Monday, May 13, 2024

Aiming for multiple targets for Huntington’s disease therapies: a hopeful report from the Yang lab at UCLA


This article is in commemoration of Huntington’s Disease Awareness Month (May).


One of the most impactful university labs focusing on Huntington’s disease, the X. William Yang Research Group at the University of California, Los Angeles (UCLA) employs a multi-pronged approach to investigating potential therapies for this deadly brain disorder.


Started in 2002 by X. William Yang, M.D., Ph.D., the lab has produced several key findings on HD, mainly through the study of genetically modified (i.e., transgenic) mice, engineered to carry the HD mutation and exhibit some of the disease-like phenotypes (characteristics).


Dr. Yang was inspired to focus on Huntington's disease because of his interaction with patients in Venezuela – the world’s largest clusters of HD families – and the HD scientists working there. In 2000 and 2002 he was invited to observe these families and assist with studies by Nancy Wexler, Ph.D., the president of the HD-centered Hereditary Disease Foundation (HDF) and leader of the landmark effort to identify the HD gene in 1993.


Dr. Yang's Venezuela experience cemented his resolve to study HD in his own lab. Indeed, the first research grant ever received by Dr. Yang was from HDF. Today he serves as its scientific advisory board’s vice chair.


Dr. Yang’s team has also collaborated with CHDI Foundation, Inc., the largest private funder of HD therapeutic research. Pharmaceutical firms such as Roche (the world’s largest) and Ionis Pharmaceuticals, Inc., the developer of the Roche drug now in its second HD clinical trial, have consulted Dr. Yang for his expertise.


Dr. Yang has emerged as a leading academic voice in HD science. Listed as the first author, in February he and two other important prominent HD researchers – Leslie Thompson, PhD., of UC Irvine and Myriam Heiman, Ph.D., of the Massachusetts Institute of Technology (MIT) – published a major co-edited book. Huntington’s Disease: Pathogenic Mechanisms and Implications for Therapeutics presents the latest work on the disease’s medical impact, genetics, the huntingtin protein, new tools and models for research, and an overview of therapeutic approaches and clinical trial programs.



The back and front covers of Huntington’s Disease: Pathogenic Mechanisms and Implications for Therapeutics (image courtesy of Dr. Yang) (Click on an image to enlarge it.)


‘The stars are aligned’ for developing HD treatments


Although the use of human data in HD research has increased dramatically, crucial research in mice has become more relevant to potential therapies because of new biotechnologies and the availability of so-called “big data” made possible by powerful computing systems.


“This is completely unprecedented in terms of the kind of study we can do,” Dr. Yang told me in a 40-minute interview on January 29, noting the advantages of a “21st century toolbox.” “Mouse models in this context are extremely useful.”


We met in Dr. Yang’s office in his lab, which is located in UCLA’s Gonda (Goldschmied) Neuroscience and Genetics Research Center. I was invited to Los Angeles to offer my perspective as an HD gene carrier on the first day of a two-day HDF scientific workshop, co-chaired by Dr. Yang.


“I know it's probably an oxymoron to say that it's time to be hopeful, because we’ve been to a hopeful stage many times before,” Dr. Yang said, acknowledging the negative results of some recent clinical trials. He added that “the stars seem to be aligned” for developing HD treatments.



Dr. Yang (left) with project scientist Chris Park, Ph.D. At the far left is a confocal microscope, which uses laser light to obtain high-resolution images of thick tissues. Behind the men is a light sheet microscope, also used for obtaining high-quality images of tissues (photo by Gene Veritas, aka Kenneth P. Serbin).


Focusing on the brain


Dr. Yang grew up in Tianjin, China, a port city located 80 miles from the capital, Beijing. In 1985, Dr. Yang was one of five students selected by the Chinese government to participate in the Rickover Science Institute, founded by Admiral Hyman G. Rickover to foster high-school science education for both domestic and international students. Rickover developed the first nuclear-powered engines and first atomic-powered submarine.


“I did a whole summer of research at the NIH [National Institutes of Health], working on signaling pathways in rat brains,” Dr. Yang wrote in a follow-up e-mail to our interview. “The research experience got me really interested in studying the mammalian brain.”


The Rickover program is now called the Research Science Institute (RSI). Among other prestigious alumni are Harvard University’s Steve McCarroll, Ph.D., a leading molecular geneticist who also works on HD; and MIT/Broad Institute's Feng Zhang, Ph.D., a CRISPR research pioneer.


After RSI, Dr. Yang briefly studied at Peking University, one of China's top universities, before transferring to Yale University, where in 1991 he completed the highly demanding joint B.S./M.S. program in molecular biophysics and biochemistry.


Over lunch Dr. Yang and I reminisced about our years at Yale. I was privileged to graduate from Yale in 1982. I told Dr. Yang that I had seen Admiral Rickover give a public lecture at the university – a poignant moment for me as a history major because of his military and scientific prominence. I told Dr. Yang of my interest in tracking the contributions of Yale and its graduates like him to HD science and medicine (click here, here, and here to read more.)


Dr. Yang completed the joint M.D./Ph.D. program at The Rockefeller University (Ph.D., 1998) and Weill Medical College of Cornell University (M.D., 2000) in New York City. In 2002, he finished postdoctoral research in the Rockefeller lab of Nathanael Heintz, Ph.D., which focuses on HD and other neurological and psychiatric disorders.


Gene Veritas (left) (aka Kenneth P. Serbin) with Dr. William Yang in his UCLA office. In the background: a mouse medium spiny neuron. In humans this neuron is one of the cells most affected by Huntington’s disease (photo by Nan Wang, Ph.D., of the Yang Research Group).


A ‘trustworthy and versatile’ invention


Dr. Yang and his lab have made key contributions to HD science, including understanding the causes and potential pathways to therapies. The team also studies Alzheimer’s disease, Parkinson’s disease, and other neurodegenerative disorders.


As a Ph.D. student, Dr. Yang co-invented with Dr. Heintz and Peter Model, Ph.D., the first method to engineer Bacterial Artificial Chromosomes (BACs) to generate transgenic mice. BACs have the advantage of holding long strands of DNA with key regulatory elements that confer accurate gene expression in transgenic animals.


In an analysis of this research, which Drs. Yang, Model, and Heintz published in 1997, one leading biologist described their technique as “trustworthy and versatile” for cloning genes and the key task of learning the specific function of particular genes.


Indeed, scientists have used this method to generate a variety of transgenic animals, from zebrafish to mammals (click here to read more).


The key BACHD mouse


In 2008, Dr. Yang and other researchers published the results of a project creating the first BAC transgenic mouse model of HD, the BACHD mouse, their term for this mouse specifically engineered to study HD.


As Dr. Yang explained in our interview, the team inserted a long strand of a mutant (irregularly expanded) human huntingtin gene into the mice. Those genetic characteristics do not normally exist in mice. As they hoped, the mice developed dysfunction, displaying impaired movements, shrinkage to the same brain regions affected in HD, and damage to the synapses (the connections between brain cells).


“We developed different versions of these mouse models to allow us to ask, for example, which cell types in the brain with mutant huntingtin are important,” Dr. Yang said.


The team demonstrated the presence of mutant huntingtin in two key areas of the brain: medium spiny neurons in the striatum and pyramidal neurons (brain cells) in the cortex. (See the photo above with Dr. Yang, me, and an image of a medium spiny neuron. Also see the photo in the next section.)


In mice, humans, and other mammals, the cortex handles important processes such as cognition, memory, motor control, and sensory processing. The striatum – an area deep in the brain and greatly affected in HD – controls motor (movement), motor and reward learning, and executive function. In humans, this region is also known as the caudate and putamen. The Yang lab also examines communication between these regions.


Dr. Yang (left) and Nan Wang, Ph.D., a project scientist focusing on Huntington’s, in the lab (photo by Gene Veritas)


Using mice and genetics to understand HD


In detecting the impact of mutant huntingtin in those areas, that initial BACHD research revealed disease phenotypes in both striatum and cortex, Dr. Yang recalled. “That study turned out to be really important because, for the longest time, people thought the striatum, the medium spiny neuron, was really the primary site of action.”


Removing the mutant huntingtin from the cortex led to improvement in the mice’s behavior and even partially helped the striatum, Dr. Yang explained. Likewise, deleting mutant huntingtin from the striatum brought some improvement.


“But most importantly, if you reduce mutant huntingtin in both cortex and striatum, the BACHD model looks really, really good, almost as good as a normal mouse,” he added.


The BACHD work, he recalled, helped to convince the field that  the cortex is one of the key brain regions that should be targeted in HD clinical trials. The Roche/Ionis ASO lowers the level of huntingtin protein more in the cortex than in the caudate/putamen, according to preclinical studies in non-human primates.


In sum, Dr. Yang said, the studies of BACHD mice represent a “proof of concept that we can use this kind of a sophisticated – genetically as accurate as we could get – type of mouse model to inform about disease pathogenesis” – how HD develops, progresses, and, significantly, might be treated.


A mouse medium spiny neuron (image courtesy of Dr. Yang)


From disease switch to vulnerable neurons


The Yang Research Group has achieved other key findings, some in collaboration with other labs.


The Yang lab teamed with researchers at UC Irvine, UC San Francisco, the University of Pittsburgh, and the University of Tennessee to study the chemical modification of the huntingtin protein itself. This research focused on so-called “chemical tags” that naturally attach to the very beginning of the huntingtin protein, a small region acts like a disease switch.


In one experiment, this research used a BACHD-like mouse to mimic the tagging. That resulted in mice that had “very little disease despite having the HD mutation,” Dr. Yang explained. The results were published in 2009.


In 2015, the Yang Research Group published a separate study showing the genetic switch is necessary to prevent severe disease including neuronal loss and movement deficits, phenotypes reminiscent of those found in HD. These studies showed that the huntingtin protein itself and its chemical tags could be a source of new targets to develop therapies, Dr. Yang said.


From watching mice in ‘log rolling contests’ to unbiased genetic analysis


In 2013, the Federal Government announced the launch of the BRAIN initiative to enhance understanding of the human brain. The Yang lab was one of the first 59 in the country to receive support in the initial round of BRAIN funding. It now has its third grant. It receives support from other government agencies, as well as the HDF and CHDI. The lab’s achievements include developing a new, genetic way to label the complete, intricate shape of single brain cells, which allows the study of their function and dysfunction in diseases such as HD.


With big data and "the 21st century toolbox," the field of HD research has advanced from more traditional ways of observing diseased mice to more nuanced molecular, cellular and systems biology analyses, Dr. Yang explained.


In earlier research, by primarily relying on the behavior and pathology of individual mice, the work resulted in “relatively few readouts” of data, Dr. Yang observed. With that methodology, scientists had mice doing activities such as “spontaneously move” in an open area or on a rotarod, “like the ESPN log rolling contest,” he said. Scientists also routinely measured loss of brain matter.


Now, scientists can do a “big-scale, unbiased molecular studies” by examining tens thousands of datapoints, including analysis of DNA, RNA and proteins, Dr. Yang added.


Clues from gene expression about neuronal vulnerability


Collaborating with CHDI, the Yang lab’s work in this area has involved study of HD’s impact in different areas of the brain, moving beyond the standard understanding that most damage comes in the striatum. The lab has done this research using different types of engineered HD mouse models carrying different lengths of CAG repeats and measured the levels of tens of thousands of RNA transcripts ("RNA-seq," that is, RNA sequencing) in the mouse brains and peripheral tissues.


Published in 2016, the results noted that despite the presence of the mutant HD gene throughout the body, the disruption in gene expression in these HD mice is highly selective to the striatum, the most affected brain region in HD. The severity of the disruption is correlated with the length of CAG repeats in these mice. Moreover, the molecular defects in the striatum appear in young adulthood, worsening with age.


“There's about 100 or so genes that have essential function selective to the striatal neurons that are most affected in Huntington’s disease,” Dr. Yang said. “And somehow the mutant huntingtin knows to go there and make them the sickest, which we thought was a remarkable find – a sense that there's some fundamental mechanism connecting this CAG expansion to selective neuronal vulnerability.”


‘Perturbing’ the mice to understand human modifier genes


Taking advantage of the gene signatures from RNA-seq studies, especially those selectively disrupted in the striatum, the Yang lab embarked on a study using such gene signatures to sensitively detect "modifiers" of the disease. To achieve this, they used these genes to genetically “perturb” the mice, Dr. Yang explained.


“We basically genetically perturb the huntingtin mouse and say, ‘which gene, if we perturb them just right, can make the disease worse – that's one thing that's interesting – but more importantly make them better. And if better, how much better.’”


Continuing this line of work, the lab has continued testing the impact of other genes. These experiments include study of some of the human HD modifier genes – about ten – previously identified by the Genome Wide Association Study (GWAS) from over 9,000 HD-affected individuals and their relatives. The modifiers found by the Genetic Modifiers of Huntington's Disease Consortium can delay or hasten HD onset.


In addition, the Yang lab tested over 100 other candidate modifier genes identified in the prior systems biology work.


The scientists have tested large number of genetic mutants in HD mice to determine whether this makes the disease better or worse, Dr. Yang said. Noting that the results are still unpublished, Dr. Yang said that the team is drilling down on discovering the best gene targets that could help advance therapies to alleviate the disease.


Three potential ways to treat HD


Dr. Yang also discussed his outlook for therapies to slow, prevent, or reverse the course of Huntington’s. As noted, he believes that “the stars seem to be aligned” for the development of treatments.


In exchanging ideas with other HD scientists, he proposed the model of a stool – which needs four legs to remain stable –  as a metaphor for the benefit of developing multiple therapies (polypharmacy) that could act synergistically for HD.  


“If one drug could work for HD, that will be great. However, for many diseases, like HIV or cardiovascular diseases, multiple drugs together can make the disease more manageable, and patients' lives much better.”


As of now, Dr. Yang said scientists are developing three potential legs of the therapeutic stool. Each leg represents a new angle in understanding HD and how it might be applied to slow or stop the disease.


The first leg: huntingtin lowering


As the first leg of the therapeutic stool, Dr. Yang pointed to so-called huntingin lowering – the reduction of the HD gene (DNA), RNA, or its toxic protein in the brain. Pioneered in patients by the above-mentioned Roche/Ionis clinical trial program, this approach has captured the attention of many academic and biopharma labs.


This Roche/Ionis drug is an antisense oligonucleotide (ASO), a synthetic strand of DNA that degrades the RNA from making the huntingtin protein. Other clinical trial programs aim to alleviate HD with ASOs, or other DNA or RNA targeting therapies. Some of them using small chemicals to reduce human huntingtin.


This approach has received ample coverage in this blog and elsewhere.


The second leg: GWAS/mismatch repair genes


Dr. Yang pointed to potential therapies based on the HD GWAS genes – which include DNA mismatch repair (MMR) genes – as the second leg of the stool.


“Lots of companies now are really excited about some of these genes,” Dr. Yang noted. “They are essential for aspects of repairing DNA. There's not much we know yet about the potential efficacy and safety liability of a drug targeting these genes. We and others are actively doing research in these areas.”


Dr. Yang said that some of these genes are known to “stabilize” the CAG repeats, which tend to expand in the brain areas affected by HD. Such "somatic" repeat expansion is thought to be a key mechanism in the disease.


A gene with great potential is MSH3, a MMR gene under investigation by academic labs and biopharma firms. Before it had to shut down for lack of funding, Triplet Therapeutics had planned to use an ASO to target MSH3 in a clinical trial.


“So far, I can tell you MSH3 looks pretty safe, at least in animal models,” Dr. Yang explained.


He cautioned that scientists still need to learn more about the basic biology of the HD GWAS DNA repair genes in the brain and select the best targets and therapeutics before advancing them in clinical trials in patients.


The third leg: huntingtin protein-protein interaction


The third leg of the therapeutic stool, he said, is how the huntingtin protein interacts with other proteins.


So far, researchers have discovered at least 100 proteins that could interact with huntingtin, including in different cell types and at different ages, Dr. Yang said. The interactions occur with both the normal and mutant versions of the protein.


At least one of these proteins, HAP40, binds very closely with huntingtin. Dr. Yang described HAP40 and huntingtin as “inseparable buddies.” The Yang lab is actively working on the normal function of HAP40 in the brain and whether it could have a modifier role in HD.


As with the GWAS genes, Dr. Yang stressed that research on protein-protein interaction and its potential benefit for patients is ongoing. He added that, in the search for potential drugs, the key is finding “a protein that binds to huntingtin and is required for disease, and ideally this protein is amenable to therapeutic intervention.”


Aiming to solve one of the ‘central mysteries of HD’


The recent HDF workshop’s focus on “cell-type specific biology” in HD took up the question of why certain brain cell types (i.e., neurons in the striatum and cortex) are vulnerable to degeneration.


Dr. Yang stated that it is unclear whether research on cell-type vulnerability could become the fourth leg of the therapeutic stool. “Cell-type vulnerability could be related to” the first three legs, “especially protein-protein interaction and GWAS mismatch repair genes.”


However, this does not diminish the importance of cell-type vulnerability.


“This question of  selective vulnerability is really a key feature for all neurodegenerative diseases,” Dr. Yang said. “So, for Huntington it's a striatal medium spiny neuron and some of the deep-layer cortical pyramidal neurons.” In Alzheimer’s and Parkinson’s, neuronal cell types in other brain areas are affected.


“So the big question is: why, for each disease, certain types of neurons die?” Dr. Yang asked. “If we can understand this fundamental question and elucidate its mechanism, we could use the knowledge to develop new disease-specific therapies to protect neurons from degeneration.   


With the workshop, Dr. Yang said, “we think the time is right to revisit what I consider one of the central mysteries for Huntington’s disease – why certain neurons are selectively vulnerable to degeneration despite that mutant huntingtin is expressed in all the cells in the body.”


As usual, this group of HD scientists used the workshop to explore new ways to solve this mystery and develop potential therapies.


At the HDF workshop: seated, from left to right, Mahmoud Pouladi, M.Sc., Ph.D., Osama Al Dalahmah, M.D., Ph.D., Ashley Robbins, Gene Veritas (aka Kenneth P. Serbin), Sarah Hernandez, Ph.D., William Yang, M.D., Ph.D. Standing, from left to right, Xinhong Chen, Andrew Yoo, Ph.D., Anton Reiner, Ph.D., Baljit Khakh, Ph.D., Nicole Calakos, M.D., Ph.D., Ed Lein, Ph.D., Beverly Davidson, Ph.D., Nathaniel Heintz, Ph.D., Harry Orr, Ph.D., Leslie Thompson, Ph.D., Myriam Heiman, Ph.D., Shawn Davidson, Ph.D., Steven Finkbeiner, M.D., Ph.D., Roy Maimon, Ph.D. (photo by Julie Porter, HDF)


Bonding with the scientists


Following our interview and tour of the lab, I made a PowerPoint presentation to Dr. Yang and other members of the lab: “Advocating for the care and cure of Huntington’s disease: a biosocial journey.”


I spoke about my family’s struggles with HD, my advocacy, and my deepening interest in the social and scientific history of the HD movement. Afterwards, I answered questions.


Once again, I bonded with a fellow Yale graduate immersed in the fight against Huntington’s disease and scientists dedicated to a cure.



The X. William Yang Research Group after hearing Gene Veritas speak on his Huntington’s disease story. Seated (from left to right) Chris Park, Ph.D., Xiaofeng Gu, M.D., Ph.D., Dr. Yang, Gene Veritas, Nan Wang, Ph.D. Standing (from left to right) Ming Yan, MPH, Masood Akram, Ph.D., Tien Phat Huynh, M.D., Ph.D., Daniel Lee, Ph.D., Nianxin Zhong, Henry Chen, Lalini Ramanathan, Ph.D., Alexandra Shambayate, Leonardo Dionisio, Amberlene De La Rocha, Linna Deng Ferguson


Thanks to Emily Farrell, Executive Assistant, Department of History, University of San Diego, for assistance with the interview transcript.


Disclosures: the Hereditary Disease Foundation covered my travel expenses to Los Angeles. In support of the HD cause, I hold a symbolic number of Ionis shares.

Wednesday, March 27, 2024

‘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.