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.

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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.

‘Inequality is unsustainable’: a view of the quest for Huntington’s disease treatments from the Global South

(I dedicate this article to the worldwide HD community as we mark Huntington’s Disease Awareness Month in many countries around the planet.)

 

Both the COVID-19 pandemic and the quest for treatments for rare and genetic diseases have laid bare deep social divisions across the world, and it behooves the scientific establishment to help resolve this ethical dilemma, says a leading Brazilian Huntington’s disease clinician.

 

“The world should not be divided between those who have money and those who don’t,” Mônica Santoro Haddad, M.D., a neurologist with 33 years’ practice at the Universidade de São Paulo (USP) School of Medicine, told me in an April 30 Zoom interview about the 16th Annual HD Therapeutics Conference. “The pandemic has already shown us that. This inequality is unsustainable.”

 

Dr. Haddad has assisted HD patients from 600 families at the USP neurology clinic and her private office. A participant in the 2013 Therapeutics Conference in Venice, Italy, and 2014 meeting in Palm Springs, CA, she watched all of this year’s three-day virtual event (April 27-29) online. The conferences are sponsored by CHDI Foundation, Inc.

 

“What we’re witnessing in Brazil [regarding the pandemic] is immoral – Brazil in relationship to the world and Brazil in general,” Dr. Haddad observed, speaking in her native Portuguese. “Two categories of people have been created: those with the vaccine, those without the vaccine.”

 

A South American giant struggles

 

Sadly, Brazil ranks second in the world behind the United States with more than 428,000 COVID-19 deaths.

 

As a history professor, I have dedicated much of my career to the study of Brazil, a country that I consider my second  home; my wife is Brazilian, and her extended family is there. Along the way, I have witnessed the development of the Associação Brasil Huntington and built ties to its leaders.

 

A major country of the Global South – the world’s developing countries – Brazil has an estimated 20,000-plus afflicted individuals and an active HD movement. An enthusiastic group of some 30 Brazilians took part in #HDdennomore, Pope Francis’ special audience with the HD in May 2017. Francis, a native of Argentina, is also the first pontiff from the Global South.

 

However, although Brazil’s medical system has gained international recognition for past vaccine campaigns and its model fight against AIDS, during the pandemic the country has lacked hospital beds, cemetery plots, and basic supplies. Like Donald Trump, Brazilian President Jair Bolsonaro denied the crisis, downplayed the dangers, and actively denounced such measures as mask-wearing.

 

In addition, Brazil has fallen victim to the international inequities in the rollout of vaccines. Both U.S. President Joe Biden and former Brazilian president Luiz Inácio Lula da Silva – a likely candidate in the 2022 presidential election – have backed waiving COVID-19 vaccine patents to assure global access.

 

Brazil’s deep internal disparities have led to inadequate vaccine distribution to the poor and marginalized.

 

Recognizing similar, longstanding neglect in other South American countries, the humanitarian organization Factor-H has continued to assist abandoned HD families during the crisis.

 

Providing everybody access to medicines

 

Echoing her concerns about COVID-19, Dr. Haddad affirmed the need for a “change in the paradigm” regarding rare and genetic diseases like Huntington’s.

 

As in the U.S. and elsewhere, fear and denial frequently underlie Brazilians’ decisions to avoid genetic testing and facing the terrible medical and social challenges posed by the disease. Many Brazilians have “prejudice against disease” in general, Dr. Haddad told me in a 2013 interview.

 

However, the trend against testing might be shifting for the younger generations, and could also change among older groups when the overall outlook for treatments has improved, Dr. Haddad wrote in a May 14 WhatsApp message. Clinical trials seeking presymptomatic HD gene carriers will require testing, she added.

 

Like medical professionals in many countries, Dr. Haddad believes genetic testing is a personal decision, with the procedure governed by established protocol and with professional medical and psychological support.

 

As of April 2021, the Brazilian government has required all private health plans and insurance to cover genetic testing. This represented a “small advance,” Dr. Haddad asserted in our Zoom interview, because health advocates want to see the country’s free public health service also provide that benefit.

 

For Dr. Haddad, for HD to be defeated, inequality must diminish.

 

“The question is: is it ethical to diagnose someone with one of those diseases and not have a treatment available?” Dr. Haddad said. “This is a question that I discuss with my patients and with my colleagues.”

 

She added: “It is certainly not ethical to have a treatment that not everybody has access to.”

 

The HD Therapeutics Conference left her with her “hope battery recharged” and confident that a treatment is possible, Dr. Haddad said.

 

 

Gene Veritas interviewing Dr. Mônica Haddad (screenshot by Gene Veritas, aka Kenneth P. Serbin)

 

Advocating for open science

 

At the close of the conference, Dr. Haddad was inspired by the presentation by featured speaker Aled Edwards, Ph.D., who in 2004 founded the Structural Genomix Consortium (SGC), which practices and advocates for open sharing of scientific information, particularly as it applies to protein science, chemical biology, and drug discovery.

 

Dr. Edwards, the SGC CEO and a scientist based at the University of Toronto, spoke on “HD drug discovery in the public domain – a model for CHDI.” A breath of “fresh air,” Dr. Edwards’ talk pointed the way to reducing inequality, Dr. Haddad told me.

 

“What we would also like to do is develop a drug discovery ecosystem that prioritizes affordability and global access, and, of course, to do this in collaboration with industry,” Dr. Edwards stated. “Now this might sound naïve, but I’d like to emphasize there’s quite a bit of drug discovery experience in the SGC and in our network.”

 

Dr. Edwards presented examples of researchers who have followed the open science model – including 16 “HD open science programs” that share science “as they go,” with some even blogging about their findings. He highlighted the work of Rachel Harding, Ph.D., an SGC researcher and postdoctoral fellow at the University of Toronto who achieved the “very challenging” task of purifying the huntingtin protein to a “resolution that is practically useful” to other scientists.

 

Dr. Harding has widely shared both the protein and reagents (compounds that facilitate chemical reactions) that enable the making of the protein, ultimately aiming to inform the discovery of potential HD drugs, in particular so-called small-molecule drugs, Dr. Edwards explained.

 

Discussed at the Therapeutics Conference, these drugs become distributed very evenly across the whole body, including the brain, whereas several drugs in other current or recently completed clinical trials need to be injected directly into the brain or via spinal tap.

 

“This is a really fantastic contribution to the public good that these folks have made,” Dr. Edwards said of Dr. Harding’s team.

 

Sharing science as they go: Huntington's disease "open science champs" as presented by Dr. Aled Edwards, at upper right (screenshot by Gene Veritas)

 

Seeking more efficient drug discovery

 

Dr. Edwards underscored a key point: despite spending $300 billion globally each year on research and development and producing many hugely successful drugs, the biomedical field is highly inefficient. “We need to do better as a society,” he asserted.

 

“For many diseases – Huntington’s, Parkinson’s, Alzheimer’s – we don’t even know the molecular mechanism of the disease, let alone how to design a therapeutic strategy,” Dr. Edwards said, adding that a system in which the “first past the post gets the money” in designing drugs has required “the pricing of medicines at levels that are unaffordable for most people on the planet.”

 

Dr. Edwards displayed data demonstrating how globally most research focuses on the familiar rather than explore new, potentially crucial areas of biology. Similarly, in industry, companies pursue drugs in parallel rather than collaborate, wasting valuable resources, he added.

 

SGC is working against the grain, trying to create the way for a new scientific culture. The SGC never files for patents “as a core principle,” Dr. Edwards explained. “All of the work we do goes into the public domain, including the reagents that we make.”

 

If labs and companies openly shared data before doing the final crucial test on a potential drug in a Phase 3 trial, the field could not only save money, but test multiple drugs at the same time, he said.

 

Rather than rely on patents, the system should take advantage of federal laws that give companies protection from competition for a fixed period, generally five to twelve years, Dr. Edwards affirmed. The law provides even longer periods for orphan and pediatric drugs.

 

Supporting the public good

 

“There is no law of physics that says industry has to invent a drug,” Dr. Edwards said. “That’s the social system that we’ve put in place. Let’s imagine a different system.”

 

To “walk the walk about open drug discovery,” SGC established the Agora Open Science Trust, a registered charity in Canada modeled on Newman’s Own Foundation, which funnels profits from food products with the picture of the late Academy-Award-Winning actor into philanthropy.

 

Dr. Edwards described its goal: “To support open science and the public good, and price new medicines to ensure global access. Whether you’re a rich American or live in Thailand, you’re going to get the medicine at a price you can afford.”

 

In its first project, Agora has focused on children’s cancers. As of yet the trust has not announced a plan for an HD drug program, although Dr. Edwards and the above-mentioned HD open science researchers have an abiding interest in finding treatments.

 

Indeed, regarding those treatments, Dr. Edwards concluded that “if we do it as a collective, we’ll get further faster.”

 

 

Dr. Aled Edwards explains the creation of for-profit drug companies to fund the Agora Open Science Trust, whose mission is to ensure global, affordable access to new medicines (screenshot by Gene Veritas).

 

Knowledge belongs to the world

 

If Dr. Edwards and SGC achieve their goals, they will have a place in history, Dr. Haddad observed. The emphasis on sharing data will “democratize” knowledge, she added.

 

“It’s obvious that a company does things to earn money,” Dr. Haddad continued. She noted, however, that Dr. Edwards is asking scientists and others to put their vanity aside to help the suffering.

 

Brazil has not yet hosted, and may not host in the future, any sites for the major HD clinical trials, Dr. Haddad pointed out. She noted that the local HD community attempted to bring to Brazil the historic Phase 3 gene silencing clinical trial by Roche, which reported the unfavorable results at the HD Therapeutics Conference. In South America, Roche ran the trial in Argentina and Chile.

 

“We did the paperwork to try to include a Brazilian research center, and because of questions raised by an ethics committee and political and legal issues, we were unsuccessful,” Dr. Haddad explained. “Brazil did not permit genetic material [from the clinical trial] to be sent out of the country.”

 

For now, Dr. Haddad said, Brazilians can at least look forward to the possibility of their government’s authorization of the drug Austedo, approved by the U.S. Food and Drug Administration in 2017 for chorea, the involuntary movements that occur in many HD-affected individuals.

 

At this time, Brazil’s lack of participation in clinical trials of drugs that aim to slow or stop the disease is “not important,” Dr. Haddad concluded. Echoing Dr. Edwards – and the hope of thousands of Brazilian HD families anxiously awaiting the arrival of effective treatments but fearful that the country might not be able to afford them – she added: “The knowledge obtained belongs to the world.”

‘The first at-bat is never a grand slam’: how Huntington’s disease drug research has matured with the Roche and Wave setbacks

Despite the disappointing clinical trial results reported last week by Roche and Wave Life Sciences, Huntington’s disease drug researchers see an upside: they are using the data collected to achieve new insights, offering renewed hope of effective treatments.

 

The news of these setbacks produced one of the most heartbreaking moments of the last several decades for the HD community and researchers.

 

“That kind of news, I hope it’s okay to say: it sucks!” said Robert Pacifici, Ph.D., the chief scientific officer for CHDI Foundation, Inc., of the Roche and Wave trial data. “All of us who hold out so much hope and recognize that there are so many families who so desperately are waiting for much needed relief and therapies – it knocks the wind out of you.”

 

The companies made their first formal scientific presentations of their data at the start of the CHDI-sponsored 16th Annual HD Therapeutics Conference, held virtually from April 27-29. A nonprofit virtual biotech, CHDI focuses solely on developing Huntington’s therapies.

 

Roche confirmed that its drug tominersen failed to alleviate symptoms in its Phase 3 clinical trial; patients receiving the highest of two possible doses may have done even slightly worse than those on placebo. Two early-stage Wave trials failed to meet the goal of reducing the amount of mutant huntingtin protein in the trial participants – an objective already achieved by Roche in an earlier tominersen trial. (Click here to read more.)

 

Dr. Pacifici offered his assessment of the Roche and Wave data and the state of HD drug research in a wide-ranging, 46-minute Zoom interview with me after the close of the event.

 

Dr. Robert Pacifici moderates panel discussion of huntingtin-lowering clinical trial results with Dr. Vissia Viglietta of Wave Life Sciences and Dr. Scott Schobel of Roche (screenshot by Gene Veritas, aka Kenneth P. Serbin)

 

Gaining perspective

 

“My reaction though, now that I’ve come back down to earth, is really not one of surprise,” Dr. Pacifici said. “Drug discovery, as we’ve discussed many times, is a really tough business. The probability of success on any given endeavor is incredibly low.”

 

Dr. Pacifici used a baseball metaphor to explain: “How often does the first batter get up to the plate and hit a grand slam home run? A grand slam, never, because you need to load up the bases with three people. Even a home run is incredibly rare.”

 

The “name of the game” in discovering effective treatments is to carry out as many trials as necessary, “doing it well, failing, but making it a good failure that we can learn from so that subsequent efforts have a much higher chance of success,” Dr. Pacifici explained. “And we continue to snowball and build on that so that we can learn the things to do better, the things that we can do differently, or the things that we should stop doing altogether because we now have confirmed that those are not viable lines of investigation.”

 

The accumulation of experience through research and clinical trials, including the crucial participation of patient volunteers, has produced “an incredibly positive thing,” Dr. Pacifici observed.

 

“Look at how the field has matured,” he said. In the past, scientists would have kept a trial running for three years, waiting for patient improvement, only to discover that “the drug really didn’t even have a chance of working” because it hadn’t done what it was “tasked with doing, which is lowering huntingtin levels.”

 

Now the process is moving “faster” and is “better informed,” Dr. Pacifici said.

 

Watch the entirety of my interview with Dr. Pacifici in the video below.

 

Huntington's disease drug research now a 'mature field' from Gene Veritas on Vimeo.

 

Huntingtin lowering still in the running

 

Dr. Pacifici commented on the critical topic of lowering (reducing) the mutant huntingtin protein, the first strategy aimed at HD’s genetic cause. Scientists believe that the mutant protein is a main driver of the disease. In mouse studies, lowering that protein led to a disappearance of symptoms, and, beginning with the Roche trial, researchers have sought to achieve similar results in humans. Thus, until now, lowering mutant huntingtin has been seen as the potentially most promising path to a treatment.

 

Both Roche and Wave used a type of drug known as an antisense oligonucleotide (ASO), an artificial strand of DNA. Other firms and labs are also investigating ASOs.

 

“When two of those things don’t move forward simultaneously, it’s perfectly reasonable to ask the question, ‘Well, is this one of those times where we’ve learned that this approach is not going to work?’” Dr. Pacifici asked. “I can say unequivocally that that’s not yet the case. There are just too many things that factor into how a drug needs to do its job that remain unanswered.”

 

He said that possible key factors affecting the outcomes of the Roche and Wave trials include the stage of disease of the participants, the concentration of the drug tested, and the proper distribution of the drug within the brain. The particular characteristics of the drugs selected could have also impacted the outcome, he added.

 

Another possible explanation involves the design of the trials, the techniques for measuring patient response, and biomarkers (signs of disease and a drug’s effects).

 

In addition, even though Roche’s tominersen reduced the level of mutant huntingtin protein in trial volunteers’ cerebrospinal fluid, researchers still do not know whether the samples of protein actually came from the brain and, if so, cells relevant to HD, Dr. Pacifici cautioned. Scientists also lack other critical details about those samples; for example, they could be fragments, he said.

 

Crucially, the “interim analysis” of the Roche data at the Therapeutics conference did not demonstrate whether lowering huntingtin can help people feel, function, or survive better, Dr. Pacifici observed.

 

Even a “whisper of efficacy” would have validated the huntingtin-lowering approach and “prepared the path for subsequent trials with gusto and confidence,” he continued, adding, however, that “the opposite is not true. We still have great hopes that this is a viable mechanism of action.”

 

Wave plans to start a trial of a third ASO later this year. Roche has also stated that it will continue to explore drugs for HD.

 

Exploring other avenues

 

Because the effectiveness of huntingtin-lowering remains an open question for the field, Dr. Pacifici renewed his call to redouble and diversify drug-hunting efforts.

 

Dr. Pacifici noted that other potential huntingtin-lowering approaches are in the works using non-ASO compounds, while others propose different methods of delivery, including a pill. In the Roche and Wave trials, participants received the drug via spinal tap.

 

“If we were in a fantasy world of the 20th new treatment for Huntington’s coming, you would worry about things like convenience: ‘I’d like to have a pill instead of an injection,’” Dr. Pacifici said. “‘I’d like to have a pill I can take once a day. I’d like to have a small pill that’s easy to swallow.’”

 

However, Dr. Pacifici observed, “we’re not at that stage yet.” Even so, “very critical advantages” exist in exploring different modes of delivery, he said.

 

Indeed, another possibility emerged at the conference. A scientist from pharmaceutical giant Novartis presented research on its drug branaplam, a pill used to treat spinal muscular atrophy (SMA), which causes severe muscle weakness in children. Novartis researchers discovered that Branaplam also reduced the amount of the huntingtin protein in a study of SMA patients. Novartis plans a trial of branaplam in HD patients, with details expected in the coming weeks and over the summer (click here to read more).

 

Like other so-called small-molecule drugs, branaplam becomes distributed very evenly across the whole body, including the brain, whereas a drug like an ASO tends to concentrate where it is administered, Dr. Pacifici explained. He added that small-molecule drugs can be dosed “creatively” – for example, weekly instead of daily – to maximize the “beneficial effect” and allow the person a rest from the drug.

 

(I will explore the quest to develop this type of HD drug in a future article.)

 

Dr. Rajeev Sivasankaran of Novartis presents data demonstrating the effect of the drug branaplam on huntingtin RNA in a study of spinal muscular atrophy patients (screenshot by Gene Veritas).

 

Sharing knowledge rises all boats

 

Dr. Pacifici emphasized that success in the fight against HD ultimately depends on the sharing of scientific information – even negative research results that private companies are loathe to reveal to protect their egos and their stock prices.

 

He cited the presentation by featured speaker Aled Edwards, Ph.D., the founder and CEO of the Structural Genomix Consortium, which practices and advocates for open sharing of scientific information, particularly as it applies to protein science, chemical biology and drug discovery. Dr. Edwards spoke on “HD drug discovery in the public domain – a model for CHDI.”

 

“I think the HD field will benefit by everybody realizing how difficult this problem is,” Dr. Pacifici concluded. “It’s not giving up a competitive advantage by being transparent about what happened. It’s sharing data. That knowledge rises all boats. Everybody needs to know about these things.”

 

Sharing of data and other knowledge has also been one of CHDI’s trademarks as a nonprofit. Dr. Pacifici pointed to specifics: knowledge about the disease, potential treatments, biomarkers, and clinical outcome measures (the techniques for measuring patient response).

 

With such sharing, he asserted, everybody will have an increased chance of success.

 

Refusing to do so will “doom us to the same failure we see in other neurodegenerative fields that have outspent us and been at this a lot longer than we have.” 

Roche confirms tominersen as ineffective, while Triplet provides key details for trial of drug to slow major driver of Huntington’s disease

 

Following up on news that it had halted dosing, Roche has confirmed that its historic GENERATION HD1 clinical trial, aimed at the genetic causes of Huntington’s disease, failed to improve symptoms in study participants.

The disappointing trial outcome for the drug candidate tominersen was revealed on April 27 by Scott Schobel, M.D., M.Sc., Roche’s medical leader of GENERATION HD1, at the virtual 16th Annual HD Therapeutics Conference, sponsored by CHDI Foundation, Inc., the nonprofit virtual biotech focused solely on developing HD treatments and a collaborator in the effort.

 

More than 1,000 people registered for this greatly anticipated meeting.

 

“Nobody wanted this result,” Dr. Schobel said in his online talk, the first scientific presentation describing why an independent review committee had recommended, and Roche accepted, that GENERATION HD1 be halted. “This is a setback, and it’s a setback which is emotional. It’s a setback which we all feel, because, after being able to lower the huntingtin protein for the first time, there’s a lot of hope in that.”

 

An opportunity to learn

 

Dr. Schobel displayed a series of slides demonstrating tominersen’s lack of effect on trial volunteers, who showed “progressive decline,” reflected in key measures of cognition and control of bodily movements. Observations by physicians also showed “increasing severity” of disease in the participants, Dr. Schobel said.

 

Still, he said the researchers established a “new setpoint for the field”: reducing the level of the mutant protein in the early-stage tominersen clinical trial.

 

That achievement was a historic first, and many HD scientists still believe that this strategy can lead to an improvement in symptoms. However, it now remains for potential future trials to demonstrate that huntingtin-lowering can actually help patients.

 

Roche is “compelled” to use the trial results “as an opportunity to learn,” Dr. Schobel said. The company still has a “wealth of data” to analyze regarding tominersen and its implications for the huntingtin-lowering approach. The firm will share results with the HD community.

 

The Huntington's Disease Society of America will hold a webinar at noon Eastern time on April 29 with an update for the community on the Roche results. (Click here to register.)

 

 

Dr. Scott Schobel of Roche displays slide demonstrating decline in volunteers' condition in the GENERATION HD1 clinical trial at the 16th Annual HD Therapeutics Conference (screenshot by Gene Veritas, aka Kenneth P. Serbin)

 

Drug candidate’s target chosen

 

On this first day of the three-day conference, Irina Antonijevic, M.D., Ph.D., the chief medical officer at Triplet Therapeutics, Inc., revealed key details of the firm’s drug program to develop a genetic strategy that contrasts sharply with the idea of lowering the huntingtin protein. The firm also issued a press release.

 

Dr. Antonijevic focused on Triplet’s efforts to slow or stop a key driver of HD, somatic expansion, the mutant huntingtin gene’s tendency for continued expansion with age.

 

Triplet’s research exploits continuing breakthroughs in HD genetics, also the topic of this year’s Therapeutics Conference. Those advances have 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.

 

Triplet scientists and others believe that the longer that expansion, the more toxic the gene and its product, the huntingtin protein, become.

 

Building on these developments, in 2020 Triplet announced its drug candidate TTX-3360, aimed at slowing or stopping somatic expansion.

 

In her conference presentation, Dr. Antonijevic announced that the specific biochemical target of TTX-3360 is the modifier gene MSH3, involved in the maintenance and repair of DNA.

 

In studies of mice, Triplet has demonstrated safe and effective lowering of MSH3 using TTX-3360. Additional safety studies were done in nonhuman primates.

 

Injection directly into the brain

 

Like the Roche drug, TTX-3360 is an antisense oligonucleotide (ASO), a synthetic modified single strand of DNA. Both the early-stage trial of tominersen and GENERATION HD1 delivered ASOs via spinal tap.

 

However, Dr. Antonijevic announced that TTX-3360 will be introduced into the brain using an intracerebroventricular (ICV) injection. The ICV device is a small reservoir implanted at the top of the head with a catheter going into the brain. ICVs have been used in medical treatments since the 1960s, including injection of anti-cancer drugs.

 

Dr. Antonijevic explained that, in contrast with the spinal tap – whereby an ASO had to travel along the spine before entering the brain – the ICV will permit Triplet to get its drug deeper into the brain, including areas severely affected by HD.

 

With spinal taps, patients can experience pain and inflammation during dosing because of scarring that results from repeated dosing, Dr. Antonijevic asserted. The ICV permits easy withdrawal of cerebrospinal fluid (which bathes the brain) for monitoring of drug safety and efficacy, she added.

 

The ICV also allows for rapid dosing – perhaps even at home – whereas the spinal tap requires a visit to a doctor’s office, Dr. Antonijevic pointed out.

 

(According to one scientific article, an ICV can remain in place for life. However, long-term usage is not well understood. The device should be monitored for leakage or failure. If necessary, the device can be removed or replaced.)

 

At the HD Therapeutics Conference, Dr. Irina Antonijevic of Triplet Therapeutics discusses a slide comparing two methods of drug delivery: spinal taps (intrathecal injections) and intracerebroventricular injection (screenshot by Gene Veritas)

 

Triplet aims to file an investigational new drug application with the U.S. Food and Drug administration (and/or a clinical trial application in Europe or Canada) by year’s end for a Phase 1/2a study of TTX-3360, which will address primarily the safety and tolerability of the compound. Triplet will recruit presymptomatic and early symptomatic individuals for the trial.

 

Triplet also announced a pledge of one percent of its equity to a “patient support fund,” to be managed independently, to support patients suffering from HD and other, similar disorders, known as repeat expansion disorders. The fund will help patients and families secure access to care and therapies.

 

(For background on the Triplet clinical trial program, click here. Stay tuned to this blog here for further coverage of the conference.)

 

(For additional coverage of the conference, click here).