Thursday, October 15, 2020

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.)

Monday, August 31, 2020

In this electoral season, let’s highlight our natural role as caregivers and support care professionals

In the Huntington’s disease community and many others facing debilitating diseases, caregiving is essential.


The COVID-19 pandemic has made the need for volunteer caregiving perhaps more apparent than at any time in recent memory. In addition, examples of “heroes” have emerged among care workers such as healthcare professionals, first responders, and other occupations.


In this electoral season, no matter what your political persuasion, let’s highlight people’s natural role as caregivers and support the care specialists, many of whom work for very low pay.


The bedrock


Caring for others forms the bedrock of human relationships. This frequently extends to assisting individuals with health challenges.


We come into the world cared for by parents and other adults. Teachers care for us and become key role models as we progress through the school system. If we attend college, professors, peers, counselors, and others provide comprehensive support.


Spouses and partners care for and support each other, and if one falls seriously ill, the other helps. The same often happens with siblings.


Just as our parents raised us, so do we often look after them in their old age. In the U.S., where extended families once took in parents and relatives, caring for the elderly has increasingly become the responsibility of assisted living facilities and nursing homes. Nevertheless, children often bear the responsibility of finding a safe, good-quality place.


Many developing countries (such as Brazil, the country I study) lack assisted living, putting the responsibility squarely onto families.

However, as discussed below, in the U.S. the demand for caregiving is shifting much of the responsibility back into people's homes.


Lessons from the Huntington’s community


As a Huntington’s advocate and family member, I have learned many lessons about caregiving and seeking professional assistance.


My “HD warrior” father Paul Serbin cared for my HD-stricken mother Carol throughout most of the 20-year course of the disease (click here to read more). She also had an in-home care worker assist her with such needs as bathing and styling her hair.


Spending the last months of her life in a nursing home, my mother died in 2006 at age 68.


Paul Serbin pushing Carol Serbin in wheelchair (photo by Gene Veritas, aka Kenneth P. Serbin)


And, as an HD gene carrier “racing against the genetic clock,” I know that the inevitable onset of symptoms could lead me to depend completely on my wife Regina and others for care.


(Two nights ago ­– perhaps in anticipation of writing this article – I had a nightmare in which a prominent leader of the HD cause told me that I had chorea, the involuntary, dance-like movements typical of the disorder. The symptoms remained throughout the dream.)


I have also witnessed how a mother like Angela Leach tenderly looked after her son Terry, hit with HD in the toddler years. He died at 18.


Demand on the rise


As I noted in a previous article, volunteer caregiving is a “prominent yet often unheralded human practice.”


I’ve also reported on how some HD-afflicted individuals face subpar institutional care, fueled by ignorance and approaching neglect.


The demand for both volunteer and professional caregiving will continue to increase as humans generally live longer, and as millions develop neurological disorders such as Alzheimer’s disease and others.


One in five is a caregiver


In May, the Family Caregiving division of the American Association of Retired People (AARP) and the National Alliance for Caregiving (NAC) issued the extensive report Caregiving in the U.S. 2020.


“Today, more than 1 in 5 Americans (21.3 percent) are caregivers, having provided care to an adult or child with special needs at some time in the past 12 months,” the report states. “This totals an estimated 53.0 million adults in the United States, up from the estimated 43.5 million caregivers in 2015.”


The report asserts that the number of recipients of care living with caregivers continues to rise.


Caregiving is also becoming more complex, because individual care recipients have an increasing number of health conditions, the report states. Caregivers also rely more on household minors for assistance.


According to the report, caregiver self-reported health is also declining, because of the added stresses of caregiving.


The report observes: “Caregivers who cannot care for themselves may become unavailable to care for others; likewise, caregivers have their own financial, health, and wellness needs, which begs the question, ‘Who will care for the caregivers?’”


Financial stress is also common: “In fact, caregivers’ savings are eroding, with 22 percent who used up personal short-term savings and 12 percent who used up long-term savings (for things like retirement or education).”


Unpaid caregivers serve as a “core piece” of the health and long-term services and supports formal care systems, “as well as the main source for long-term care for adults living at home and in the community.”


Supporting caregiving


With the AARP-NAC findings, and as we approach the November 3 election for president and other key offices, we once again should pause to reflect on a crucial question:


How can meet the caregiving challenge – including paying professional caregivers more, providing respite for family members, and improving the regulation and overall quality of facilities?


The AARP-NAC report informs that 68 percent of caregivers surveyed support an income tax credit for caregiving. A similar percentage want back pay for caregivers for some of their hours worked. More than half favor establishing the right to partially paid leaves of absence from work for caregiving.


The party platforms


For the upcoming election, the Republican Party did not develop a new platform, simply readopting the 2016 version. It does not mention “caregiving” or “caregivers.”


The 2020 Democratic Platform proposes Social Security reform to provide benefits to assist those who forego paid work because they are caregivers. The platform further proposes making it easier for unpaid caregivers to save for retirement.


In addition, the Democrats advocate expanding access to home and community-based long-term care services and supports; eliminating waiting lists for home and community-based care; and bolstering Medicaid’s capacity to fund such services. The Democrats support a tax credit for informal and family caregivers and increasing the Child and Dependent Care Tax Credit.


“Democrats will also pursue policies to improve nursing home staffing and quality standards, strengthen accreditation processes, and combat corporate abuses in nursing homes,” the platform states. The party also supports a “roadmap to citizenship” for undocumented caregivers.


Building a better society


The benefits desired by the surveyed caregivers and the Democrats’ policy statements bear serious consideration.


In my more than two decades as an HD advocate, I have heard many stories of families whose resources were depleted by caregiving costs, lost work opportunities, and the government requirement that practically all assets be spent before receiving public aid for nursing home care.


I believe that highlighting our common role as caregivers can benefit all of us.


As a nation, we must embrace caregiving and professional care work as a non-partisan issue. Perhaps in some way this could serve as an antidote to the deep political polarization that afflicts us.


At the very least, it can help point us in the direction of building a better society.

Friday, July 10, 2020

Wonder if you’ll get Huntington’s disease? Preparing for the big, ‘intensely personal’ decision to undergo predictive testing

One of the most daunting challenges facing families affected by Huntington’s disease involves genetic testing.

Huntington’s is a 100-percent genetically caused disease, and it now can be foreseen – but not yet cured or treated. All humans have the huntingtin gene, which is essential for life. HD’s devastating, ultimately deadly symptoms are caused by a specific mutation (called a “CAG repeat expansion”) in the gene. Definitive testing for HD became available after the historic discovery of the gene in 1993.

Because every child of an affected HD parent has a 50-50 chance of inheriting the expanded gene, the mere decision to test is often frightful. A positive test result for the expansion means not only that the tested person will develop HD, but carries an added burden: the knowledge that both immediate and extended family members are also at risk of carrying the expansion.

Three scenarios

A person showing no symptoms, or suspecting symptoms, undergoes a predictive test, that is, to see whether the individual carries the expansion and therefore might have HD or later develop it. (Diagnostic testing confirms whether a person already displaying symptoms has HD. Prenatal testing determines whether a fetus or embryo carries the expansion.)

These three scenarios were poignantly portrayed in the July 3 ABC News feature “Living with Huntington’s Disease.” The 15-minute program focused on the stories of Scott and Kelsey Porter and Justin Furstenberg, who received his test result on camera (starkly reminiscent of the film The Lion’s Mouth Opens.)

The report’s detailed, deeply personal rendering of the genetic testing process also illustrated how HD families rely on supportive genetic counseling and psychological and medical assistance – as well as solid scientific information – to navigate the many challenges involved.

Scott and Kelsey Porter in a Huntington's Disease Society of America video

According to recommended guidelines, individuals like the at-risk Kelsey must prepare for this procedure by speaking to a genetic counselor and a mental health professional, and should have a support person (such as a spouse or close friend) physically present throughout the process. For testing in the United States, this “protocol” was established by the Huntington’s Disease Society of America (HDSA). It was most recently updated in 2016. Testing centers should do the utmost to ensure confidentiality, especially since news of a positive test can risk changing perceptions in the workplace and elsewhere, even if there are new guarantees against genetic discrimination.

Testing centers often intentionally slow the testing process, so that there is time for the individual to reconsider the decision to be tested, to think about the potential downside of testing, and to prepare for the impact of the result. Because of survivor’s guilt and other psychological factors, a negative test result can also prove traumatic and disruptive to a person’s relationships with family and friends.

In my quarter century of attending the local monthly HDSA support group and advocating for the HD cause, the topic of predictive genetic testing and its many implications has come up regularly. My own family faced all three modes of tests over five years: my mother’s positive diagnostic test in 1995, my positive predictive test in 1999, and my daughter’s negative prenatal test in late 1999/early 2000. (Click here for details of my family’s fight against HD.)

Based on these experiences and my study of the many related issues, this article provides an overview of key steps and resources for people preparing for HD testing, in particular the predictive type.

Helpful HDSA resources

HDSA, in addition to its genetic testing protocol, provides a brochure to HD families, Genetic Testing Huntington’s Disease, that in simple language answers basic questions about the disease, testing procedures, and resources.

The brochure emphasizes a cardinal rule that I learned early in my family’s journey with HD, and which I have repeated to other HD family members coming to grips with disease for the first time:

“The decision to undergo genetic testing is an intensely personal one that cannot be taken lightly. Testing should never be forced on an at-risk individual. There are no ‘right’ or ‘wrong’ answers. Each individual will have to take his/her own circumstances into consideration before making the decision.”

The HDSA family guide to genetic testing (copyright, HDSA)

The HDSA website furnishes valuable information on “genetic testing and your rights,” including the Genetic Information Nondiscrimination Act of 2008 (GINA). As explained on the site, GINA prohibits “health insurance companies and group health plans from denying coverage or charging a higher premium based on genetic information.” It also “prohibits employers from using an employee’s genetic information to discriminate when making employment decisions about hiring, firing, promotion, or terms of employment.”

In chapter 2 of HDSA’s A Physician’s Guide to the Management of Huntington’s Disease, leading HD specialist Martha Nance, M.D., provides additional critical information about testing and counseling. The chapter includes a detailed medical discussion of HD genetics.

A diagnosis of HD “affects the entire extended family,” Dr. Nance writes. “The person who is diagnosed with HD grieves not only for himself, but also for his at-risk children, and a young adult child caring for an affected parent understands that the parent’s disease could one day affect him.”

Dr. Nance stresses the importance of “accurate information” necessary for families to make “informed decisions” about genetic testing and family, financial, and life planning. Unfortunately, even decades after the discovery of the gene, “misinformation and misunderstandings” about HD genetics are still common, she notes.

(You can also watch a panel discussion titled “Looking to the Future: Life After Testing,” held at HDSA’s 35th annual convention, which took place online last month.)

Moving towards ‘genetic education’

In 2018, the international Huntington’s Disease Youth Organization (HDYO) added to its website a very readable “Genetic Testing Checklist,” covering key topics such as motivation for testing, coping with the test results, the testing process, and key things to do before testing, such as lining up insurance coverage (discussed below). This resource echoes many of the points made in HDSA materials.

In 2019, veteran University of Washington neurologist Thomas D. Bird, M.D., published Can You Help Me? Inside the Turbulent World of Huntington Disease, a book based on his more than 40 years’ experience seeing HD patients and their families. It includes detailed discussion of the many issues involved in what Dr. Bird calls the “genetic testing conundrum.”

Individuals contemplating genetic testing will find many valuable stories in Dr. Bird’s book. He describes the gamut of people’s reactions to testing – from individuals who have tested negative but still require a while for it to “sink in,” to (sadly) the risk for suicide among people testing positive.

“Suicide represents the cause of death in about 5-6% of persons with HD – five times higher than the national average,” Dr. Bird explains. “It can happen at any time but it is most common when a person at risk decides he or she is developing symptoms.”

Dr. Bird observes, crucially, that the “genetic test result is not black and white, all or nothing.” This reflects the latest genetic research on HD, which has demonstrated that the age of onset of symptoms is driven not just by the severity of the mutation but also by modifier genes (click here to read more).

This is why Dr. Bird stresses a comprehensive understanding of genetic counseling.

“Some people don’t like the term counseling,” he writes. “It sounds too much like psychotherapy, and they are wary of that. In fact, genetic counseling does sometimes have a heavy dose of psychotherapy, but it entails much more. Perhaps the best word would be education – genetic education.”

(I will review Can You Help Me? more fully in a future article.)

Ten key steps 

With these resources in mind, I list below ten key steps in preparing for a predictive genetic test and dealing with its short- and long-term consequences. These are my personal thoughts; this list is not meant to be exhaustive or official. Individuals should always consult their physicians. Each individual’s situation is unique.

1. Learn as much as you can about HD by studying the resources cited in this article, as well as others.

2. Join a support group, where you can learn from and share ideas with others confronting HD, as well as from facilitators and health professionals.

3. Contact the nearest HDSA Center of Excellence (or other HD or neurology clinic), where you can obtain information about testing and clinical services. You also can become involved in critical efforts towards treatments such as clinical trials and research studies like Enroll-HD

4. Know your rights regarding genetic testing and healthcare access under federal, state, and local law in your country of residence, and, in the U.S., learn about GINA.

5. Obtain life, disability, and/or long-term care insurance prior to testing. GINA does not protect consumers in these areas. In 1999, before testing, I was able to secure a long-term care policy with lifetime coverage. Since then, the long-term care market has gone into crisis, with many fewer policies issued, and far more limited coverage (click here and here to read more). At the time, I found it very helpful to work with an insurance broker recommended by an insurance agent specializing in long-term care who had been a guest speaker at the HD support group.

6. Set up a will, an advanced directive for end-of-life care, and, if appropriate, a living will to help protect assets. Also plan for the potential impact of HD on family finances by consulting a trusted financial advisor.

7. Research and select the testing center for your genetic test, including the cost of the procedure, which can run from a few hundred dollars to more than $1,000. (Some HDSA Centers of Excellence offer free or reduced pricing on testing. One foundation has paid for in vitro fertilization of non-HD-affected embryos but temporarily suspended grants because of the COVID-19 pandemic.) Some HD family members have criticized the quality of guidance provided at some centers. Be your own best advocate, and don’t be afraid to ask questions.

8. Find a trusted family member or friend to be your support person.

9. Build a relationship with a trusted psychotherapist.

10. Become active in HDSA and/or other advocacy organizations.

With potential treatments, an expected boom in testing

As the geneticist who revealed my test results in 1999 stated, “a positive test is not a diagnosis.” Physicians and scientists underscore this point. Like me, many people live years and even decades after their test before symptoms start.

Currently, no more than ten percent of at-risk individuals choose to be tested. The vast majority fear a potentially depressing result, “and there is no means of prevention,” Dr. Bird observes.

However, as clinical trials such as the historic GENERATION HD1 proceed, the potential for the first effective treatments has grown significantly.

Indeed, doctors and HD clinics are preparing for the likely boom in testing for the HD mutation that will occur if GENERATION HD1 or trials of other possible disease-modifying treatments are successful, as people seek to learn their status before starting on a treatment. (Click here and here to read more.)

More than ever, people seeking HD predictive testing and their families will need what Dr. Bird describes as “an experienced, compassionate team to help them through this challenge.”