More optimistic than ever, CHDI head scientist sees unprecedented mobilization in the fight to treat Huntington’s disease

 

In the wake of last week’s 20th Annual Huntington’s Disease Therapeutics Conference, the chief scientific officer for CHDI Foundation, Inc., declared that HD scientists had mustered unprecedented efforts toward therapies (treatments).

 

“I’ve been in the drug discovery business for over 30 years now,” Robert Pacifici, Ph.D., the CHDI head scientist, told me in a 37-minute video interview after the conference, referring to the key theme of crucial modifier genes, a focus of the meeting. “I’ve never seen the mobilization of efforts as quickly and as deliberately – from the identification of those genes to the understanding of how those genes mechanistically are having their effect – to actually developing candidate therapies that are modifying those processes.”

 

Dr. Pacifici observed that, in the HD field, “everybody’s pushing wherever they can to accelerate therapeutics. But we all know that sometimes you just hit roadblocks, you hit bottlenecks.”

 

He said that those difficulties can be overcome with “new technologies, new methods, new techniques,” which often result in “breakthrough moments. They allow you to do things that you just could never contemplate doing before.”

 

Dr. Robert Pacifici, wearing a Team Hope shirt from the Huntington's Disease Society of America, overseeing the 20th Annual HD Therapeutics Conference (photo by Gene Veritas, aka Kenneth P. Serbin)

 

The efforts forming around this hottest of topics in the HD field are “incredibly exciting,” Dr. Pacifici said. The “big news” over the next two years should include getting drugs that imitate the effect of the modifier genes – which research has demonstrated delay the onset of HD symptoms – into clinical trial programs.

 

As reported in this blog, the now defunct Triplet Therapeutics had aimed from 2020-2022 to develop and test a modifier gene drug (click here to read more).

 

Dr. Pacifici said that he is “more optimistic” than ever that HD drugs will get approved.

 

I attended the conference. Below you can watch a video of my interview with Dr. Pacifici.

 

 

 

Attacking the harmful protein

 

While this year’s Therapeutics Conference did not include any major positive announcements like the approval of a drug, Dr. Pacifici observed that it also did not bring the kind of disappointing news experienced by the HD community in 2021 with negative results from trials run by Roche and Wave Life Sciences.

 

The conference did bring reports from both Roche and Wave about their revised clinical trial programs. PCT Therapeutics and uniQure also reported on their ongoing clinical trials.

 

All four programs use drugs to lower the amount of harmful mutant huntingtin protein in the brain cells of patients. This is the first of three approaches to defeating HD, Dr. Pacifici recalled.

 

I will detail these updates soon.

 

‘Lucky’ and ‘unlucky’ genes

 

The second, more recent approach involves the search for drugs to imitate the modifier genes, as Dr. Pacifici noted above. These genes are related to somatic instability – the tendency of the expanded HD gene to expand further with time. This process can be triggered by negative modifier genes.

 

Dr. Pacific described those genes as “lucky” or “unlucky.” A good modifier gene can delay HD onset, whereas the bad one can hasten the start of the disease, he explained.

 

These genes act as “sentinels” in the bookkeeping of our DNA, Dr. Pacifici added. “We want our DNA to stay clean and error-free.”

 

Dr. Pacifici emphasized how more than 12,000 HD-affected individuals and their relatives in genetic research helped lead to the discovery of the modifier genes a decade ago. A study of a large group of people’s DNA is known as a Genome Wide Association Study (GWAS).

 

Fixing broken cells

 

The third approach to treating HD involves yet another set of genes that emerged from the HD GWAS. They were a key topic at the conference.

 

Dr. Pacifici stated that these genes are “every bit as validated” as the ones involving somatic instability. “We just don’t know the effect yet,” he said.

 

Dr. Pacifici added that understanding these genes will help answer a key unanswered question about HD: “what is it actually inside a cell at the molecular level that’s broken” and how to fix it.

 

All three of these areas could be targeted by an eventual cocktail of HD drugs, Dr. Pacifici said.

 

Key new genetic research and ‘rock star’ HD families

 

“We keep on thinking of ways of getting even more information out of persons with HD,” Dr. Pacifici said.

 

CHDI has announced that all 22,000 participants in Enroll-HD, the global registry of HD patients and relatives, will be full-genome-sequenced. That means their entire DNA will be  mapped.

 

“That’s a lot of data,” Dr. Pacifici noted. “It’s going to be the next set of breakthroughs, where we understand not just little bits of DNA information but the whole story for every participant.”

 

This will be “incredibly impactful,” he said.

 

The HD families that have provided all of this crucial data underlying these approaches to treatments are true “rock stars,” Dr. Pacifici said. Their interaction with HD scientists is critical, he concluded, to advancing scientific breakthroughs.

‘Striving for a cure’: highlights from the 19th Annual Huntington’s Disease Therapeutics Conference

 

Progress towards effective treatments for Huntington’s disease relies on the affected families’ collaboration with researchers exploring the frontiers of science.

 

The potentially pathbreaking findings featured at the recently completed 19th Annual HD Therapeutics Conference, sponsored by the nonprofit CHDI Foundation, Inc., led CHDI Chief Scientific Officer Robert Pacifici, Ph.D., to declare that the community will achieve therapies.

 

In this article I highlight the scientists’ work with a photo essay on their conference presentations and some of their key observations.

 

I cover most of the presentations. For detailed reports on the conference, see the articles in HDBuzz by clicking here, here, and here. Later CHDI will post videos of the presentations on its website. It is also preparing a video “postcard” of the event.

 

In recent decades, Huntington’s breakthroughs have resulted from the increasing amount of human data, which Dr. Pacifici and other scientists say is the best way to study the disease and develop potential therapies. The presentations at this conference especially reflected this trend. Researchers such as Matthew Baffuto, B.S., of the Heintz Lab at The Rockefeller University (in the photo above), recognized the importance of postmortem donations of HD-affected individuals’ brains and other human samples for their research. Baffuto’s final slide included a dedication: “To the HD patients and families who make this human research possible and for whom we continue to strive for a cure.” (All photos by Gene Veritas, aka Kenneth P. Serbin) (Click on an image to make it larger.)

 

The first wave of attempts by pharmaceutical companies to defeat Huntington’s has involved attempts to lower the amount of the abnormal huntingtin protein (HTT) in patients’ brains. In many of these approaches, this also means lowering the amount of normal HTT. The lab of Jeff Carroll, Ph.D., a scientist at the University of Washington and a HD gene expansion carrier like me, has extensively studied huntingtin lowering in mice. Normal huntingtin is necessary for adult mice to function, Dr. Carroll observed. Huntingtin lowering is not a “bad idea, just that there’s a floor between 50 percent and zero percent HTT,” he said.

 

Tony Reiner, Ph.D., of the University of Tennessee Health Science Center, presented the latest findings of his work comparing HD mouse brains to human tissue from deceased HD-affected individuals. He also focuses on how HD affects the various regions of the brain differently. This photo illustrates how Dr. Reiner uses antibodies to measure the complications that arise in HD mouse brains.

 

Sarah Tabrizi, M.D., Ph.D., of University College London, discussed her lab’s research on somatic expansion, the tendency of the abnormal huntingtin gene to expand with time and become more harmful to the brain. She presented data on developing drugs to interact with modifier genes, which can impact somatic expansion and therefore the age of disease onset. Dr. Tabrizi focused on the modifier gene MSH3 as an ideal therapeutic target. For this research, the Tabrizi lab has utilized stem cells, CRISPR gene editing techniques, and antisense oligonucleotides, used in huntingtin lowering drug programs and other HD research projects.

 

Ricardo Mouro Pinto, Ph.D., of Harvard University Medical School, presented his lab’s work on genetic modifiers of somatic expansion. Dr. Pinto has implicated the so-called DNA mismatch repair pathway as a critical driver of somatic expansion. His lab is also developing CRISPR-based strategies as potential therapies. Dr. Pinto’s team was recently awarded a grant from the Hereditary Disease Foundation to continue the search for therapies.

 

Mark D. Bevan, Ph.D., of Northwestern University, spoke on his lab’s latest findings in HD mice, in particular the dysregulation and rescue of subthalamic nucleus, involved in the suppression of movement. Dr. Bevan highlighted the need for both huntingin-lowering and somatic expansion therapies to have widespread delivery into the brain.

 

Osama Al-Dalahmah, M.D., Ph.D., of the Columbia University Irving Medical Center, discussed the major role of astrocytes in HD. There are over 100 different brain cell types. Astrocytes are cells that provide physical and chemical support to other cells such as neurons, key in the brain. As a neuropathologist, Dr. Al-Dalahmah analyzes post-mortem brain tissues. Among other observations, he noted that astrocytes can be neuroprotective. His lab is working on ways to protect neurons in HD.

 

Scientist Baffuto’s wide-ranging presentation focused on specifying cell types in unraveling both the molecular mechanisms underlying somatic expansion and also the path of the disease. The Rockefeller team developed what it describes as an “innovative methodology” for deep profiling of cellular processes in the brain. The technique is fluorescence-activated nuclear sorting (FANS). As shown in one of Baffuto’s slides, they used FANS to detail the disease process in key areas of postmortem HD-afflicted brains: the striatum, cortex, thalamus, hippocampus, amygdala, and cerebellum.

 

Scientists continue to debate exactly what triggers Huntington’s. Assessing the impact of somatic expansion, the Harvard University Medical School team studying HD proposed a new model for how somatic expansion contributes to HD pathology. Bob Handsaker, B.S., explained that, until recently, scientists thought that the DNA triplet repeat creates a toxic protein whenever the CAG repeat length is greater than 40 and that HD pathology arises from lifelong exposure to this toxic protein, similar to how smoking damages the lungs. (The abnormally repeated DNA word CAG is the genetic root of HD.)

 

New research has challenged this idea in three important ways: First, there is much more somatic expansion than had been appreciated, with affected neurons expanding to reach over 400 CAG repeats. Second, this somatic repeat expansion starts slowly and then accelerates over time, like a "slowly ticking DNA clock” in each individual neuron. Third, the evidence suggests that modest somatic expansion, up to a repeat length of 150 CAGs, does not create a protein that is toxic - the toxic effect in each individual neuron only begins above this longer repeat-length threshold. Along with other research presented, this finding underscored that there may be a longer window of opportunity than had previously been appreciated for any therapeutic interventions that act to slow or block somatic expansion. This is because in the first few decades of life in a person with HD, the DNA in most neurons has typically not expanded to reach this toxic threshold.

 

Darren G. Monckton, Ph.D., of the University of Glasgow, presented his new research on biomarkers, signs of a disease and indicators of whether a drug has efficacy. Dr. Monckton focused on biomarkers in areas of the body outside the brain such as blood, in particular regarding the degree of somatic expansion and measuring it over time.

 

Carlos Bustamente, Ph.D., a Venezuelan American geneticist and the founder and CEO of Galatea Bio, Inc., advocated for enabling precision medicine around the globe. Dr. Bustamante observed that new technological advances have made it faster and less expensive to understand human genomes but most of such resources have gone to understanding predominantly northern European communities. He pointed out the need to expand the genetic dataset to other parts of the globe. Dr. Bustamante also explained how genetic differences in the global population have contributed to differences in the geographic prevalence of Huntington's.

 

David Margolin, M.D., Ph.D., the vice president for clinical development at uniQure, presented an update on the early-stage (Phase 1/2) clinical trial of the company’s gene therapy drug, AMT-130, involving 39 trial volunteers in the U.S. and Europe. Dr. Margolin reported that, relative to baseline, volunteers treated with AMT-130 showed evidence of preserved neurological function. So far, the drug has proved to be safe.

 

Amy-Lee Bredlau, M.D., the senior medical director at PTC Therapeutics, presented interim safety and biomarker data for the company’s huntingtin-lowering pill, PTC-518, in PIVOT-HD, a Phase 2 trial. At this stage, the drug has been shown to be safe and has achieved a lowering of huntingtin in the blood – although data do not yet show whether the lowering is also occurring in the brain.

 

From left to right, Roche researchers Jonas Dorn, Ph.D., Peter McColgan, M.D., Ph.D., and Marcelo Boareto, Ph.D., reanalyzed the data from the firm’s first attempt at a Phase 3 huntingtin-lowering trial program, which in 2021 ended without the drug tominersen showing the necessary efficacy for approval as a drug. The scientists discussed ways to improve clinical trial design, including for GENERATION HD2, a less ambitious, Phase 2 trial of tominersen in a smaller number of volunteers. GENERATION HD2 is in progress.

Huntington’s disease community will 'get there' in search for therapies, CHDI chief scientist declares after ‘terrific’ conference

 

After presiding over a “terrific” research conference, CHDI Foundation Chief Scientific Officer Robert Pacifici, Ph.D., declared that the Huntington’s disease community will “get there” in the search for long-awaited therapies.

 

Dr. Pacifici commented in an interview with me on March 1, after the CHDI-sponsored 19th Annual HD Therapeutics Conference, held in Palm Springs, CA, from February 26-29.

 

The CHDI chief scientific officer (CSO) provided his optimistic assessment in referencing the featured presentation by David Altshuler, M.D., Ph.D., CSO of the Boston-based Vertex Pharmaceuticals.

 

“They’ve solved some unbelievably difficult problems,” Dr. Pacifici said of Vertex, noting that it found a cure for hepatitis C.

 

Vertex has also developed therapies for three tough diseases that, like HD, are genetic: cystic fibrosis, sickle cell disease, and transfusion-dependent beta thalassemia.

 

At future therapeutics conferences, “we would love for the last talk” to focus on a new drug that is “now going to be approved,’” Dr. Pacifici told me.

 

“We’re going to get there,” he continued. Dr. Altshuler, who Dr. Pacifici said carefully calibrates his optimism, “was very complimentary and very confident that if we stay on this path, we’ll actually achieve that. He felt that the collective efforts that CHDI is trying to catalyze throughout the community are going to be successful.”

 

Dr. Pacifici pointed out how CHDI has adhered to another key principle of drug discovery emphasized by Dr. Althsuler: studying HD in human cells, tissues, and postmortem samples.

 

Dr. Pacifici said he expects the HD field will hear more from Dr. Altshuler and welcomed Vertex’s possible revived involvement.

 

In 2010 I spoke on my family’s fight against HD at the Vertex labs in San Diego and chronicled its search at the time for an HD therapy, though so far without results reported by that lab.

 

Dr. David Altshuler presenting a timeline of Huntington's disease scientific landmarks at the 19th Annual Therapeutics Conference, February 28, 2024. Pictured in the slide is James Gusella, Ph.D., whose lab discovered the huntingtin genetic marker in 1983 and the gene in 1993 (photo by Gene Veritas, aka Kenneth P. Serbin, and posted with permission of CHDI Foundation). (Click on the image to make it larger.)

 

The need to celebrate milestones

 

“But I think what you will see is incremental successes,” Dr. Pacifici continued. “We’re going to have these new findings, these critical milestones and stepping stones along the way that we should embrace and celebrate and use those as a source of hope that, even though it never moves as fast as we would like, we’re making very real, tangible progress”

 

Dr. Pacifici described the 19th conference as “terrific,” noting that more than 450 people – a record – 50 companies, and 70 academic institutions took part. He recalled how no biopharma firms attended the first few conferences. Now such companies “come to a conference because they think an area is ripe for discovery,” he observed.

 

“Everybody commented on how quickly the conference went this year,” Dr. Pacifici said. “There was just so much information and so much happening and actually people were sad when it was over.”

 

I found this, my twelfth CHDI conference, particularly exhilarating because of the amount of new data and the high quality of the presentations.

 

A virtual nonprofit biotech, CHDI is the largest private funder of HD research. As in our interviews at past therapeutics conferences, Dr. Pacifici summarized the key findings of the scientists’ presentations. Watch our 39-minute interview in the video below.

 

 

Key developments

 

Dr. Pacifici explained several key developments.

 

The session on new data and insights into the basic biology of HD included presentations that help “to understand exactly how we can custom craft the profile of candidate drugs to make sure that they hit the right things and are as safe as possible,” Dr. Pacifici said. Such crafting would mean that drugs could effectively address the numerous specific problems in HD, he added.

 

Another session “shined a bright light” on DNA repair, modifier genes, and somatic instability, the tendency of the deleterious expansion of the DNA to worsen with age and therefore trigger disease onset, Dr. Pacifici said. The new findings can contribute to the ongoing effort to “manipulate” these processes to slow or stop instability and therefore prevent the disease, he explained.

 

Including talks detailing HD at the cellular and molecular level, the session titled “It’s a Brain Disease” was “unbelievably informative” about specifying how HD harms the brain, Dr. Pacifici said.

 

Clinical trial news and the importance of participation in research

 

The final session featured clinical trial updates from uniQure, PTC Therapeutics, and Roche. None of these has yet reached Phase 3, the definitive test of a drug.

 

Referring to the 2021 results of Roche’s first attempt at a Phase 3 trial, Dr. Pacifici noted that the firm’s scientists “have really gone to town and reanalyzed the samples, reanalyzed the data in a way that is hopefully going to teach us not only why that particular trial didn’t meet its endpoints” but also “what we can do differently.” Roche’s reassessment of its drug, tominersen, in a Phase 2 trial, GENERATION HD2, is in progress.

 

Ultimately, the field needs a “conveyor belt” of new drug possibilities to develop the multiple kinds of drugs necessary for treating different aspects of HD, Dr. Pacifici concluded. Not all those new drugs will be successful, he said, but the more produced, the greater likelihood for successful therapies.

 

Dr. Pacifici pointed out that many of the discoveries discussed at the meeting resulted from the human data collected from tens of thousands of research volunteers.

 

Future projects and breakthroughs will continue to rely on large numbers of participants, he said. Some individuals may carry unique genetic characteristics revealing new kinds of therapies.

 

“Hang in there,” Dr. Pacifici said in his closing comment for the HD community. “I hope that next year at the 20th [conference] we’ll have some more good news to communicate.”

 

Stay tuned for further news from the conference!

At CHDI conference, advocates inspire acceleration of quest for Huntington’s disease therapies

 

With a record 420-plus participants, the 19th Annual Huntington’s Disease Therapeutics Conference got under way on February 26 with the aim of speeding the quest for therapies to slow, halt, or reverse the symptoms of this incurable disorder.

 

Sponsored by CHDI Foundation, Inc., the largest private funder of HD research, the event runs through February 29 at the Parker hotel in Palm Springs, CA, and will feature three days of scientific and clinical presentations.

 

“In recent years the quest for HD therapeutics that will make a real difference to affected families has accelerated and deepened,” CHDI Chief Scientific Officer Robert Pacifici, Ph.D., wrote in a welcome letter to the participants. “Accelerated in the sense that every week seems to bring new scientific insight, whether from publications or reports on new and ongoing clinical initiatives. Deepened in the sense of the sophistication of our understanding of the underlying HD biology that informs our drug development work.”

 

HD research has also “broadened,” Dr. Pacifici added, noting that participants are displaying a record 140-plus posters. Representatives from 55 pharmaceutical and biotech companies and 69 academic institutions will take part.

 

In his letter and opening remarks to the conference, Dr. Pacifici outlined how CHDI has reorganized its scientific-thematic approach to “better align” its activities “with this burgeoning body of knowledge.”

 

The conference, following such themes, will focus on new research into the roles of mutant huntingtin DNA, RNA, and protein in HD. Conference-goers also will focus on the hot topic of somatic instability, the tendency of the deleterious expansion of the DNA to worsen with age and therefore trigger disease onset.

 

A caregiver’s moving keynote and a vital TED Talk

 

Following Dr. Pacifici’s overview, the audience watched a deeply moving 80-minute keynote speech, not to be shared publicly, by Cheryl Sullivan Stavely, RN. Stavely recounted her 30-plus years as an advocate and caregiver to her late husband John and daughter Meghan, who both succumbed to HD.

 

Stavely thanked the scientists for their dedication and said she hoped that 30 years from now HD conferences will become unnecessary with the development of treatments.

 

Choking up at Stavely’s recollections of Meghan, I found the keynote highly effective in summing up the many health and social challenges faced by HD-affected people and their families such as the affected person losing the ability to work and making insurance and end-of-life arrangements.

 

Scroll to the end of this article for photos of Stavely’s presentation and others.

 

Earlier, I interviewed leading HD global advocate, Emmy Award winning television journalist, and fellow HD gene expansion carrier Charles Sabine about his compelling TED Talk “The Unlimited Capability of Every Human.” Launched on February 1, the talk already has had 4,500 views.

 

Sabine stressed the importance of making the presentation “gather viral momentum” and transform the way HD is viewed by the general public everywhere. I will explore the implications of Sabine’s vital talk in a future article.

 

Stay tuned for further coverage of the therapeutics conference. 

 

Displaying a slide of daughter Meghan, Cheryl Sullivan Stavely delivers the keynote address at the 19th HD Therapeutics Conference, February 26, 2024 (this and the photos below by Gene Veritas, aka Kenneth P. Serbin).

The audience watching Stavely's presentation

Cheryl Sullivan Stavely and husband Kevin Stavely

 

Leslie Thompson, Ph.D., of the University of California, Irvine, greeting Kevin and Cheryl Stavely

 

Stavely with Karen Anderson, M.D., of Georgetown University

 

Stavely (left) with Haiying Tang, Ph.D., of CHDI and Wenzhen Duan, M.D., Ph.D., of Johns Hopkins University
 

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.