urged, “so that you are not disproportionately spooked or elated when these bits of information come out.”


Featured conference speaker Christopher Austin, M.D., the director of the National Center for Advancing Translational Sciences/National Institutes of Health, presents part of the Drug Discovery, Development and Deployment Map the research and pharmaceutical community must navigate in today's complex and challenging scientific world (photo by Gene Veritas, aka Kenneth P. Serbin).

‘Genuinely interested’ in treating HD

Dr. Pacifici began the interview noting the excitement generated by the conference and within the HD field, with a record 380 participants, overflow seating, and more than 100 people turned away. However, CHDI’s goal ultimate goal is not to host well-attended conferences, but to stop HD, he emphasized.

“There are that many people who are genuinely interested in presenting the results and learning about the incredible developments that are unfolding in Huntington’s disease drug discovery and development,” he said of the response to the conference.

Dr. Pacifici also noted the very high quality of the presentations, in comparison with the early years of the event. 

“We’re batting 1,000 this time – every single talk very relevant,” he observed.

Considered science fiction a decade ago, the new technologies applied in HD research are transforming the field and allowing for a more thorough analysis of cells in the quest to understand the disease, he added.

Dr. Pacifici cited the example of whole-genome sequencing on individual brain cells, which permits the reading of the DNA sequence of “every single gene in there, and doing that thousands of times.” 

You can watch my interview with Dr. Pacifici in the video below. For my video album of the conference, please click here (and check back in the coming days as I add videos).


New understanding of the protein

Dr. Pacifici also discussed new research into the huntingtin protein presented at the conference. Such research suggests that the protein might have a key role in maintaining the integrity of the huntingtin gene and also in the way the gene expands over time (known as somatic expansion), which researchers now see as a key driver of the disease (click here to read more).

With this potential new finding, a single drug might be developed to counteract the mutant protein by both reducing its quantity and preventing it from causing somatic expansion, he speculated.

He pointed in particular to the presentation by Jeffrey Carroll, Ph.D.

A possible key biomarker

Dr. Pacifici also commented on the discussion around phosphodiesterase-10 (PDE-10). A PDE inhibitor was seen as a potential “Viagra for the brain” but ultimately showed no improvement in a clinical trial run by the drug giant Pfizer.

However, PDE-10 might still play a role for the HD community as a biomarker (sign of disease and/or effect of a treatment), Dr. Pacifici said.

“It is pretty uniquely expressed in the neurons that we know are affected by Huntington’s disease, the medium spiny neurons,” he explained. 

If PDE-10 decreases in HD because the gene is shut down or cells die or some combination of both, and “if you had a molecule that bound to PDE10 and sent out a signal, then you could know how much PDE10 was in that brain, and if it was declining, that would mean that the disease was progressing.” Similarly, with an effective therapy, “you would see PDE10 levels going up,” Dr. Pacifici added.

The U.S. Food and Drug Administration is unlikely to approve a drug based solely on evidence from a biomarker, because it needs to see actual clinical benefits in patients, Dr. Pacifici said. However, the biomarker could give a drug maker the “confidence” that the “intervention is doing its job biologically and now it’s worth waiting for the clinically meaning outcome.”

(The presentation by Steven A. McCarroll, Ph.D., of the Harvard Medical School, included discussion of the role of PDE-10.)



Above, Dr. Steven McCarroll answers a question from the audience after his presentation on single-cell analysis of HD biology. Below, McCarroll lab researchers Nora Reed (left) and Christopher Mullally with the lab's poster on single-cell analysis, which took second prize in the poster competition (photos by Gene Veritas).



The terrifying truth about drug development

Dr. Pacifici reflected on the in-depth talk by the conference’s featured speaker, Christopher Austin, M.D., the director of the National Center for Advancing Translational Sciences (NCATS) of the National Institutes of Health. NCATS, founded in 2011, aims to speed the development of treatments and cures.

I asked Dr. Pacifici to comment on the phrase that struck me from Dr. Austin’s presentation: “The hard work that nobody else wants to do.”

Scientific research is “unsexy” and “difficult to understand,” but Dr. Austin challenged the field to forge ahead, I observed.

“He painted a pretty bleak picture of how we’re sadly finding diminishing returns on our investment,” Dr. Pacifici said regarding drug investigation in general. “In other words, he kind of flipped around Moore’s law. Instead of things getting better and faster, the more money we spend, the fewer treatments we see coming out, especially for the harder neurological diseases.”

Dr. Austin presented to the audience what he called a “truly terrifying fact”: “The number of new drugs approved per billion dollars spent, inflation-adjusted, has gone down by half every nine years, since 1950.”

You can learn why this is so – and its very serious implications for HD – by watching Dr. Austin’s presentation by clicking here.

The HD field hopes to be the exception and the model

Dr. Pacifici pointed to the difficult and complex challenges involved in drug discovery, as illustrated by Dr. Austin.

Everybody wants to be the “star” that “made the compound that turned out to be the cure,” Dr. Pacifici said. But imagine: the compound is there, but no patients are available to do the clinical trial. Or patients participate, but researchers lacked the “outcome measures to see whether people were actually getting better.” Or, antibodies and assays needed to measure the samples derived from patients weren’t there.

Those things are the not-so “sexy” but need to get done, he said.

The HD field will need to overcome the inertia of diminishing returns, Dr. Austin emphasized. Deeply familiar with HD science, he believes that HD as a monogenetic disease has the potential to do so and could serve as the model for treating other, more common neurological disorders.

Dr. Pacifici agreed. He praised the HD research and biotech community not only for its commitment to make sure that key elements of the drug-hunting process are “proactively put in place,” but the “selflessness with which they are shared, so that those don’t represent competitive advantages for one company or another. I think everybody has come to the realization that this is a really hard problem. It’s no use competing with each other. We’re going to have to help each other.”


At the start of his talk on huntingtin-lowering strategies, Ignacio Muñoz-Sanjuán, Ph.D., a CHDI scientist and the co-founder of Factor-H, reminded the audience of the goal of the HD cause: to help individuals like Anyervi (in cap) and Brenda, two youths from South America with juvenile HD (photo by Gene Veritas).

Thursday, February 27, 2020

At Therapeutics Conference, landmark study of young gene carriers highlights how Huntington’s disease researchers seek to solve critical puzzles


Armed with ever more impressive data and a deeper understanding of Huntington’s disease, scientists and drug hunters convened at the 15th Annual HD Therapeutics Conference this week, facing the complex puzzles that still hinder the quest for treatments for this deadly neurological disorder.

One of those puzzles: how to not only treat symptoms, but to prevent them, especially in young presymptomatic carriers of the HD gene, so that they don’t have to spend their lives fearing the currently inevitable onset of this devastating disease.

On February 26, Sarah Tabrizi, FRCP, Ph.D., of University College London, answered key questions about what kinds of health consequences young presymptomatic gene carriers suffer decades before they’re likely to develop the disease in midlife.

Previous studies have demonstrated that brain shrinkage can occur as early as 15 to 18 years before predicted age of onset. Ranging in age from 18-40, the 64 gene carriers in Dr. Tabrizi’s HD Young Adult Study went through state-of-the art brain scans and cognitive testing, and also provided samples of blood and cerebrospinal fluid (CSF) for analysis. These at-risk volunteers are, on average, 24 years from estimated onset.

This study, in line with “The Path to Prevention” (one of five major themes of the 2020 conference), is aimed at helping identify the optimal time to treat gene carriers to slow or prevent their neurological decline.

“Comprehensive cognitive testing was normal,” as compared to 67 non-HD-affected individuals, reported Dr. Tabrizi in her presentation to the conference. “There were no significant psychiatric differences, which I found very interesting, because I would have predicted they would’ve been big differences.”

Dr. Tabrizi said that "there’s always been a thought that carrying the HD gene hard-wired you for psychiatric burden,” but the Young Adult Study suggests that such symptoms become more prominent closer to onset.

“I think that was – and I don’t say this lightly – a landmark presentation,” Robert Pacifici, Ph.D., the chief scientific officer for CHDI Foundation, Inc., the conference sponsor, told me today, adding that Dr. Tabrizi’s team carried out the study with “a high degree of rigor and granularity.”

“The participants seem to be remarkably well,” Dr. Pacifici observed. The absence of many of the neurological and other problems typical of HD is an encouraging prospect for developing safe and well-tolerated treatments that could “not just reverse, but actually prevent” HD, he said.

Dr. Pacifici lauded the study volunteers for their "unbelievably selfless participation," including submitting to the study's "incredibly rigorous battery."


Above, Dr. Sarah Tabrizi presenting her talk on the HD Young Adult Study at the 2020 HD Therapeutics Conference, February 26, 2020, and, below, a closeup of Dr. Tabrizi (photos by Gene Veritas, aka Kenneth P. Serbin)


Overall, ‘good news’ for young gene carriers

The young gene carriers in the study did appear to go through a small change in the area of the forebrain known as the striatum, consisting primarily of the putamen and the caudate, the deep brain regions that are most affected by HD. The striatum helps to control our movements and rewards system.

The study found a significant reduction in the size of the putamen, but an insignificant reduction in the caudate. Nevertheless, Dr. Tabrizi explained that, based on this study, these differences (in comparison with the normal subjects) were “not associated with predicted years to onset.”

“So what we now know, based on the data, is that the striatum never appears to be the same size as the control group,” she explained. 

The “very slightly smaller” striatum may suggest a “neurodevelopmental effect” (the way the brain develops) that is “well compensated for,” Dr. Tabrizi said, meaning that the brain adjusts without clear damage. She added that it “might be why the striatum is vulnerable later in life, because it has a double hit.” As mentioned by Dr. Tabrizi, this interpretation resonates with the research of Peg Nopoulos, M.D., who has studied the compromised development of the brains of people affected by juvenile HD.

Alternatively, neurodegeneration early on could be “too subtle and variable” to associate with predicated age of onset, Dr. Tabrizi noted.

Other imaging results showed no decrease in the white matter (the tissue in the brain made of nerve fibers and possibly involved in cognitive problems in HD) or any other aspect of the brain measured in the study, indicating that the subjects were still “very far from onset,” Dr. Tabrizi continued.

“This is really good news,” Dr. Tabrizi stated.


Douglas Langbehn, M.D., Ph.D., a psychiatrist and biostatistician at the University of Iowa who did the statistical analysis for the HD Young Adult Study, listens to Dr. Tabrizi at the Therapeutics Conference (photo by Gene Veritas).

The ongoing search for reliable biomarkers

The study also involved the ongoing search for reliable biomarkers (signs of disease and drug efficacy).

The study detected mutant huntingtin protein in the subjects’ cerebrospinal fluid. “CSF mutant huntingtin was higher in those closer to [predicted] onset, suggesting that some injury is releasing mutant huntingtin [from the brain], but very subtle,” Dr. Tabrizi said.

Several other biomarkers were elevated in the subjects’ CSF, again indicating an early, subtle injury, but most of those subjects had readings showing levels very close to those of the unaffected control subjects, Dr. Tabrizi continued. Furthermore, six other biomarkers were normal, she added.

The Young Adult Study points to the one CSF biomarker in particular, neurofilament light, a marker of brain damage, as potentially helpful in measuring disease progression and treatment response in people decades from onset, Dr. Tabrizi concluded.

A drug that kept neurofilament light at very low levels could prevent degeneration of the brain, she added.

You can watch Dr. Tabrizi’s presentation in the video below.


A moving keynote address

With a record attendance of 380, the conference opened on February 24 with a moving keynote speech by Amy Merkel, a 45-year-old nurse from Wisconsin and the founder of Starfish Yoga.

A small company, Starfish focuses on encouraging constructive coping skills, primarily for people affected by past imprisonment, sexual abuse, and neurological disorders, including HD.

Amy, who titled her talk “Life is Good,” belongs to a family deeply affected by HD. She recounted her extended family’s decades-long struggles with HD. Amy received a standing ovation.

Stay tuned to this blog for additional reporting on the conference, including an overview provided in my interview with Dr. Pacifici.


Above, HD advocate Amy Merkel addresses the 15th Annual Therapeutics Conference, and, below, poses with researchers Dr. Sarah Tabrizi (far left), Leslie Thompson, Ph.D. (second from right), and Gillian Bates, Ph.D. (photos by Gene Veritas).


Monday, February 24, 2020

Striving to overcome the doom of Huntington’s disease


Usually, I experience a whirlwind of emotions during and especially immediately after the annual Huntington’s Disease Therapeutics Conference, held in Palm Springs, CA.

This year, however, intensifying my advocacy in what I call the “HD movement,” I feel that I’ve reached another level of engagement. Paradoxically, at the same time, I feel that I’ve attained greater calm and insight regarding the disease and its impact on the community.

After my last article – on the pathbreaking scientific evidence suggesting how and why the HD age of onset varies widely and how I’ve reached 60 healthy – I’ve read stories in Facebook HD groups confirming that variability.

Some pointed to extremely early, very tragic onset, but others resonated with my (very fortunate) situation of having gone more than a decade beyond the point of my mother’s first symptoms. Significantly, scientists are seeking ways to use the biological mechanisms behind delayed onset to produce treatments.

As I pondered those more optimistic scenarios, I thought: “Does HD have to be only a story of doom?”

Clearly, in many instances, it still is.

On February 19, at the packed, moving screening of the HD documentary Dancing at the Vatican at my university, one HD family member recalled how, out of ignorance, both a parent and a grandparent had been kept in a straightjacket.

However, the collective celebration of the film’s portrayal of Pope Francis’ historic audience with HD families in Rome also demonstrated how far the HD cause has come. Thanks to Francis – but also to thousands of family members and advocates around the world – HD is “hidden no more.”


A life-size stand-up poster of Pope Francis at the February 19 screening of Dancing at the Vatican at the University of San Diego (photo by Gene Veritas)

How far we've come

An illuminating panel discussion at the screening illustrated how awareness has grown on all fronts. The presence of representatives from four biotech sponsors underscored the growing commitment to discover effective treatments.

The evening of February 21, the mother of a young man who died of juvenile HD left me a voicemail. She spoke of how the near-20-year struggle to care for her son led her to develop bipolar disorder and PTSD.

That sounds devastating. However, she also reminded me of an important trend in the HD community, in which the affected are no longer referred to as “HD people” but as “people with HD.”

“You’re not Huntington’s disease,” she said. “How could I ever look at my son and think, ‘disease?’”

At this evening’s opening of the 15th Annual HD Therapeutics Conference, sponsored by CHDI Foundation, Inc., I will have renewed hope for the development of effective treatments. As understanding of the disease has evolved, so have the approaches to achieving those treatments.

On February 27, conference attendees will hear a report on a clinical study investigating RG6042, the gene-silencing drug also currently under evaluation in a Phase 3 clinical trial run by Roche.

If successful, that trial will have produced the first treatment to slow, halt, and perhaps even reverse HD.

That could signal the end of doom for tens of thousands of HD-affected families around the world.

Wednesday, February 12, 2020

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.)