A veteran neurologist’s book offers tools for navigating the ‘turbulent world’ of Huntington’s disease

 

In the fight against any disease, affected individuals and health professionals can arm themselves with an invaluable tool: detailed, cutting-edge knowledge about a condition’s medical and social impact.

 

For the Huntington’s disease community and related disorders, Thomas Bird, M.D., has made a key contribution with his book Can You Help Me? Inside the Turbulent World of Huntington Disease, published last year (Oxford University Press).

 

A retired neurologist who has observed more than 1,000 individuals with HD, Dr. Bird has produced one of the most important – and most accessible – introductions to this devastating disorder. Can You Help Me? will remain relevant for years.

 

Dr. Bird is an Emeritus Professor of Neurology and Medical Genetics at the University of Washington in Seattle, WA. His career spanned more than 40 years, including pioneering work in the field of clinical neurogenetics (diagnosing and evaluating hereditary nervous system disorders). His patients included sufferers of Alzheimer’s disease (AD), Parkinson’s disease (PD), and other severe, chronic brain conditions.

 

“I have been […] constantly amazed, puzzled, distressed and impressed by the trials and tribulations of these families coping with it,” Dr. Bird writes of Huntington’s. (As with some in neighboring Canada and elsewhere, he calls it “Huntington disease.”) “Dealing with HD has been so moving, so unsettling and so challenging for me that I felt compelled to write about it.”

 

“Can you help me?” a desperate HD-affected man wrote Dr. Bird from the state penitentiary in 1980 seeking medical assistance. That question reverberated in Dr. Bird’s encounters with many other HD people and their families and caregivers.

 

With non-technical, limpid prose, Dr. Bird tells the full story of HD’s wide-ranging medical, socioeconomic, and legal implications through a series of poignant vignettes, based on hundreds of HD cases. He changed identifying information to preserve patient privacy, and in some cases created composites of two or three different individuals.

 

Can You Help Me? will ring familiar to veterans of the HD cause, but it also offers new revelations and insights about HD’s impact. Also, it provides an excellent primer for families new to HD.

 

 

Key lessons about bioethical challenges

 

Many of the stories in Can You Help Me? center on the bioethical challenges faced by HD families, such as the complex ramifications of genetic testing.

 

Dr. Bird retells the story of a deeply troubled young man from an HD family killed by the police after a life of drug use and many clashes with the law – anti-social behavior perhaps resulting from the disease. The man’s aunt pleaded with Dr. Bird to have the coroner confirm the man’s HD status, because he had a three-year-old daughter for whom the test result would someday hold great relevance. Divorced, the man had lost contact with the mother.

 

“Needless to say, this was uncharted territory for us,” Dr. Bird writes of his clinical team. “The appropriate legal or ethical aspects of this case were not clear to me, but I called the University Hospital genetics lab and explained the situation.” On Dr. Bird’s orders, the lab performed the test.

 

The test demonstrated that the man indeed did have HD – “another burden” for the extended family, as Dr. Bird writes.

 

“To this day, I do not know if we followed the correct strategy in trying to help this family,” he concludes. It seemed like “quick thinking” to ask the coroner to save a sample of the dead man’s blood for HD testing, he observes. But many questions remained, including when and how to tell the girl of her at-risk status, he adds.

 

Dr. Bird believed that he might encounter the family again, when the little girl had grown up.

 

Dr. Thomas Bird (book jacket photo by Chang En Yu)

 

No ‘typical’ patient

 

In an appendix, Dr. Bird provides an overview of the genetics of HD and the genetic testing process. In general, as I noted in a previous article, Dr. Bird’s book has helped move the HD field from a traditional, more limited kind of genetic counseling to broader “genetic education.”

 

Can You Help Me? reflects on many other key issues for the HD community.

 

He offers valuable insight into the challenges faced by health professionals working with HD patients, as exemplified in the story of a patient clinic who shot himself. “Could we have done more?” Dr. Bird asks. “These situations are heavy burdens for everyone to bear.”

 

Dr. Bird’s vignettes underscore another crucial point in line with the latest medical and scientific research into the disease: there is no “typical” HD patient, as symptoms manifest uniquely in each case.

 

Notably, Dr. Bird does not describe HD as being like a combination of other diseases such as AD and PD, a shorthand some in the HD community use. Dr. Bird instead compares HD to these and other conditions, thus adding vital context.

 

Dr. Bird also emphasizes the need to end the false dichotomy between psychiatric “mental” diseases like schizophrenia and “brain” diseases like HD. Both originate in the brain, he points out, and both cause “mental illness.” Psychiatry and neurology should intersect more, he argues.

 

A contribution to the history of HD

 

In researching the book, Dr. Bird did important historical legwork. For instance, he painstakingly tracked down important episodes such as the use of lobotomies as an attempt to treat HD.

 

“It is estimated that 50,000 lobotomies were performed in this country between 1938 and 1955,” Dr. Bird writes. “Since persons with HD were often institutionalized and lobotomies were common, it is likely that many of these operations were performed on patients with HD.”

 

Although the procedures on HD people were “not easy to document,” Dr. Bird finally found evidence by examining medical texts. In all, Dr. Bird estimates that “perhaps more than 100” people with HD had the operation. It is not currently recommended for HD.

 

A ‘Princess in Pink’

 

Although many vignettes are gut-wrenching, Can You Help Me? also highlights the sometimes-brighter side of the HD story, such as individuals with late onset, mild symptoms, and productive lives.

 

That message holds two-fold meaning for me as an asymptomatic 61-year-old HD gene carrier who saw his mother develop the disease in her late 40s and die at 68.

 

First, I remember how fortunate I am to have reached this stage without symptoms.

 

Secondly, as a writer and advocate, it reminds me that, no matter how badly the disease has turned people like my mother into shadows of themselves, we should see them as humans struggling with disabling symptoms.

 

A caring community can seek to alleviate some of that burden.

 

One of my favorite stories from Can You Help Me? spotlights the “Princess in Pink,” Bobbi, a little girl who, although afflicted with juvenile HD, maintained her cheerfulness.

 

Bobbi’s fifth-grade teacher, Miss Perry, “decided to be proactive,” Dr. Bird writes. “She wanted to make Bobbi more comfortable in the classroom and educate her other students about Bobbi’s disease and how to relate to persons with disabilities.”

 

The class created the “Princess Project” to discuss HD and create a booklet ­– with a pink cover and a picture of Bobbi wearing a pink crown – about Bobbi and her condition. The classmates wrote perceptive and compassionate entries and also made drawings of Bobbi.

 

“It was a learning experience for everyone, including the adults,” Dr. Bird recalls.

 

Sadly, by age 15, Bobbi’s conditioned worsened, requiring a feeding tube, a frequent end-of-life measure for HD patients. She died in a hospice setting. Several of her old classmates attended the memorial service, where they fondly remembered Bobbi, Dr. Bird writes.

 

A resounding ‘yes’ in wanting to help

 

Can You Help Me? is one of the best and most important books about HD. It builds on the work of historian Alice Wexler, in particular her book The Woman Who Walked into the Sea, which uncovers many of the prejudices associated with HD (click here to read my review).

 

Dr. Bird has provided us with a deeply rich documentation of life in the HD trenches.

 

The title Can You Help Me? asks a question that I and so many other HD family members have posed when confronted with the frightening prospects of HD. (It also holds great value for people in the AD, PD, and other neurological disease communities.)

 

“Sometimes we can help a great deal, sometimes we can only help a little, and sometimes we just muddle through as best we can, navigating our way between suffering and harm,” Dr. Bird concludes, noting briefly that research towards treatments “heralds better days ahead for the world of HD.”

 

Fortunately, for the HD community, Dr. Bird’s book indicates a resounding “yes” regarding the desire by him and so many other professionals to alleviate the suffering caused by HD.

 

(For an interview of Dr. Bird about the book, click here).

After a horrid year, free streaming of ‘Dancing at the Vatican’ is an inspirational gift and a call to aid Huntington’s disease families

Dancing at the Vatican, the 38-minute documentary featuring South American Huntington’s disease-afflicted families’ remarkable 2017 encounter with Pope Francis at the Vatican, will be streamed indefinitely on YouTube for free starting December 1.

“The film has a distinct Christmas theme – the surprise invitations to the HD families in Latin America all arrived on the Epiphany,” wrote Dancing at the Vatican producer and narrator Charles Sabine in a recent e-mail to me, referring to the Catholic feast day, January 6, on which the HD families in South America received the official invitations to meet the pope. “So, I am going to be encouraging people to regard this as an inspirational gift at the end of a pretty horrid year.”

 

HD families from Colombia, Venezuela, and the pope’s homeland, Argentina, had met with the pontiff at #HDdennomore: Pope Francis’ Special Audience with the Huntington’s Disease Community in Solidarity with South America (click here to read more). Some 1,500 HD family members and their supporters – including my family and me – attended from around the world.

 

For the first time, a world leader had recognized Huntington’s disease.

 

Pope Francis with HD families in Rome, May 18, 2017 (photo by #HDdennomore)

 

Online starting December 1

 

Starting December 1, you can watch Dancing at the Vatican by clicking here. Also, the English-language film now has versions with subtitles in French, German, Italian, Portuguese, and Spanish.

 

The producers request that people click on the “subscribe” button on YouTube and leave comments on the film to help facilitate tracking of its viewings and to further support the HD cause. In the spirit of a heartwarming holiday gift, they also ask that viewers share the video with at least two people who have not heard about HD before.

 

According to Ignacio Muñoz-Sanjuán, Ph.D., a leading HD researcher and a co-organizer of #HDdennomore along with Sabine, the papal audience brought “critical” recognition to HD families living in “extremely vulnerable conditions.”

 

“This has touched them and their communities in many ways,” Dr. Muñoz wrote me. “But their plight continues, and the documentary should be a call to action to help those in most need, regardless of where they live in the world.”

 

In the spirit of Dancing at the Vatican, the HD community can come together to “give voice to the voiceless” and raise badly needed funds for local patient associations as well as Factor-H, a nonprofit organization that he co-founded to aid Latin American HD families, Dr. Muñoz added.

 

A message for all faiths and backgrounds

 

Dancing at the Vatican captures key moments of the impoverished, disease-stricken families’ extraordinary journey – some had never ventured beyond their home towns; some even lacked birth certificates – to their meeting with the Spanish-speaking Francis, the first Latin American pontiff in the Catholic Church’s 2000-year history.

 

#HDdennomore was open to people of all faiths and backgrounds, as were the three in-person screenings of Dancing at the Vatican in Los Angeles, London, and San Diego.

 

Sabine and the film’s organizers had hoped to organize additional screenings in the U.S., Europe, and South America.

 

However, the COVID-19 pandemic – which has made 2020 a trying year for all of humanity – forced the organizers to scuttle those plans. Instead, they have focused on the plan to provide free online access to Dancing at the Vatican.

 

Depending on the local impact of the pandemic, some communities might organize in-person screenings, Sabine explained.

 

“For example, in New Zealand, where COVID-19 has been virtually eradicated, there will be screenings in the first week of December in actual full movie theatres,” he noted.

 

Taking on HD families’ suffering

 

Sabine said that the Vatican’s communications department will help promote the online launch. In addition, the producers will promote the film “on all the relevant family organization websites and social media” and also reach out to clinicians, pharmaceutical companies, and nonprofits involved in HD, he said.

 

The screenings and publicity about the online screenings have been sponsored by Roche, Ionis Pharmaceuticals, Inc., Wave Live Sciences, and Takeda.

 

According to Sabine, the film demonstrates that “anything can be achieved if you put together enough people who believe that nothing is impossible.”

 

Also, he suggested, the HD community can use Dancing at the Vatican to promote the cause by “showing that, as Pope Francis said, it is time for HD families to be ‘Hidden No More.’” 

 

Dr. Muñoz pointed out that HD continues to devastate the South American families portrayed in the film. (An upcoming article will update the families’ stories.)

 

The film and the efforts of advocates such as Sabine and Dr. Muñoz echo the words of Pope Francis, who in his speech at #HDdennomore emphasized “what Jesus himself taught us.”

 

“Throughout his ministry, he met many sick people,” Francis stated. “He took on their suffering; he tore down the walls of stigma and of marginalization that prevented so many of them from feeling respected and loved.”

Happy Thanksgiving! And hail to the pharmaceutical and biotech industries – and the scientists!

Thanksgiving this year is going to be radically different for many Americans, including my family.

 

I will celebrate my favorite holiday just with my wife Regina, home in San Diego.

 

As it has for many Americans, the COVID-19 pandemic has prevented us from hosting our usual small group of friends.

 

After eating a healthy brunch, we plan to have a Zoom call with our HD-free “miracle” daughter Bianca, a junior history major at the University of Pennsylvania. We are ever thankful that Bianca did not have to face the devastating possibility of juvenile HD. We will miss her, but are reassured knowing that she will spend the day with her boyfriend and his immediate family in the East.

 

We also hope to Zoom with some of our local friends. 

 

However, despite the terrible pall cast by the pandemic over the 2020 holiday season, I feel extremely optimistic that researchers will find a highly effective vaccine for the coronavirus.

 

The announcements of preliminary data by Moderna and the team of Pfizer and BioNTech revealed that their vaccine candidates reduced COVID-19 infections by 95 percent in clinical trials.

 

Dr. Anthony Fauci, the director of the National Institutes of Allergies and Infectious Diseases (NIAID), described the Moderna data as “stunningly impressive,” noting that he would have settled for 70-75 percent efficacy in a vaccine.

 

“It is really a spectacular result that I don’t think anybody had anticipated would be this good,” Dr. Fauci said. He had similar praise for the Pfizer/BioNTech data.

 

Both of these trials use genetic approaches: they introduce the virus’s own genes into cells to provoke an immune response.

 

According to the New York Times’ Coronavirus Vaccine Tracker, several dozen other companies have embarked on clinical trial programs using some form of approach based on genetics or other cutting-edge strategies. Only ten projects are making vaccines using the traditional approach of injecting weakened or dead coronaviruses.

 

In all, scientists are testing 54 vaccines in clinical trials, and at least 87 more are under investigation in animals.

 

Genetics-based approaches are familiar to the HD community, where researchers have investigated the potential of gene silencing drugs for more than a decade. Researchers in the lead program, Roche’s historic GENERATION HD1 Phase 3 clinical trial, hope to analyze data in 2022. 

 

When I heard of the initial reports of Moderna’s genetics-based approach, I felt deeply confident that humanity would ultimately defeat the coronavirus. 

 

The potentially record speed in getting a vaccine to the world is testimony to the ingenuity, dedication, and focus of the biotech and pharmaceutical industries, which I have observed with deep interest in my nearly quarter century as an HD advocate and student of the science – and as a writer summarizing the science in simple terms.

 

In October, posting on Facebook an article on the bold Triplet Therapeutics clinical trial program – yet another genetics-based effort – I wrote the following: “Hail to the many imaginative and hard-working companies in America’s pharmaceutical industry!”

 

I also salute the scientists involved, and the many pharmaceutical and biotech firms of other nations engaged in the fight against COVID-19 and HD.

 

Also, we must not forget the millions of doctors, nurses, and other healthcare workers and first responders who have heroically attempted to hold the line against COVID-19, thus giving the researchers the time necessary to develop the vaccines.

 

Thanksgiving is our quintessential American holiday. This year, with the pandemic, it takes on a global significance. Across all cultures and nations, the virus has led us to realize once again our common humanity – and the collective efforts needed to safeguard life for all.

 

 

Photo by Bianca Serbin, taken in fall 2009 at the San Diego Botanic Garden (click here to read more).

Annual Huntington Study Group meeting reveals an HD community energized to aid families, develop treatments

Moved online because of the COVID-19 pandemic, the 27th Annual Huntington Study Group Meeting nevertheless revealed an HD community committed to aiding affected families and developing cutting-edge treatments.

Originally scheduled for Atlanta, GA, the virtual conference took place from October 29-31, with more than 800 scientific and medical participants from around the world. The meeting featured two days of presentations concerning care of HD-afflicted individuals, as well as updates on key clinical trial programs, aimed at producing drugs.

 

On Family Day, which drew an estimated 180 additional people, the affected, caregivers, and advocates heard both expert presentations on coping with HD and highlights regarding research.

 

Research moving full steam ahead

 

Martha Nance, M.D., a long-time member of the Huntington Study Group (HSG) and the director of Family Day organizing committee, kicked off that event with a reflection on the “highlights and lowlights” of 2020 so far. A neurologist and frequent sounding board for this blog, Dr. Nance is also the medical director of the Huntington’s Disease Society of America (HDSA) Center of Excellence at Hennepin County Medical Center in Minneapolis, MN.

 

We all know the lowlights, Dr. Nance said: the COVID-19 pandemic, the death of George Floyd in Minneapolis, the 2020 election with its uncertainty, and climate change.

 

“For me, a highlight of this entire year was this meeting,” Dr. Nance said, referring to the great progress in HD research. “The last two days we heard about more things than you can shake a stick at.”

 

Dr. Nance listed the important developments detailed in the scientific talks, including several innovative ways to potentially block the harmful effects of the mutant huntingtin gene. Both the scientists and family members got updates on GENERATION HD1, the historic, in-progress gene silencing clinical trial by Roche aimed at reducing the amount of toxic huntingtin protein in the brain.

 

At the conference, several speakers referred to temporary slowdowns in research programs because of the new safety protocols resulting from COVID-19. Dr. Nance also noted difficulties in accessing some HD community members because of the pandemic in the U.S. and abroad, although she also has observed a helpful “explosion” in telemedicine.

 

However, despite the uncertainty about overall scientific research funding because of the COVID-19 crisis, “research is alive and well in Huntington’s disease,” Dr. Nance stated. “If what happened at this meeting continues, research in Huntington’s disease is moving full steam ahead.”

 

“I found the meeting to be energizing,” Dr. Nance concluded in an e-mail to me on October 31.

 

For detailed reports of the research presentations, see HDBuzz’s coverage by clicking here and here.

 

For the next year, HSG is providing access to on-demand recordings of the conference talks and other events. Click here to register for access.

 

‘Heroes,’ and a thank-you for me

 

Dr. Nance devoted most of her Family Day introduction to counterpoising the difficulties of 2020 with the stories of “heroes” who have stepped up to assist others in the HD community by exercising their unique skills.

 

“We need to hear about some people who’ve done good things,” she explained. “I hope that you can emboldened, empowered by some of these heroes.”

 

Dr. Nance – to my surprise and appreciation – began with the example of me, Gene Veritas (aka Kenneth P. Serbin), the author of this blog, now in its sixteenth year. Dr. Nance recalled how she and I had worked together on our college newspaper (click here to read more). She said that I use my journalistic skills to help inform the HD community, and to be “very up front about my struggles and fears” as a carrier of the HD mutation.

 

I write in this article about myself because Dr. Nance stressed how important it is for the HD community to be informed about its social ramifications.

 

‘I can’t breathe’

 

Dr. Nance recalled my September 2014 report on Jeffrey Bane, a West Virginia man arrested because the police misunderstood his HD symptoms to be the result of narcotics abuse (click here to read more).

 

Dr. Nance replayed the video of a bystander who had filmed Jeff suffering injuries as the police held him to the ground, thinking that, with his involuntary, HD-caused movements, he was resisting arrest. “I can’t breathe,” Jeff said desperately as he asked the officers for help.

 

Jeff only received the help of paramedics after the police had held him to the ground for almost ten minutes, Dr. Nance pointed out. 

 

Then she asked the attendees “to just take a deep breath, pause, and think for a minute.”

 

After 54 seconds elapsed, she resumed her presentation. “Hopefully you took a deep breath,” she said. “I think probably you felt anger, hate, sorrow, sadness, fear, anxiety.”

 

She continued: “We can’t change something that happened six years ago. What we can do is try as hard as we can to keep events like this from happening against in the HD community.”

 

Dr. Nance noted that HDSA has a toolkit for educating first responders, police officers, and fire personnel about HD. The organization provides other resources (such as a special HD ID card) to help HD-affected individuals and their families prepare for potential encounters with the police, she added.

 

(I have explored these crucial themes in other articles. Click here to read more.)

 

‘Your life matters’

 

In examples surely moving to the audience, Dr. Nance presented the stories of several other HD “heroes.” 

 

Inducted into the Minnesota Auctioneers’ Hall of Fame in 2005, Joe, whose wife and daughter died of HD, took “his grief, his sadness, his sorrow” and raised money and bought electric toothbrushes for hundreds of HD-afflicted people, Dr. Nance recalled.

 

As a ten-year-old watching his mother face HD, B. J. Viau started an annual basketball hoop-a-thon that over the years raised some $750,000 for HD research. Among other things, B. J. went on to become one of the founders of the highly active international Huntington’s Disease Youth Organization. 

 

Diagnosed at ten with juvenile HD, Elli started kickball tournaments to support the cause. She became an internationally recognized HD advocate.

 

Dr. Nance also recognized the 791 “heroes” who are taking part in the GENERATION HD1 clinical trial.

 

With HD, she said, it’s easy to become angry, sad, and depressed. However, people can also “stand up tall” to help others. We need more everyday heroes, she added.

 

“Your life matters – not to take away from anybody else whose life matters,” Dr. Nance said in closing. “What you do makes a difference.”

 

Dr. Martha Nance (left) praises the advocacy of juvenile Huntington's disease-affected Elli Hofmeister (in images at right) at the virtual 2020 HSG Family Day (screenshot by Gene Veritas).

Triplet Therapeutics aims to transform the approach to treating Huntington’s disease, similar disorders

Huntington’s disease causes complex symptoms and attacks the brain ­– the most difficult organ to access with drugs. Thus, current remedies only help manage symptoms. They do not stop the disorder from progressing and, ultimately, causing death.

 

Now, building on groundbreaking research into the genetic roots of HD, Triplet Therapeutics, Inc., is taking a bolder stance: restoring the idea of transformative treatment onto the agenda by directly attacking the disease's underlying causes.

 

Founded in late 2018, Cambridge, MA-based Triplet aims to start a clinical trial in the second half of 2021 for a potential drug, for now called TTX-3360, targeted at stopping the mutant huntingtin gene’s tendency for continued expansion with age. That expansion compromises brain cells and triggers disease. Using the same mechanism, Triplet hopes to develop transformative treatments for many of the more than 50 other so-called repeat expansion disorders (REDs). For REDs of the central nervous system, it would use the same drug as for Huntington’s.

 

The DNA that comprises the mutations of many REDs – as with Huntington’s – occurs in triplets of the letters of the genetic alphabet. This helped inspire Triplet’s name. But other repeats, from 3-12 letters long, have also been described. Also as in HD, the DNA in other repeat expansion disorders grows longer and thus may cause disease.

 

“There's a lot of the genome that we actually don't know about, and a lot of putative genes there that, frankly, we don't know functionally what they do,” Triplet founder and CEO Nessan Bermingham, Ph.D., said in a January interview on the podcast BioBoss. “So, I think of the opportunities in our industry as we think about treating disease is very much going in and trying to actually understand and segment these regions of the genome to understand how targeting them may actually prevent or treat or cure disease.”

 

The efforts for treatments have taken “significant steps forward,” Dr. Bermingham observed.

 

Triplet secured $59 million in initial financing and investment. The company’s scientific advisory board includes key researchers in the fight against Huntington’s such as Harvard University geneticist James Gusella, Ph.D., the leader of the team that discovered the huntingtin gene in 1993, and Sarah Tabrizi, FRCP, Ph.D., a professor at University College London and one of the chief medical collaborators in the development of the historic Phase 1/2a HD gene-silencing clinical trial run by Ionis Pharmaceuticals, Inc., followed by an in-progress Phase 3 trial run by Roche (discussed below).

 

Triplet has also consulted with CHDI Foundation, Inc., the nonprofit virtual biotech dedicated solely to developing HD therapies (drugs and/or other treatments) and sponsor of the 15th Annual HD Therapeutics Conference in February. Produced by former NBC-TV foreign correspondent and global Huntington’s advocate Charles Sabine, this year’s conference highlights video featured Triplet and its senior vice president for research, Brian Bettencourt, Ph.D. Dr. Bettencourt was the lead scientist in the design of TTX-3360.

 

As I wrote nine years ago, preventing onset in premanifest (presymptomatic) gene HD gene expansion carriers like me has been the “Holy Grail” not only for Huntington’s, but other neurological disorders, given that brain damage starts many years before visible symptoms occur. 

 

“To hear what has been up and coming in the past five years and to hear what Triplet Therapeutics has been doing is so exciting for somebody like me who is premanifest and who has kids, one who is at risk,” said leading advocate Lauren Holder, 34, during her July 22 interview of Irina Antonijevic, M.D., Ph.D., Triplet’s chief medical officer, on the Help4HD Live podcast.

 

Above, Brian Bettencourt, Ph.D., Triplet’s senior vice president for research, explains a slide illustrating the firm’s pathway to a potential HD drug at the 15th Annual HD Therapeutics Conference (photo by Gene Veritas, aka Kenneth P. Serbin). Below, Nessan Bermingham, Ph.D., Triplet founder and CEO (Triplet photo).

 

Leveraging trailblazing insights of HD genetics

 

As a December 2019 news release stated, Triplet is “leveraging insights of human genetics to target the underlying cause” of REDs.

 

Those insights from genetic data collected over decades in more than 9,000 people affected by HD have changed standard thinking about Huntington’s genetics. This type of broad-ranging study is known as GWAS, genome-wide association study. 

 

“My company, Triplet Therapeutics, was quite literally founded based on the information that came out of the Huntington’s GWAS,” Dr. Bettencourt said in his interview with Sabine. “The GWAS provided us a really, really rich list of good gene targets for drugs.”  These genes modify the age of onset and progression of HD.

 

“The research in HD has really driven the research in this entire field,” Dr. Antonijevic told me in an interview via Zoom on October 4. From 2009-2010, she served as CHDI medical director. Later, she worked for Wave Life Sciences, which is conducting an HD clinical trial with a drug similar to the one developed by Roche for its historic clinical trial. 

 

Dr. Antonijevic pointed to the “trailblazing” work of Harvard University HD genetics researchers Dr. Gusella, Marcy MacDonald, Ph.D., and Jong-Min Lee, Ph.D. With others, they demonstrated why people with the same repeat length in the huntingtin gene can experience widely different ages of onset (click here to read more).

 

This might very well explain why HD 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, while I, with the same degree of mutation, have reached 60 essentially healthy, without motor onset, and able to function normally.

 

Somatic expansion: a driver of disease

 

The disease-causing expansion of the relevant portion of the huntingtin gene is the trinucleotide repeat CAG, letters in DNA alphabet. The expansion over an individual’s lifetime is known as somatic expansion or somatic instability. The breakthrough in HD genetics has revealed that so-called modifier genes linked to the speeding or slowing of somatic expansion can hasten or delay the age of HD onset by just a few years or by as many as 40.

 

Most of the modifiers contribute to the maintenance and repair of DNA, which, in general, helps cells remain healthy. Scientists call this process the DNA damage response (DDR) pathway.

 

“We tend to think of DNA as a fixed blueprint, an overarching plan for the biological bricks and bridges that constitute our cells, organs, and bodies,” a recent HDBuzz article explained of somatic instability. “But like any good plan, DNA is actually dynamic and adaptable.” 

 

Roche/Ionis achievement a ‘stimulus’ to other companies

 

Like Roche’s historic, in-progress Phase 3 gene-silencing clinical trial (GENERATION HD1), the Triplet program will use an antisense oligonucleotide (ASO), a synthetic modified single strand of DNA that can alter production of certain proteins.

 

In its Phase 1/2a trial, the Roche ASO successfully reduced the amount of mutant huntingtin protein in participants’ cerebrospinal fluid (CSF), obtained from lumbar punctures (spinal taps). The CSF bathes the brain. Roche researchers are looking hard for biomarkers (signs of disease and a drug’s effectiveness) in the CSF. Triplet and other research programs are also studying CSF. 

 

Roche and its partner Ionis, which designed the drug candidate Tominersen over nearly a decade, did the scientific heavy lifting required to develop the first HD ASO and administer it safely to clinical trial volunteers using lumbar punctures.

 

To date, Roche has not reported any serious adverse effects after the many lumbar punctures done on the hundreds of volunteers in its clinical trial program. The company expects to complete GENERATION HD1 and start analyzing data in 2022.

 

“The demonstration in a clinical study that a drug can lower mutant huntingtin levels was a critical development for the field,” Ignacio Muñoz-Sanjuán, Ph.D., the CHDI vice president for translational biology, told Sabine in the HD Therapeutics Conference highlights video. “It really provides stimulus to many other companies to use similar approaches and similar methodologies to try to establish treatments that really benefit the life of patients.”

 

Ionis has also been studying the control of somatic expansion as an additional Huntington’s therapy. Researcher Jeff Carroll, Ph.D., presented on this topic at the HD Therapeutics Conference. In July he co-published a paper on this subject with a team of researchers, including two Ionis scientists. The research demonstrates that lowering the huntingtin protein with an ASO in mice and human neurons in a lab (but not yet in a clinical trial) decreases somatic expansion and may also decrease the size of the expansions.

"We remain committed to finding effective treatments for Huntington's disease and are investigating multiple targets beyond lowering of huntingtin in our drug discovery group and with academic collaborators," Frank Bennett, Ph.D., Ionis executive vice president and chief scientific officer, wrote me in an October 12 e-mail.

 

Taking the foot off the disease accelerator

 

Dr. Antonijevic indicated that Triplet has leveraged publicly available knowledge gained from the Roche/Ionis program and others to plan Triplet’s development program.

 

“I think it is great to see that there is trial activity,” she said. “Ultimately the more trials with different approaches there are, the better the chance that there will be a treatment for the patient.”

 

Dr. Irina Antonijevic (Triplet photo)

 

However, Dr. Antonijevic pointed out a key difference between Triplet’s approach and Tominersen: lowering the amount of the mutant huntingtin protein does “nothing” to block the harmful expansion of the huntingtin gene, because it does not “touch the DNA.”

 

As with all ASOs, the Triplet approach blocks the action of RNA. However, Triplet’s drug will act “upstream” of the mutant, disease-causing gene itself by targeting another gene that promotes huntingtin’s somatic expansion, Dr. Antonijevic explained. 

 

“This is why we say it’s upstream: it affects the huntingtin gene at the DNA level,” she observed. “This is where we think it matters. The continuously increasing toxicity of the mutant gene is stopped, because the expansion at the DNA level is stopped.”

 

At the HD Therapeutics Conference, Dr. Bettencourt drew a contrast between the huntingtin lowering done by the Ionis/Roche ASO and Triplet’s targeting of somatic expansion. Huntingtin lowering is like “putting a brake on the process,” he said. As a result, the drug is “not dealing with the constant foot on the gas, whereby the DNA repeat is continuing to expand.” Triplet is different: “our therapies quite simply seek to remove that foot on the gas,” with the DNA no longer expanding, he said.

 

Dr. Brian Bettencourt (Triplet photo)

 

Drug candidate now ready

 

Triplet announced the selection of its ASO drug candidate, TTX-3360, in July. “TTX” stands for Triplet; 3360 is the number of the molecule.

 

Triplet very quickly developed its ASO because of “luck and expertise combined,” Dr. Antonijevic told me, explaining that TTX-3360 has been tested in animals, including non-human primates (monkeys). “We are excited to move it forward.”

 

To help select candidate compounds, Dr. Bettencourt stated at the Therapeutics Conference that Triplet relied on computational screening, experiments in animals, and tests in cells derived from HD patients. The company has also used siRNAs, small interfering RNA molecules, to test potential drug targets.

 

In its studies in non-human primates, one of Triplet’s test drugs was safe, well-tolerated, and had significant “knockdown” (reduction, a desired positive effect) on the targeted gene, Dr. Bettencourt added.

 

Dr. Antonijevic stated that TTX-3360 will target a modifier gene, but did not reveal which one. The modifier gene itself is “not pathologic,” she added. However, by reducing this gene’s expression as a protein that acts on the huntingtin gene, Triplet hopes the deleterious expansion of the huntingtin gene will slow or stop.

 

Triplet has not yet announced how it will deliver TTX-3360 in in the Phase 1/2 trial.

 

“Ultimately what we think is most important is that we get the drug to those areas in the brain that are important to target when treating an individual with Huntington’s disease, and we will let the science drive what the right delivery is,” she said.

 

SHIELD HD: preparing for a clinical trial

 

Before Triplet can launch a study of its drug aiming to cure HD, it wants to understand in greater detail how the disease progresses. It also wants to confirm existing biomarkers and measure new ones to help track the effectiveness of its drug. 

 

Under Dr. Antonijevic’s leadership, last May Triplet initiated SHIELD HD, a critical, two-year “natural history study” of approximately 60 HD gene expansion carriers to help prepare the Phase 1/2 clinical trial of TTX-3360 that the firm hopes to launch in the second half of 2021. Triplet is recruiting volunteers in Canada, France, Germany, the United Kingdom, and the U.S.

 

“SHIELD HD” aligns with some of the letters in the study’s longer scientific name, “but ultimately it reflects that we think of our approach as a protection from the disease,” she told me. 

 

A natural history study involves no “intervention or treatment,” she added. “We are studying the disease as it would normally progress, using clinical [observation] and biomarkers. So, it is really the natural course of the disease.”

 

As part of the study, Triplet scientists are analyzing volunteers’ CSF, MRI brain scans, blood, and data from cognitive tests, including HD-CAB, a refined “cognitive assessment battery” developed with input from the U.S. Food and Drug Administration and researchers predominantly for premanifest individuals, Dr. Antonijevic said in the Help4HD Live interview.

 

“It is really a performance test,” Dr. Antonijevic told advocate Holder. “This is something that does not require the physician or the investigator to assess a patient, but it is the individual who performs the test.”

 

The cognitive tests provide a “snapshot in time” of the individual’s decline because of HD and measures change over time, Dr. Antonijevic continued. “It’s really more objective than, for instance, a rating scale.” (Physicians use rating scales to determine a person’s level of HD.)

 

The study is also measuring DDR gene expression and the brain protein neurofilament light chain, the latter a marker of disease progression. SHIELD HD participants are also evaluated by a physician. Increasing somatic expansion in HD models was associated with elevations of neurofilament light chain, Dr. Bettencourt noted in his conference talk.

 

A slide from Dr. Bettencourt's presentation explaining SHIELD HD (screenshot by Gene Veritas)

 

Participants before official onset

 

Because of Triplet’s ultimate goal to prevent onset of symptoms, SHIELD HD is enrolling volunteers who have not yet experienced motor onset ­– the involuntary movements and problems with gait that form the classic criteria for diagnosing HD but have been called into question over the past few decades.

 

As Dr. Antonijevic told advocate Holder, studies of postmortem HD brains demonstrate that somatic expansion occurs many years before motor onset.

 

“There are a number of symptoms that are measurable, trackable, and predictable long before motor symptom onset,” Dr. Bettencourt noted at the Therapeutics Conference. He described the three groups of individuals under study in SHIELD HD as “prodromal,” “peri-manifest,” and “manifest.”

 

Prodromal refers to a period of years before motor onset, during which gene carriers have already shown some cognitive and emotional symptoms. Within the prodromal period, peri-manifest signifies the start of so-called “soft” motor symptoms. Manifest individuals have an official diagnosis of HD.

 

(For an in-depth discussion of premanifest and early-HD stages, click here.)

 

Aiming to improve clinical trial design, researchers continue to refine definitions of onset and disease progression. For instance, IBM has produced a model of the disease with nine stages instead of the traditional three. The traditional stages are after motor onset and do not include the first two of early-stage categories indicated above. 

 

SHIELD HD volunteers can do Phase 1/2 trial

 

Significantly, eligible SHIELD HD participants can later participate in the TTX-3360 Phase 1/2 trial, Dr. Antonijevic explained to Holder. This will enable the clinical trial investigators to compare an individual’s performance in SHIELD HD, with no drug, to a period on treatment. 

 

“This can be statistically a very powerful tool to measure the effect of a therapy,” Dr. Antonijevic observed.

 

Triplet projects the trial as a Phase 1/2 so that it can test for the crucial safety and tolerability typical of a Phase 1 but also perform measurements that could “tell us a little bit more about the mechanism of our drug,” Dr. Antonijevic told me. “We’ll be looking at the totality of data from this Phase 1/2 study to inform the subsequent study.”

 

Helping hundreds of thousands of patients

 

Triplet’s leadership has emphasized how the company’s search for an HD drug might work for other REDs, the repeat expansion disorders. These include myotonic dystrophy type 1, fragile X syndrome, familial amyotrophic lateral sclerosis (ALS), and spinocerebellar ataxias as well as dentatorubral-pallidoluysian atrophy.

 

Large-scale genetic studies such as the Huntington’s GWAS “have revolutionized the way we identify the underlying genetic drivers of repeat expansion disorders,” CEO Bermingham stated in the news release about SHIELD HD. “Our targeted approach is based on results from these studies with our internal research providing insight into the central role the DDR mechanism plays in these diseases. Our approach has the potential to address a broad range of repeat disorders addressing unmet medical needs for hundreds of thousands of patients.”

 

As Bermingham stated in the BioBoss podcast, the potential now exists to treat large numbers of diseases with the same drug.

 

According to Dr. Antonijevic, the number of REDs is actually increasing: scientists are discovering new disease genes, and a growing number of existing disease genes are now known to undergo somatic instability. She believes that ranking them by number of affected people is not helpful, in part because for each diseased person there can be many more asymptomatic gene carriers.

 

For example, there are an estimated 41,000 HD-affected individuals in the U.S., and more than 200,000 at risk for having inherited the gene. Some 140,000 people in the U.S. suffer from myotonic dystrophy type 1, and, Dr. Antonijevic noted, additional people are at risk. Myotonic dystrophy type 1 symptoms include skeletal muscle weakness and myotonia (difficulty relaxing muscles after use), cardiac dysfunction, respiratory dysfunction, excessive daytime sleepiness, cataracts, and other abnormalities.

 

The focus on a one-drug-for-all approach distinguishes Triplet from other companies that have developed ASOs against a specific disease gene, she added.

 

Previously, scientists have sought a way to address energy loss in HD-affected brain cells and other disorders such as epilepsy as a possible path to a common drug to correct the problems in bioenergetics (click here and here to read more), but without success so far.

 

To further its strategy, on August 18 Triplet announced that it would take part in a large international natural history study of myotonic dystrophy type 1 aimed at deepening understanding of the disorder and developing therapies.

 

Rescuing neurons – and people

 

Despite the COVID-19 pandemic, SHIELD HD – the natural history study ­– is “definitely on schedule,” Antonijevic told me. Dr. Bettencourt said that Triplet plans to provide a report on its research, including SHIELD HD, at the 2021 HD Therapeutics Conference.

 

Triplet’s plan for a Phase 1/2 trial of TTX-3360 in 2021 is exciting news for the HD community and beyond – not just for individuals with diseases caused by repeat expansion disorders, but for the hundreds of thousands of asymptomatic gene carriers (like me) fearful of their futures.

 

As Dr. Antonijevic said to Holder, “We think that, by intervening early, we could rescue more neurons and have ultimately hopefully a greater therapeutic benefit.”

 

The Triplet drug development program became possible because of the decades of research by scientists around the globe – and the participation of thousands of HD families in research studies.

 

A growing number of companies are competing to develop HD therapies. However, thanks to CHDI’s nonprofit role, academic researchers, and the overall ethos of the HD cause, researchers have collaborated in remarkable ways.

 

The HD community can take great comfort and pride in the hope that its efforts can potentially benefit so many other rare and neurological disease communities.

 

More than ever, #CureHD can become a dream fulfilled.

 

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