Huntington’s disease advocates, scientists generate hope after a difficult year in the search for treatments

 

In one of the most difficult years emotionally in the fight to conquer Huntington’s disease, advocates, scientists, and HD-affected individuals have generated hope as 2021 draws to a close.

 

The “heartbreaking” news in March about the disappointing results of the greatly anticipated Roche and Wave Life Sciences clinical trials was compounded by the devastating, ongoing coronavirus pandemic.

 

Last year at this time, leading global HD advocate Charles Sabine, a British former international correspondent for NBC-TV, launched his inspiring film Dancing at the Vatican, about Pope Francis’ embrace of the global HD community, on YouTube.

 

Like the pope’s 2017 special audience with the HD community in Rome, Dancing at the Vatican brought great hope and joy.

 

Now Sabine has just released another heartening film, Hoping Machine, a 60-minute documentary that, he says, “encapsulates many core principles” of the pope’s declaration that it is time for HD to be “hidden no more”: the “corrosive nature of denial and hidden secrets” and the “empowerment that springs from knowledge, understanding, collaboration and community.”

 

“I truly believe Hoping Machine offers the most important perspective that anyone involved in HD right now – researchers, clinicians or families – could hear,” Sabine wrote me by e-mail.

 

You can watch Hoping Machine for free by clicking on this link.

 

Powerful HD journeys

 

Hoping Machine takes its title from the song by American folk music giant Woody Guthrie, who died from HD in 1967, the year his former wife Marjorie founded the Huntington’s Disease Society of America (HDSA).

 

The film depicts the gripping recollections of HD family members, and also several scientists, of their experiences as keynote speakers at what I have called the “Super Bowl” of HD research, the annual Huntington’s Disease Therapeutics Conference. Beginning in 2006, the conferences are sponsored by CHDI Foundation, Inc., the abundantly funded, nonprofit virtual biotech aimed solely at developing HD therapies.

 

These speakers have all told powerful stories about their HD journeys, including using the keynote to go public about their HD status for the first time (my case in 2011) and exploring the most intimate and difficult aspects of life with HD.

 

Inspired by the scientists’ dedication

 

They have also sought to both inspire and thank the scientists.

 

“Here I am, affected by Huntington's disease, and I'm relying on all of you guys, all of the scientists, everybody working in the HD community,” keynoter Amy Merkel recalled of her talk in Palm Springs, CA, in February 2020. “I'm relying on you for life.”

 

Sometimes, when she has experienced symptoms, “I just kinda wanted to crawl under the covers and stop trying,” Merkel continued. “That speech and that time in Palm Springs kind of lifted me a little. You can do this.”

 

A licensed practical nurse, Merkel had abandoned her “dream” of becoming a registered nurse (RN) “because I knew I was gene-positive” for HD, she said. However, “the advances that all of the scientists have made in Huntington’s research” convinced her to study to become an RN.

 

Amy achieved her goal: "I'm a registered nurse, and I currently am working as a sexual abuse nurse examiner in southern Arizona."

 

 

Amy Merkel poses with researchers Dr. Sarah Tabrizi (far left), Leslie Thompson, Ph.D. (second from right), and Gillian Bates, Ph.D. (far right), at the 15th HD Therapeutics Conference, held in in Palm Springs, CA, February 2020 (photo by Gene Veritas, aka Kenneth P. Serbin).

 

Good news from the KINECT-HD trial

 

Another glimmer of hope – and a sign that HD science marches on – came on December 7 with the release of “positive” data from the KINECT-HD phase 3 clinical trial to test the efficacy, safety, and tolerability of Neurocrine Biosciences’ drug valbenazine. The initial trial data demonstrated that valbenazine, as intended, reduced chorea, the involuntary, dance-like movements that are the principal motor symptom of HD.

 

Marketed by San Diego-based Neurocrine as Ingrezza and already approved by the U.S. Food and Drug Administration (FDA) for the neurological disorder tardive dyskinesia, valbenazine is the same type of drug as the two other FDA-authorized drugs for chorea, Xenazine (2008) and Austedo (2017).

 

According to the Neuocrine press release, Ingrezza reduced the total motor score (a measure of the severity of chorea) by 3.2 points versus placebo in the trial participants.

 

This result was very close to reduction of the 2.5 points in Austedo and the 3.5 points in Xenazine.

 

As the release explained, the total motor score is part of the motor assessment of the research tool known as the Unified Huntington’s Disease Rating Scale (UHDRS®) and “measures chorea in seven different body parts, including the face, oral-buccal-lingual region, trunk and each limb independently.” The total motor score is the sum of the individual scores and ranges from 0 to 28.

 

Like Xenazine and Austedo, valbenazine is a VMAT2 inhibitor.

 

Initial data about Austedo (deutetrabenazine) indicated that patients “felt better” overall after taking this drug. In addition, Austedo requires only two daily doses, versus Xenazine’s three (click here to read more).

 

Ingrezza is even more convenient: the KINECT-HD trial used just one daily dose.

 

Critical: no suicidal behavior observed

 

Critically, and also in contrast with the other two drugs, “no suicidal behavior or worsening of suicidal ideation was observed in the valbenazine-treated subjects in this study,” the Neuocrine statement said.

 

Neocrine partnered in KINECT-HD with the Huntington Study Group (HSG), the leading HD clinical trial administrator and research platform. In a first for the HSG, KINECT-HD trial participants used wearable sensors for continuous monitoring of their movements and other biological functions, even at home. (Click here to read more.)

 

In 2022, after a complete review of the trial data, Neocrine will report its findings in greater detail at a medical conference, and it will submit the drug for FDA approval for use in HD.

 

“The positive results of the KINECT-HD study are very exciting for the HD community,” Jody Corey-Bloom, M.D., Ph.D., the director of the HDSA Center of Excellence at the University of California, San Diego, wrote me on e-mail. “Although valbenazine is not a disease-modifying therapy, it will clearly be a highly effective therapeutic option for one of the most common symptoms in HD – chorea.”

 

“Completing ANY clinical research trial successfully in the midst of the COVID-19 pandemic is cause for excitement, and a testament to the tenacity of HD patients, families, and research teams,” wrote Martha Nance, M.D., the Center of Excellence director at Hennepin Health Care in Minneapolis, MN. “The favorable results are not terribly surprising, since two other similar drugs have been approved previously – but they are certainly reassuring.”

 

Maintaining the commitment to patients

 

The “holy grail” for the HD field – and other neurological diseases – is a treatment that prevents people from ever developing symptoms.

 

Comparing Ingrezza’s success with this bigger challenge, Dr. Nance offered a partial explanation to what she described as a large and complex challenge.

 

“It only takes a few weeks or months to document that a drug reduces the severity of a symptom (chorea, depression, insomnia), but takes years to show that a drug is slowing the progression of a disease that progresses slowly over years,” she wrote. “We have not gained a toehold on slowing nerve cell loss in any of these conditions.”

 

However, because the scientists have advanced to attempting treatments aimed at the disease’s roots ­– DNA and RNA – “there is good reason to hope.”

 

“Building on the unsuccessful trials that were so disheartening to the global HD community earlier this year, I counted no fewer than thirteen companies moving towards clinical trials of DNA/RNA-directed treatments at our recent HSG research conference in November,” she noted.

 

Dr. Nance wrote that we should be “thrilled” that 2021 has ended on a favorable research result and “maintain our commitment to work together to find better treatments for the HD patients of the future.”

A proud Huntington’s disease gene carrier’s message to his ‘miracle baby’ daughter on her senior year in college

 

When I tested positive for the Huntington’s disease genetic mutation in 1999, at 39, I was convinced I was doomed to repeat my HD-stricken mother’s onset of symptoms in her late 40s.

 

I had tested because my wife Regina and I wanted to plan for children, who, if I had the mutation, would also have a 50-50 chance of inheriting it.

 

We decided to have a child before the availability of preimplantation genetic diagnosis (PGD), which involves in vitro fertilization of embryos without the mutation. So, we had our daughter Bianca tested in the womb. Her negative result in early 2000 was one of the happiest moments of our life. She was our “miracle baby.”

 

Now, 21 years later, Bianca has started her senior year at the University of Pennsylvania, where she is finishing a U.S. history honors thesis. She has flourished in her classes and successfully taken on several leadership roles.

 

Bianca understood from about the age of two that her grandmother was ill with a genetic disease. HD transformed my mother into a mere physical and mental shadow of herself, taking her life at 68 in 2006. Four years later, when Bianca was 9, she learned that I, too, was at risk but that she was not.

 

I have been extremely lucky. I am almost 62 and was found to have no HD symptoms at my recent annual neurological checkup. I have perhaps benefited from the positive action of modifier genes and a far greater opportunity than my mother had – we had never heard of HD prior to her diagnosis – to prepare for the disease.

 

As Bianca navigates the challenges of senior year and prepares for post-college life, I want to provide her with a message of hope, challenge, and some of the wisdom I have picked up along my own life’s journey, including our family’s struggle against Huntington’s. My letter to Bianca follows after the photo below.

 

Regina Serbin (left), Gene Veritas (aka Kenneth P. Serbin), and Bianca Serbin at the Edge sky deck during a visit to New York City in August 2021 to celebrate Bianca's 21st birthday (photo by Devon Riley)

 

Dearest Bianca,

 

When you graduate next May, you and your classmates will come of age at a time of immense challenges.

 

I am impressed with how you (and so many other students of all levels) have shown great fortitude and flexibility when forced into the new reality of online learning and social distancing during the monumental disruptions of the COVID-19 crisis.

 

I was happy to see that this semester Penn has moved students back into the classroom, allowing you to recover some of the lost joy of the college years.

 

With the rapid development of highly effective RNA-based vaccines, many of us are reaping the fruits of the biotechnological breakthroughs of our era. Researchers are also exploring a variety of such genetics-based approaches as potential Huntington’s treatments. Because many of these advances promise to change our very nature, they will pose ethical dilemmas.

 

Our family has lived this in the flesh. The biomedical revolution made it possible for you to know your life will be free of Huntington’s. However, as you have learned, being HD-free does not mean being challenge-free. Far from it!

 

But the freedom from HD has enabled you to plan a life in which you can strive for academic and professional excellence, and to develop your personal qualities.

 

As you venture forth, remember always that you’re not going it alone. You can rely on others, just as you should be available to support others. Life is a collective endeavor, as our family has learned so well from the fight against HD. As I always tell people dealing with the initial shock of discovering Huntington’s in their families, “together we will beat this disease!”

 

In your drive for personal success, cherish the preciousness of time, as I have learned to do in confronting the fears of HD. Use ambition to push ahead, but don’t let it dominate your inner good. Always make time for family and friends.

 

Take time to meditate and cultivate your spirituality, because I believe that we all have such a dimension, independent of any belief system or organized religion. As you have done at Penn, find ways in your life to connect to something larger than you.

 

Bianca, I’m elated with how we have come to share many passions: for writing, the study of history, historical movies (especially war films), music, our dog Lenny, and our family.

 

Because of HD, your grandmother could barely hold you as a baby. Your “HD warrior” caregiver grandfather loved you deeply. I wish they could have shared your college years.

 

I have not wanted you to worry about me getting HD, which is a major reason that I have strived so hard to maintain good health – and to support the search for treatments that could save me from HD’s inevitable though often unpredictable symptoms.

 

You and Mom have joined me at Hope Walks and other fundraisers, and in 2017 you gave up the chance to attend your junior prom to take part in Pope Francis’ special audience with the HD community in Rome. I so deeply appreciated having you by my side during that breathtaking moment.

 

I am thrilled and thankful to have the clarity of mind to enjoy your progress towards graduation. You have made me deeply proud.

 

Because of our and so many other families’ dedication to the HD cause, and also thanks to the researchers, I remain ever hopeful for an HD treatment in my lifetime. If that moment comes, I know that no matter where you are geographically and professionally, we will celebrate with tears of joy.

 

I hope HD strikes me minimally and very late in life, as I have seen in some cases. Together our family has seen many people with HD fight tremendously to overcome the disease, and their caregivers devote every ounce of strength. As it has throughout our journey, the hope for both my good health and the arrival of treatments will continue to sustain us ­– even beyond the start of any symptoms that might occur.

 

No matter what difficulty, please remember that I have always treasured our great moments together and watching you grow as a person.

 

No one knows what tomorrow will bring. In this moment, let’s cherish the positive, including the fact that you, Mom, and I are healthy. As your senior year progresses, I want to celebrate our joy together as you prepare to graduate.

 

Raising you has brought Mom and me greater meaning and purpose – and, above all, lots of love to share.

 

Healthy and ambitious, you are poised, with your generation, to leave your mark on the world.

 

Congratulations on your senior year! Enjoy the ride!

 

Love,

 

Dad

 

 

 

The Serbin Family Team of the Huntington's Disease Society of America San Diego Chapter's  2014 Hope Walk: from left to right, Dory Bertics, Bianca Serbin, Jane Rappoport, Gary Boggs, Yi Sun, Kenneth Serbin, Regina Serbin, and Allan Rappoport (photo by Bob Walker)

Bidding farewell to my ‘mind coach,’ a major ally in in my fight to avoid Huntington’s disease

 

In December, my psychotherapist will retire, ending for me a professional relationship of 24 years that became the most personal of bonds and an emotional bulwark in my fight to delay – and prepare for – the inevitable onset of Huntington’s disease.

 

I had consulted therapists in my twenties and early thirties for non-HD-related matters. However, after my mother’s diagnosis with HD in 1995 and her inexorable physical and mental decline, I spiraled downward into clinical depression and anxiety. I needed more profound, long-term psychological support.

 

I contacted the local psychoanalytic society, which, after an intake interview, put me in touch with a psychoanalyst who best matched my needs and goals. I was fortunate that she proved to be a good fit. I recommend a proactive attitude about therapy, with a willingness to ask questions, and, if necessary, switching to another analyst or therapist.

 

For me, so began a journey of seeking greater personal and social enrichment. HD researchers and physicians have long encouraged a healthy lifestyle, although no one has found evidence to prove its effect. However, as discussed below, scientists are seeking ways to use HD-affected individuals’ sense of meaning and purpose as a possible path to alleviating symptoms.

 

My psychotherapist has certainly helped me build meaning and purpose not just in my fight against HD, but in life in general.

 

As the format of my therapy went from classic psychoanalysis (multiple sessions per week lying on a couch) to a face-to-face encounter on a weekly, bi-weekly, and then monthly basis, I have referred to my therapist in different ways.

 

“My therapist is like a personal trainer,” I wrote in 2009. “She’s my mind coach. She helps me keep my mind working at its best to meet the challenges of living at risk for HD, just as a personal trainer or coach helps a professional athlete keep his body in top shape.”

 

Gene Veritas, aka Kenneth P. Serbin (photo by Yi Sun, Ph.D.)

 

Psychoanalysis: unleashing personal growth

 

Founded by the Viennese doctor Sigmund Freud in the early 1900s, psychoanalysis became the basis for modern talk therapies, in which the patient shares inner thoughts with the analyst, or therapist.

 

Although in the United States in the latter 20th century psychoanalysis was reduced to a small branch of the burgeoning psychological profession, it remained important in parts of Latin America, including Brazil, my second home. I researched the history of the Roman Catholic Church in Brazil for my Ph.D. dissertation, published as Needs of the Heart in 2006.

 

From the 1960s to 1980s, the Brazilian Church became the world’s most progressive. In Needs of the Heart, I wrote that in this period Brazil helped give birth to the important and controversial

liberation theology, “but also to liberation psychology, whose implications for the Church were even more revolutionary than the new theology.”

 

“Liberation psychology had a dual significance,” I asserted, referring to psychology in the broad sense, including psychoanalysis and many other approaches. “It could free people not only from poverty of spirit and mind but also from the repressive structures of Catholicism.” Liberation psychology sought to release people from such beliefs as the need to repress sexuality and unquestioningly accept religious authority. This history resonated deeply with my Catholic upbringing.

 

Igor Caruso, a Viennese Russian Orthodox analyst and an inspiration for Brazil’s pioneers of liberation psychology, viewed psychoanalysis as ultimately an encounter of love “between two unique and equally valuable personalities.” As I wrote, he believed that without love, there was no cure.

 

One leading priest-analyst in Brazil described psychoanalysis as a “special grace received from God” because of the profound self-discovery and personal growth it unleashed in people.

 

Although psychoanalysis in the U.S. fell behind other areas of psychology and medicine in terms of scientific innovation, it has, with the rise of neuroscience and molecular biology, experienced a renaissance. Using brain imaging, researchers have been exploring how different types of psychotherapy, including psychoanalysis, affect brain structure. (For details, see Nobel Prize laureate and brain scientist Dr. Eric Kandel’s In Search of Memory.)

 

Also, as I experienced, psychoanalysis could be aided with psychiatric medications.

 

About a year after learning about my mother’s HD diagnosis, during a year-long research stay in Brazil, I did therapy with a local analyst for several months. She urged me to continue analysis in the U.S. after my return in mid-1997.

 

Sharing the trials and triumphs of the HD cause

 

I, too, became liberated by psychoanalysis. As is often the case, the process took years.

 

In December 1997, I met my analyst for the first time. After a few preliminary weekly conversations, I lay on my therapist’s couch four times weekly, for 45 minutes, over about five years.

 

I always paid out-of-pocket: my insurance did not cover psychoanalysis. Fortunately, the psychoanalytic society sought to help people of all income levels. In retrospect, paying privately gave me a greater sense of security about confidentiality, because (in one of those terrible ironies of the U.S. health system!) I was deliberately keeping my HD status from my health plan, for fear of discrimination and losing my health coverage, until fully going public in 2012 (click here to read more).

 

As we talked, my analyst took copious notes on my thoughts and asked questions. I spoke mainly about my fears, feelings, and past, especially with regard to my relationship to my family, in particular my mother, who was slowly dying of Huntington’s.

 

My therapist listened intently and compassionately to my many struggles with HD and, more than anyone else, came to know how my fear of the disease – along with other factors – hindered clear thinking and the ability to enjoy life. She also shared my pride and joy in the many fundraising and awareness-building triumphs I achieved with others for the local chapter of the Huntington’s Disease Society of America (HDSA).

 

My psychotherapist helped me cope with the impact of my positive test for the HD mutation in 1999, my daughter’s negative test in the womb in 2000, and my mother’s death from HD in 2006.

 

Descending into the bedrock

 

By early 2003, we had reached a point in the analysis where I needed – and wanted ­– to descend into what I called the “bedrock,” the deepest, most difficult feelings, fears, and memories, which are the hardest to access and confront. Rooted in childhood and adolescence, they long preceded my family’s struggles with HD. However, I seemed incapable of entering the bedrock. Part of my mind resisted both my therapist, and myself, preventing me from being completely honest with myself and gaining more self-understanding.

 

My therapist gently pushed me to consider psychiatric medication to overcome that resistance.

 

Holding a Ph.D., but not an M.D., my therapist could not prescribe medicines, leading me to work with psychiatrists at my health plan.

 

That process proved difficult and frustrating; rather than specify my true concerns to these doctors, who knew nothing of my HD status, I had to speak in generalities.

 

Finding a winning combination

 

In addition, finding the right medication and the right dosage required years of trial and error. My first attempt, with Zoloft (sertraline), nearly proved disastrous: while driving my wife and daughter, I blanked out and ran the car onto the curb. Luckily, no one was injured. I immediately quit the medication.

 

Next, Prozac (fluoxetine) left me disoriented and extremely drowsy, so I was switched to Zyprexa (olanzapine). My mother was also taking this drug for her HD symptoms as an alternative to Haldol. Haldol was one of the standard prescriptions for HD but, we heard from the HD community, not recommended in many cases.

 

With worsening clinical depression and especially anxiety after my mother’s death in 2006, and working with a highly sympathetic psychiatrist (but who still did not know my risk for HD), I found a winning combination of escitalopram and risperidone for the respective conditions.

 

Since the late 1990s, I had also taken trazodone for sleep but quit in 2016 because I had improved on that front considerably. I have also wanted to avoid overloading my system with medications.

 

In contrast with Zoloft and Prozac, escitalopram and risperidone apparently did not cause any unpleasant side effects, although, according to my doctors, I have taken these last two drugs at very low doses. A general caution I heard from doctors: certain antidepressants can negatively impact sexual function.

 

Taking these medications was a huge step, because growing up I learned that psychological counseling and especially anything psychiatric were taboo and seen as shameful by many in my extended family.

 

Fear of HD diminished dramatically

 

In my late 40s, this successful treatment of escitalopram and risperidone relieved me of depression and greatly reduced my anxiety. In tandem with my therapy, these drugs finally helped me psychologically to feel as well as I ever had in my adult life. I have now taken them at the same dosage for more than a decade, and will do so for the foreseeable future.

 

Entering the bedrock, I continued to gain new insights with my therapist. The fear of unconditionally trusting her disappeared. I was able to comprehend my psyche. I became more perceptive and more self-aware – and also more accepting of others and more loving towards my family.

 

My fear of HD diminished dramatically – even though I knew that each day brought me closer to the likely onset.

 

I have the normal ups and downs we all have, but the medications continue to help keep me stable.

 

The benefits of stability

 

In 2011, my therapist helped me prepare for, and then marveled at, a major achievement in my HD advocacy, the first major step outside the “terrible and lonely HD closet”: my keynote speech at the Sixth Annual HD Therapeutics Conference, sponsored by CHDI Foundation, Inc., the nonprofit virtual biotech firm that is the largest private funder of efforts to develop treatments.

 

My therapist provided support for another milestone, and the beginning of the fully public phase of my advocacy: the publication of my article “Racing Against the Genetic Clock” in The Chronicle of Higher Education in 2012.

 

Psychological stability enabled me to work ever more effectively as an advocate and to concentrate on activities such as exercise that have bolstered my health. By then, I had also come off the couch, and our meetings became less frequent.

 

My therapist also became a regular reader of this blog. In some sessions, we have discussed concerns I have expressed in articles. On other occasions, therapy has helped suggest blog topics.

 

My therapist has been a true friend and partner in the fight against HD!

 

A broad strategy for avoiding symptoms

 

In recent years, as I have proceeded into my sixties, I have reflected on how I have so far avoided HD symptoms. On September 17, during my annual neurological checkup, the doctor found no signs of HD. My mother became symptomatic in her late forties and died at age 68. (Click here to read more.)

 

Psychotherapy forms part of a broad range of interrelated strategies for keeping healthy, including physical and mental exercise, blogging on HD, and taking supplements, some of which were ultimately proved ineffective. I also eat a healthy diet, and I meditate and practice spirituality. I have the benefit of a stable, solid-paying job and a close relationship with my wife and daughter.

 

As psychotherapy has helped enrich my life, it has also given me a greater overall sense of meaning and purpose.

 

Researchers are carefully studying these factors as a way to alleviate symptoms.

 

Meaning and purpose are key

 

In July, a team of twelve researchers published “Meaning and purpose in Huntington’s disease: a longitudinal study of its impact on quality of life,” in Annals of Clinical and Translational Neurology, a journal of the American Neurological Association.

 

The researchers studied 322 HD-affected individuals: 50 just starting to experience symptoms, 171 with early-stage disease, and 101 with late-stage disease. The participants did both an in-person assessment and an online survey. Data were collected between 2012 and 2016.

 

The results of the study demonstrated that “higher” meaning and purpose were “positively associated” with “positive affect [mood] and well-being,” the researchers stated.

 

Meaning and purpose also were associated with “decreased depression, anxiety, anger, emotional/behavioral disruptions, and cognitive decline at 12 and 24 months across all disease stages,” they wrote.

 

More research needed

 

The article pointed out the study’s limitations: correlation does not necessarily mean causation.

 

Thus, the researchers recognized the need to verify their findings with “additional instrumentation” to measure the connection between meaning and purpose and the patient-reported data. The study also did not account for possible bias from people on “psychoactive medications.”

 

Nevertheless, the researchers described the study as a “compelling first step” toward understanding the primary mechanism behind meaning and purpose – and how they might improve quality of life in HD-affected individuals.

 

Finding ways to help patients

 

The researchers concluded that their findings “parallel” those seen in those affected by cancer and might help point the way to “palliative HD interventions,” approaches that might relieve symptoms without removing the root cause.

 

They also pointed to the value of psychotherapy. They cited articles from studies of cancer patients and other conditions focusing on psychotherapy and other palliative measures such as spirituality.

 

Critically, a sense of meaning and purpose “may serve as a resiliency factor for suicide in people with the HD gene in that it can impact factors associated with suicidal ideation (e.g., depression, anxiety) as well as suicidal behaviors (e.g., impulsivity and anger).”

 

As the article pointed out, and as is well-known in the HD community, “suicide is a leading cause of death.”

 

Nostalgia, and looking ahead

 

As I read the journal article, I recalled my own fantasies about suicide in the first few years after my mother’s diagnosis and as I worried whether I had inherited the mutation.

 

The birth of our daughter in 2000 gave me immense meaning and purpose. I stopped thinking about suicide as a way to escape HD. My fight against HD became not only advocacy for the cure, but a personal quest to maintain stable health so that I could see my daughter grow up.

 

My mind coach has been an invaluable companion in this journey.

 

As we have our final sessions, I will become deeply sad. It feels like a lifelong friend moving to another city, with little chance of a visit.

 

My therapist and I have discussed the pain of separation. As usual, she will be helping me to remain stable and find a good path forward.

 

With nostalgia, we have also discussed the tremendous progress I have made, including the highlights of my HD advocacy.

 

In July, I began meeting occasionally with another therapist, so that I have psychological support beyond my mind coach’s retirement.

 

I am looking forward to discovering another ally in the fight against Huntington’s.

CRISPR, curing Huntington’s disease, and humanity’s future in Isaacson’s ‘Code Breaker’

In a new book about the broad issue of editing human DNA, a prominent biographer of scientific innovators proposes that such cutting-edge, potentially curative gene editing research prioritize Huntington’s disease.

 

“Our newfound ability to make edits to our genes raises some fascinating questions,” writes historian Walter Isaacson – author of studies of Leonardo da Vinci, Steve Jobs, Albert Einstein, and Benjamin Franklin – at the outset of his recently published The Code Breaker: Jennifer Doudna, Gene Editing, and the Future of the Human Race.

 

Code Breaker presents a crucial account of the biggest breakthrough in genetics since the discovery of DNA’s structure in 1953 by Francis Crick and James Watson.

 

Editing our DNA, the molecule that makes up our genes and guides our biological lives, to make us less susceptible to microbes like the coronavirus would be a “wonderful boon,” Isaacson suggests in the introduction.

 

“Should we use gene editing to eliminate dreaded disorders, such as Huntington’s, sickle-cell anemia, and cystic fibrosis?” he asks. “That sounds good, too.”

 

Jennifer Doudna, Ph.D., the subject of Code Breaker, has also embraced the concept of gene editing for HD if it can become a safe and effective therapy. Dr. Doudna won the 2020 Nobel Prize in Chemistry for her work in identifying and understanding the natural gene editing process now widely known as CRISPR, and the insight that this tool could potentially be refined for use not only in the laboratory, but ultimately also in the clinic, to alter human DNA.

 x

Above, author Walter Isaacson learns CRISPR editing, and, below, the cover of Code Breaker (images from Simon & Schuster website).

 

A historic breakthrough, major consequences

 

In Code Breaker, Isaacson traces the influence of the controversial Watson, now 93, on Dr. Doudna and others. He also interviewed Watson.

 

For both general readers and specialists, Code Breaker furnishes an excellent description of Dr. Doudna and others’ investigation of the structure and actions of CRISPR-Cas9, the specific type of gene editing feasible for use in humans.

 

CRISPR stands for “clustered regularly interspaced short palindromic repeats,” a strand of RNA, and Cas-9 for the enzyme associated with the RNA. Cas-9 acts as a type of scissors to cut DNA. The RNA guides the enzyme to the cutting target. There are other types of CRISPR.

 

Ultimately, Isaacson delves into the significance of CRISPR (and related themes such as biohacking and home genetic testing) for the future of humanity. CRISPR can perhaps end single-gene disorders like Huntington’s – but might ultimately also permit us to change such characteristics as IQ, muscle size and strength, and height. Russian President Vladimir Putin has extolled CRISPR as a potential way to produce “super-soldiers,” as Isaacson notes.

 

A powerful bioethical story

 

Isaacson has produced a powerful bioethical study of when and how gene editing should be done. He interviewed Dr. Doudna other scientists on their views. He also consulted bioethicists and their writings.

 

He also contrasts competing political theories regarding editing, pitting the idea of a free-market “genetic supermarket,” where the individual decides, against that of a society (and its government) that would permit editing only if it did not increase inequality.

 

Thus, Code Breaker is a major contribution to bioethics (the ethics of medical and biological research). Isaacson analyzes the potential social, moral, ethical, political, and ultimately biological consequences of gene editing and the conflicts it might produce. Editing the human race could produce many wonders, but also less biological diversity and greater and more permanent inequality, as the rich will almost inevitably gain privileged access to therapies and enhancements.

 

Isaacson illuminates this dilemma by recounting Dr. Doudna’s own “ethical journey” on gene editing.

 

“By limiting gene edits to those that are truly ‘medically necessary,’ she says, we can make it less likely that parents could seek to ‘enhance’ their children, which she feels is morally and socially wrong,” he writes. The lines between the different types of edits can be blurry.

 

“As long as we are correcting genetic mutations by restoring the ‘normal’ version of the gene – not inventing some wholly new enhancement not seen in the average human genome ­ – we’re likely to be on the safe side,” Dr. Doudna affirms.

 

Code Breaker also offers important evidence of the tension between so-called open science, where researchers (and some biohackers) freely share data, and the scientists, universities, and corporations that fight to establish patents and earn profits. (Click here for more on this development.)

 

Making the case for editing the HD mutation

 

Isaacson recounts how, in 2016, Dr. Doudna was especially moved by a visit at her workplace, the University of California, Berkeley, with a man from an HD family, who described to her how his father and grandfather had died of the disease, and that his three sisters, also diagnosed with the disorder, now “faced a slow, agonizing death.”

 

Putting Huntington’s first in a series of bioethical case studies, Isaacson underscores the crucial need for an HD CRISPR treatment, noting the disease’s devastating symptoms and rare, dominant genetic nature (inheriting the mutation from just one parent is sufficient for getting symptoms).

 

“If ever there was a case for editing a human gene, it would be for getting rid of the mutation that produces the cruel and painful killer known as Huntington’s disease,” Isaacson asserts.

 

Eliminating HD forever

 

For HD, Isaacson suggests a germline edit—removing the elongated piece of DNA in the huntingtin gene that causes HD in an embryo. A treatment done at this stage would restore the normal function of the HD gene in all the body cells, including that individual’s eggs or sperm. This genetic repair would then be inheritable, thus erasing HD forever from the future generations of the family.

 

Scientific protocol and governments have not yet approved such edits, though they have been done in animal subjects. As narrated in great detail in Code Breaker, a Chinese researcher did such an edit – to prevent AIDS – in twin babies in 2018, only to be punished by his country’s government and criticized as irresponsible by scientific colleagues. However, Dr. Doudna and other pioneers of CRISPR remain hopeful that safe, inheritable edits will become acceptable for at least some conditions.

 

Isaacson mentions two alternatives to germline editing that can eliminate HD from a family’s lineage. First, adoption. Second, preimplantation genetic diagnosis (PGD), which involves in vitro fertilization using embryos screened for the mutation. PGD has been used in the HD community for about 20 years. Before PGD arrived, some families, like mine, have had our offspring tested in the womb. However, neither of these strategies have been used widely in the HD community by at-risk couples.

 

If it can be harnessed safely, to target only the abnormal HD gene, and delivered effectively to human cells, CRISPR could provide the all-out cure for Huntington’s long sought by science and so deeply hoped for by HD families.

 

Isaacson concludes, “it seems (at least to me) that Huntington’s is a genetic malady that we should eliminate from the human race.”

 

For now, don’t ‘hold your breath’ for an HD CRISPR therapy

 

Isaacson states that “fixing Huntington’s is not a complex edit,” but he does not elaborate further.

 

However, while leading HD scientists are eagerly using CRISPR as a research tool, the technique is far from ready as a therapy.

 

CRISPR was a key topic at the “Ask the Scientist … Anything” panel of the virtual 36th Annual Convention of the Huntington’s Disease Society ofAmerica (HDSA), held June 10-13. Noting that many in the HD community have inquired about CRISPR, HDSA Chief Scientific Officer George Yohrling, Ph.D., asked the panel to comment on its potential as a therapy.

 

“CRISPR is really an exciting tool,” said researcher Jeff Carroll, Ph.D., co-founder of the HDBuzz website and, like me, an HD gene carrier who lost his mother to the disease. “CRISPR allows us really for the first time to edit DNA itself in a very precise way, to make very precise cuts in the DNA of a cell or even in an intact organism.” He added: “scientists are using it like crazy” in lab experiments.

 

In his own HD-focused lab at Western Washington University, Dr. Carroll and his team have developed a line of experimental mice with cells containing enzymes (proteins that act as chemical catalysts) necessary for doing CRISPR edits, Dr. Carroll explained. Such enzymes do not normally occur in human cells, he added.

 

Using CRISPR, “we can mess with these mice’s genome [DNA] in ways that were unimaginable just a few years ago,” Dr. Carroll continued.

 

Dr. Jeff Carroll commenting on HD science at the virtual 2021 HDSA national convention (screenshot by Gene Veritas, aka Kenneth P. Serbin)

 

For an HD family, “the idea of cutting out the DNA and fixing it is very, very appealing and something we can do in animal models and [animal and human] cell lines in the lab already, and it looks really promising.”

 

However, Dr. Carroll offered a blunt assessment of the current state of research on CRISPR as an HD treatment.

 

“As an actual HD therapy, I’m less excited about CRISPR,” he said. “I think it’s many years away. Something based on it may someday help us, but you have to realize that these enzymes that you need to enact CRISPR are themselves giant proteins that actually originate from bacteria, and we have to put them into the cell.

 

“So, if you want to use CRISPR as a therapy for Huntington’s and we want to modify all the DNA in the whole brain, we have to get into every one of your 84 billion neurons and put a CRISPR factor in there and modify the DNA.”

 

As a result, “Huntington’s will not be the first disease treated with CRISPR,” Dr. Carroll concluded. “I wouldn’t hold your breath for it as a therapy for HD in the medium or short term.”

 

Currently, a possible better candidate for a CRISPR treatment would be a disease involving immune cells that could be removed from the body, edited, and then reintroduced into the individual, Dr. Carroll observed.

 

Elaborating on Dr. Carroll’s comments, Ed Wild, M.D., Ph.D., another speaker at the HDSA science panel and also a co-founder of HDBuzz, cited the example of a blood cancer as a possible early target for CRISPR.

 

He agreed with Dr. Carroll that an HD CRISPR treatment remains difficult at this time and underscored why: unlike parts of the body like blood cells or bone marrow, brain cells cannot be removed, treated, and reinserted or given replacements.

 

Further cautions

 

An August 2020 HDBuzz article also urged caution in the use of CRISPR for HD and other genetic diseases in the wake of three experiments with human embryos that resulted in “unintended changes in the genome.” These so-called “off-target” effects suggest that “CRISPR is less precise than previously thought,” the article stated. Like desired edits, the unwanted ones make permanent changes to the DNA.

 

Such unintended edits are “bad because our DNA code is a very precise set of instructions, which can be thought of like a cooking recipe,” the article explained. “If you rearranged the steps in a recipe or got rid of some of the ingredients the outcome would not be good!”

 

When CRISPR is used in an embryo, the mistaken edits would not only affect that individual, but could also be passed on to the next generation.

 

Clarifying some key points

 

As an HD advocate and family member who has tracked the research for two decades, I felt that Code Breaker could have gone into greater depth about HD science. Given all the valuable detail about Dr. Doudna’s and other scientists’ efforts to discover the workings of CRISPR, it would have been helpful to present some scenarios about how it might work in HD.

 

Code Breaker also states that in HD the “wild sequence of excess DNA serves no good purpose.” This is a confusing term, as so-called “wild” type DNA in this context usually means “normal” DNA. Isaacson might better have done better to avoid the use of this term, but instead to emphasize that the normal huntingtin gene is essential for life and brain cell stability, as HD research has demonstrated. Normal huntingtin is present in all humans without the mutation and even in those who have inherited a mutation from one parent, because the non-HD parent has passed on a normal copy of the gene.

 

The book could have further benefited from additional references to both the scientific and social significance of the disease as presented in works such as Dr. Thomas Bird’s Can You Help Me? Inside the Turbulent World of Huntington Disease. There was also no reference to the pathbreaking research on modifier genes, which can hasten or delay the onset of HD.

 

Contemplating the ‘gift’ of life

 

Citing the philosopher Michael Sandel, Isaacson points out that finding “ways to rig the natural lottery” of genetics could lead humanity to humbly appreciate the “gifted character of human powers and achievements. […] Our talents and powers are not wholly our own doing.”

 

Still, I agree with Isaacson that “few of us would regard Alzheimer’s or Huntington’s to be a result of giftedness.”

 

Even so, it’s important to recall that HD researchers continue to investigate the role of the huntingtin gene not only in the disease, but, in the words of one study, in intelligence and the “evolution of a superior human brain.”

 

Faced with the daunting challenges of the disease, many HD mutation carriers and affected individuals have also grown in unexpected ways. I, for one, consider myself a lucky man because of the richer life I have lived as a result of my family’s fight against Huntington’s.

 

In this new reality, advocating once again for our families

 

HD families like mine have lived on the frontier of bioethics, facing challenges such as genetic testing, prenatal testing, genetic discrimination, decisions on family planning, and many others.

 

Perhaps, as Code Breaker speculates, gene editing may someday be considered morally acceptable in the way that in vitro fertilization and PGD have come to be.

 

However, as seen in the case of abortion, the HD community does not have a monolithic bioethical stance (click here and here to read more).

 

It remains an open question as to whether the HD community would wholeheartedly embrace CRISPR as a therapy. Some might celebrate it as a cure, but others might see it as going against nature or even as a return to the era of eugenics in the early- to mid-20th century, when medical professionals advocated sterilization for HD-affected individuals. Taking a cue from the United States, the Nazis were said to have forcibly sterilized as many as 3,500 people affected by Huntington’s.

 

No book can offer a definitive answer to these ethical quandaries. Code Breaker provides us with at least some basic guideposts.

 

It will ultimately fall to HD-affected individuals and their families (and those families affected by other diseases) to navigate what could very soon become the new reality of gene editing – and, when necessary, to act as powerful advocates. To assist us in this journey, we will need ethically informed health professionals and patient organizations.