HDBuzz is back for the last day of the CHDI HD Therapeutics Conference: Thursday February 29th in Palm Springs, California. This article summarizes our real-time updates of the conference in community-friendly language.

From genes to medicines

The morning session will focus on how human genetics is driving the development of therapeutics. “Genetic modifiers” are genes that influence when HD symptoms onset, and human data is extremely valuable to discover new drug targets.

Scientists can only find these modifiers when they have access to huge amounts of genetic data, so every single person from an HD family who contributed samples and signed those consent forms played an important role in all of these discoveries.

Vanessa Wheeler: expansion of CAGs and HD modifiers

The first speaker of the morning is Vanessa Wheeler, from Massachusetts General Hospital & Harvard Medical School. Vanessa’s team are experts on somatic instability (expansion of CAGs) and have been busy researching modifiers.

Vanessa is telling us about the work of a large consortium of scientists who all collaborated in a big team effort to do the best science possible. A lot of what we know about the genes that affect HD onset has come from these genome-wide association studies (GWAS). They first looked at modifiers in a very large dataset – from over 12,000 people from HD families! With such large amounts of data, they can start to parse out which modifier genes may contribute to which HD symptoms, such as movement or thinking.

The newest study highlighted familiar modifier genes, like FAN1 and MSH3, as well as a whole host of new ones, like MED15 and POLD. This is very exciting for HD researchers who are always looking for new possible drug targets or ways to alter the progress of HD. Based on this new data, Vanessa proposes a 2 stage model of HD – CAG expansion first due to faulty DNA repair, followed by the harmful effects of other proteins that mess up the normal biology of cells.

Vanessa and her colleagues at Harvard are looking to see how the human modifiers influence CAG expansions in mouse models of HD. Getting rid of these modifier genes in the mouse can have lengthening or shortening effects on CAG repeats. One of the new modifiers in Vanessa’s mouse model is a gene called HMGB1. Other HD scientists have already been working on HMGB1 because it sticks to huntingtin and plays a role in DNA repair – this is a cool connection.

Vanessa is proposing different roles for her favorite modifiers in the process of CAG repeat expansion and in other parts of HD biology. When science enters new territory, it’s interesting to hear many perspectives at global meetings like this one!

Darren Monckton: HD biomarkers to track disease progression

Next up is Darren Monckton from the University of Glasgow. Darren will be presenting his team’s recent work on HD biomarkers – different measurements scientists and clinicians can use to track how disease progresses over time or how it is affected by a treatment.

One of the challenges of creating drugs that combat somatic expansion is measuring whether the drug is working over time. Somatic expansion happens very slowly throughout a person’s lifetime, so how can we measure differences in a shorter timeframe, like in a clinical trial? Even more tricky is that changes in HD are happening in the brain! We can’t take out a piece of the brain to measure the effects of a drug, like we can with organs like the liver. Darren’s team have been investigating blood samples to see if this might work as a convenient, safe and reliable proxy.

Darren’s team are experts at doing very detailed analyses of the genetic code. They developed a cool technology to measure tiny changes in the CAG number which happen over time. Using blood from folks who generously donated samples to ENROLL-HD, they can see general patterns of somatic expansion as HD worsens. When they look at the level of individual people, they see there is actually a lot of variation in how their CAG numbers change.

The key thing to measure is how the CAG number changes in an individual over a reasonable timeframe, such as 1-3 years. This is not easy! To figure this all out they used a lot of different samples from the amazing and generous HD community. Darren’s team have been doing all kinds of cool science math to figure out exactly how many measurements they need to accurately and reliably detect a change in CAG number from blood samples, no matter the person’s age or initial CAG repeat number.

The most reliable measurements come from people with very long CAG repeats, such as those that cause juvenile HD. Darren and his team are working to ensure that they can make good measurements across the board, which would be important for clinical trial recruitment. Darren is also exploring these ideas in other diseases caused by CAG repeat expansions, like movement and balance disorders called ataxias.

The conference has featured so much work in the field of somatic instability. The ability to reliably measure how CAG length changes in blood, and connect it to what happens in brain, will be invaluable when research efforts lead to clinical trials.

Alice Davidson: insights from Fuchs’ disease

Next up is Alice Davidson. She’s an ophthalmologist who studies Fuchs disease, an eye disorder caused by a triplet repeat. Her work on genetic modifiers could inform HD research – it’s always fantastic to see the exchange of ideas across disciplines!

Fuchs’ disease is caused by a repeat of CTG letters in the DNA code. Alice has found that these CTGs get longer over time, just like the CAGs in HD. Her team discovered this using eye tissue donated by people with Fuchs’. Alice and her team use lots of cool technology to really get into the details of changes to the DNA code throughout the entire genomes of different Fuchs models. The CTG expansions seem to be happening in the types of eye cells that are most vulnerable in Fuchs’.

In HD, superlong CAG repeats are found in the most vulnerable brain cells. In Fuchs’, this is happening in the eyes. Similar findings about repeat expansion across different diseases lends strength to a new hypothesis that somatic instability is a major driver of symptoms. Alice’s team even found that some of the same modifier genes discovered by HD researchers seem to be coming up for Fuchs’ disease too.

Another line of research in her lab reveals that changes in the way that genes turn on and off in eye cells can also contribute to Fuchs’ disease. Some of yesterday’s talks suggest that this is also happening in HD. There are lots of interesting parallels here in techniques and findings from researchers in two different fields! The more the merrier.

Carlos Bustamante: tailored healthcare and medicines for all

Carlos Bustamante, Founder and CEO of Galatea Bio, spoke about how we might work towards the possibility of tailored healthcare and medicines for all people.

Carlos starts by reminding us how powerful DNA sequencing can be and how much we’ve learned about world relationships and diseases as technologies have evolved. He also stresses the importance of diversity in large-scale human research. As we’ve heard this morning, genetic studies can lead to drug targets, but Carlos shares the statistic that about 95% of what we know comes from studying white European populations. This is not only an ethical and moral problem, but a scientific problem, if we want to make sure we have all the information needed to design drugs.

Carlos suggests that we may learn completely new things and find new paths towards therapy, if we commit to studying the genetics of more HD families in Africa and Asia, and more diverse populations in North America, South America, and Europe. He uses the example of studies in transmission of COVID-19 to show that not only social factors, but genetic factors, contributed to who was getting sick when the virus began to spread in the USA.

Galatea Bio is building a large database and biobank that focuses on a more diverse population. This is allowing them to more accurately make predictions about people’s risk factors for heart disease and other disorders, based on their genetics. Although Galatea focuses on health issues relevant to a much wider population, the HD research community can learn from this more inclusive approach to strengthen the genetic information that fuels our drug discovery pipeline.

Sahar Gelfman: how the huntingtin gene varies across a million people

Sahar Gelfman shared work from the Regeneron Genetics Center. Regeneron has been looking at how the huntingtin gene varies across almost a million different folks!

Regeneron’s approach will allow us to better understand how often the HD mutation occurs across people from different ancestries from around the world, and what range of CAG numbers they see. They are using genetic techniques and fancy statistics in lots of samples to identify when people may have been mis-diagnosed with HD and other repeat disorders. They see a similar incidence of HD and variation in CAG numbers as others have previously reported.

Although we often see HD being reported as occurring in around 1 in 10,000 people, from this study with lots and lots of data, it actually looks closer to 1 in 2000 people with 40 or more CAGs in this particular dataset. They also see higher levels of HD in folks of European ancestry. However, there aren’t a lot of samples from people outside of Europe and North America, because of historical biases and exclusion. Lots of folks are working to correct this sampling bias so we can have insight to the true numbers.

What’s happening in the clinic

The best was saved for last, with the final session covering UPDATE ON CLINICAL TRIALS!

David Margolin: uniQure’s ongoing Phase1/2 trial of AMT-130

First up is an update from David Margolin from uniQure on their ongoing Phase ½ trial of AMT-130, a gene therapy for lowering huntingtin that involves a brain surgery to deliver the drug to deep areas of the brain that are affected by HD. The drug is packaged in a harmless virus which is injected into specific areas of the brain through a well-controlled surgery. This is a one-shot therapy so folks who are treated will only have the surgery once and then their huntingtin levels should be lowered permanently.

This is exciting as it means that if this drug works, it could be a one-and-done approach. On the other hand, if things don’t pan out as we all hope, it could be bad news. Because of this, uniQure did a ton of safety testing in all sorts of HD animals and their trial in people proceeded very slowly to make sure everything was going ok.

UniQure are running two trials at the same time in the US and in Europe. Both trials are testing out a high dose and a low dose of the drug but only the US trial has a placebo arm – people who have the surgery but don’t receive the drug.

David is summarizing results from the most important question this trial will answer: whether the drug is safe and tolerable. The drug seems to generally be safe and side effects that did occur could be managed with treatment. We wrote about most of these findings back at the end of last year which you can find here: https://en.hdbuzz.net/355

UniQure next explored preliminary results asking whether the drug may have beneficial effects on slowing the signs and symptoms of HD. Things seem to look ok but it’s tricky to tell as not many folks in the trial have been on the drug very long. So we can’t expect a conclusive difference quite yet. Other measurements uniQure looked at were ok too, and there were possibly some positive effects…. However, it’s too soon to say for sure with such a small number of folks in this trial.

The key message is that nothing really bad has happened in people who received the drug. This is a big deal since this is the first gene therapy for HD to move to the clinic and we had very little idea how a one-shot therapy like this might work in people with HD. David shared that uniQure will have another update with more data in June.

Amy-Lee Bredlau: PTC Therapeutics’ update on the Phase2 trial for PTC-518

Amy-Lee Bredlau from PTC Therapeutics shared an update on a Phase 2 trial for PTC-518, a drug taken by mouth to lower huntingtin.

The oral drug that PTC is developing for HD is called a splicing modulator; this works to lower huntingtin by targeting its message copy and sending the message molecule to the cell’s trash can so the huntingtin protein is not made.

Before trialing this drug in people, the PTC team tested whether it could lower huntingtin in different cell models of HD as well as in the brains of mice that model HD. They found lower huntingtin levels in the blood and in the brain – this is important as getting drugs to work in the brain can be very tricky.

The next step is to test if the drug is safe in people, which they are doing in the PIVOT-HD trial. PTC was one of the first companies to adopt the HD-ISS staging system and recruited folks into their trials in stages 2 and 3. We previously wrote about the HD-ISS staging system, which you can read about here: https://en.hdbuzz.net/325

People in the trial received either 5 or 10 mg of the drug, while some folks only received a placebo. The study is taking place across North America, Europe, and Australia. We are now seeing interim data from a small group of just 33 folks who participated in the trial. It looks like PTC-518 was pretty safe and there were no significant changes to the levels of NfL – a biomarker which tells us about overall brain health.

Importantly, they see that huntingtin levels are lowered in the blood in a dose-dependent manner – this means that folks who got more drug had more huntingtin lowering. No data was shown for whether lowering is happening in the central nervous system, such as the brain or fluid that bathes the brain, but we hope PTC will share that in their next formal update, which is promised soon.

Peter McColgan, Jonas Dorn, and Marcelo Boareto from Roche

Up next were two talks from three scientists: Peter McColgan, Jonas Dorn, and Marcelo Boareto from Roche.

Peter is starting by focusing on biomarkers in CSF, the fluid that bathes the brain. Levels of different biomarker proteins found in this fluid can give us information about different aspects of brain health. Peter and the folks at Roche are looking at these biomarkers from the spinal fluid they collected in the GENERATION-HD1 clinical trial which was sadly halted back in 2021 because of safety concerns. That trial was testing the HTT lowering drug tominersen.

Folks who received a low dose of tominersen had lower levels of huntingtin, but flat levels of NfL, YKL-40 and other markers of brain health. People receiving much more drug had more huntingtin lowering, but increased levels of NfL and brain markers indicating the brain was sick. These results have helped Roche decide on doses to use in their ongoing trial for tominersen, GENERATION-HD2, so that they get good levels of huntingtin lowering but without making brain cells sick. GENERATION-HD2 is well underway at many sites around the world, and is now more than 50% recruited.

Digital biomarkers, such as an app measuring finger tapping speed or shape drawing, allow data to be collected every day, not just when someone goes to the clinic for testing. Jonas tells about how these frequent digital biomarker measurements can give us a different picture of how folks are doing and how their disease progression might be affected by the drug.

In the future this may enable the same amount of information to be drawn from smaller groups of people so lots of different trials might take place more quickly and get us to treatments for HD faster. Jonas and the team are comparing the digital biomarkers they have measured with other traditional measures like brain imaging. They see some promising results! The data suggests these digital biomarkers are robust measures of how HD progresses.

In the Roche triple bill, we are now hearing from Marcelo Boareto, who will tell us about natural history studies. These studies don’t test the effect of a drug, but rather follow people with and without HD to see how the disease progresses as they age. Natural history studies help researchers understand what to expect in terms of changes in disease trajectory in HD clinical trials. The more we understand the normal course of HD, the better we can measure if a drug is changing the progression of HD and if it is helping folks with HD.

For many measures, people in the placebo group of GENERATION-HD1 not taking drug initially looked like they were improving. But then they proceeded to follow the same course as what we would expect from the natural history study – the placebo effect can be strong! Now that Roche has analyzed the placebo effect and how it compares to the natural disease progression, this information can be used to better design future trials to account for the placebo effect.

Swati Sathe: updates from the SHIELD-HD natural history study

Swati Sathe from CHDI shared data from SHIELD-HD, a natural history study that was initiated by Triplet Therapeutics. They were working on somatic instability but the company unfortunately closed down.

This study was designed to look at people with HD before they started to show symptoms and follow them for 120 weeks. They collected lots of different samples from the people in this study, like the fluid that bathes the brain, blood, and MRIs. The main purpose of the study was to understand how CAG repeat numbers change over time and track progression of HD with the different samples collected and tests performed. It was run in 9 sites in 5 different countries.

After Triplet closed down, the HD research foundation CHDI (which is hosting this conference) took over the study to ensure these precious samples and all of the data gathered so far would not be wasted and could be used to help inform future trials. The HD-ISS staging system was also used in this study. Incorporating it in clinical trials and natural history studies will help researchers target specific disease stages to hopefully move drugs forward faster by matching them to the people that will benefit most.

The CHDI team looked at which measurements changed over the course of the study, such as scores on movement tests, volume of vulnerable brain areas, and other metrics. They also compared their data with other studies, like TRACK-HD. The great wealth of data generated from all of the SHIELD-HD participants will inform which tests and measurements are the best ones to use over the length of a drug trial so there is the best chance of detecting whether a treatment is working.

That’s all from us for this year! The 2024 HD Therapeutics Conference was a fantastic look at ongoing trials, upcoming research, and fantastic data. We hope you all follow along next year!

The HDBuzz team recently convened in Palm Springs, California, along with hundreds of other scientists from all over the globe, for the 19th Annual HD Therapeutics Conference, hosted by the HD research foundation CHDI. From Tuesday February 27th through Thursday February 29th, we live-tweeted dozens of scientific talks by world experts in Huntington’s disease research, from bench scientists to clinicians. We’ve compiled our tweets into a summary of the entire conference, beginning with Day 1.

Huntingtin Homework: Teaching an Old Dogma New Tricks

The first session of the conference focused on huntingtin, the gene that expands to cause HD. The meeting kicked off with Gill Bates, who reviewed what we know about the genetics of HD, which is that the length of CAG repeats in the huntingtin gene dictates whether people will develop HD. More recently, lengthening of the CAG repeat in some brain cells, known as somatic expansion, has been implicated in driving the disease.

There are many unanswered questions about exactly how the CAG expansion results in the death of brain cells. This session addressed a wide range of approaches, at the epigenetic, RNA, and protein levels.

Karine Merienne: DNA tags in the striatum

The first speaker of the conference was Karine Merienne from the University of Strasbourg who told us about changes in certain types of markers in HD associated with aging. Karine reminded us that it is still a mystery why the nerve cells of the striatum are so vulnerable to the CAG expansion in the huntingtin gene. One hypothesis she is investigating are changes in how genes are turned on and off.

Karine’s research looks into how so-called epigenetic changes occur in HD. These aren’t changes to the DNA code itself but certain markers which affect how DNA is packaged. This in turn changes which genes are switched on or off, which affects the properties of cells, making a nerve cell a nerve cell, or a skin cell a skin cell.

The epigenetic markers change with age in all people, not just folks with HD. Karine’s team found that certain epigenetic markers are altered further in mouse models of HD. Using cutting-edge technologies, they were able to look at changes to markers at the level of single brain cells from a mouse. They saw that nerve cells from the striatum, the vulnerable brain region in HD, were missing an important epigenetic mark.

This gives us insight into why cells in the striatum might be more likely to get sick in people with HD. Perhaps if we can fix these epigenetic marks, we could make the cells better again? We will see; there are a lot of smart folks working on this!

Yinsheng Wang: chemical tags wreaking havoc

The next talk of the morning came from Yinsheng Wang, who is based at the University of California, Riverside. Yinsheng investigates how genetic message molecules are modified with chemical tags in HD and other CAG diseases.

The repeating CAGs in the message of the huntingtin gene can be “tagged” with extra molecules. In the course of HD, the extra tags can inappropriately recruit proteins in the cell, sopping them up and keeping them from their normal jobs. Interestingly, these changes to the tags on the huntingtin message molecule seem to happen most often in the striatum in HD mice. Could this be another reason why these brain cells get the most sick?

Special molecular machines add or remove these tags from the huntingtin message molecule. Yinsheng and colleagues figured out which of these machines was responsible for the changes they could measure. If they got rid of the machine, the message molecule tags went back to normal.

They also found that changes in molecular tags alter the ability of the huntingtin message to stick to a protein called TDP-43, which plays a role in other neurodegenerative diseases. (Like huntingtin, TDP-43 can also form clumps.) Huntingtin along with its CAG repeats and tags can affect formation of these clumps. This team’s data suggest that expanded repeats on the huntingtin message molecule led to clumping of TDP-43.

Yinsheng explains yet another way that chemical tags on the huntingtin message molecule may wreak havoc in the cell: by causing the message molecule to get off kilter and make toxic proteins it is not meant to encode. Maybe if we can restore the way the HD message molecule is tagged by these molecular machines, brain cells will get less sick. This is an interesting new avenue for drug discovery research in the HD field.

Jeff Carroll: how low should we go?

We also heard from HDBuzz’s very own Jeff Carroll. Jeff’s lab, which is based at University of Washington, has been busy investigating HTT-lowering in mouse models of HD. Jeff’s lab is asking what they can do to help speed up and improve upon clinical huntingtin lowering strategies. One major question is how much to reduce huntingtin and in which types of cells to improve symptoms of HD without negative effects.

Key questions Jeff’s team is trying to answer are how low is too low for huntingtin lowering, and how low do we have to go to have a positive effect. Experiments in mice have shown that going too low might not be very good. One of the projects Jeff’s lab has been working on is looking at huntingtin lowering in adult mice. This represents what we are doing in the clinic, giving adult people with HD different types of drugs to lower huntingtin protein levels.

Jeff’s lab showed that it was not safe to completely remove huntingtin in the brains of mice – they literally had holes in their brains! Of course, complete removal of huntingtin in human brains is not what clinical trials are aiming for. The trick is probably going to be getting the balance right. Jeff reiterates this does not mean that huntingtin lowering is a bad idea per se, we just need to figure out how low to go.

We know from genetic studies that 50% (what most clinical trials are aiming for) seems to be ok in people and animal models of HD, but perhaps below that is not a good idea. One interesting thing Jeff’s group noticed was that lowering huntingtin with ASOs in mice seems to alter somatic instability, the expansion of the CAG repeat in some cells. This seems to happen in the liver at very high ASO doses. Figuring out why this is the case has been complicated!

More importantly, would the clinical approaches, which use lower amounts of ASOs, do the same? It doesn’t appear so. But it’s probably something scientists should keep an eye on moving forward.

Next Jeff’s team looked at selective lowering approaches – therapies which only target the toxic huntingtin and leave the regular huntingtin levels untouched. Again they saw that somatic instability seemed to be blocked by these treatments – this could be a cool two for the price of one therapy!

Altogether, Jeff’s work is helping us better understand what huntingtin-lowering means at a molecular level, which will help us better understand what’s happening in the current clinical trials, and any extra considerations we might need to think about to give this approach its best shot.

Ileana Cristea: huntingtin and its dance partners

We’re back and up next is Ileana Cristea who leads a research group at Princeton University. They study the huntingtin protein and the other proteins it likes to hang out with in cells, and how these relationships change in HD. This work lies in the area of “omics” research where researchers look at changes in proteins and how they interact across many cells, tissues, and brain areas. There’s tremendous collaborative effort!

Ileana’s talk continues the theme of figuring out why some cells get sick in HD, while others seem to be ok. Her lab looks at the locations of different proteins and which ones hang out together. They are trying to address what drives disease, and what are the consequences of lowering huntingtin levels with drugs. They are doing so by studying what proteins interact in the presence and absence of huntingtin.

They found that in cells from mice which don’t have huntingtin protein, the levels of all sorts of proteins were changed, as well as which proteins were hanging out together. The biggest changes occurred in proteins with jobs in energy generation and DNA repair. The next step was to understand how these changes lead to disease, so they zeroed in on the striatum of HD mice, since this is the region of the brain most affected in HD.

They narrowed down a list of proteins involved in specific cell functions that may give us clues to what goes wrong in HD. After getting a bird’s eye view of networks that interact, they confirmed some of their “hits” in collaboration with scientists who work on other models and techniques, like cells and fruit flies. In different types of cells, different protein buddies of huntingtin are altered, which once again could explain why different cells are affected in different ways in HD.

Not only can Ileana’s team work out which proteins huntingtin hangs out with, but through which surfaces they might all stick together, giving a very detailed molecular view of what is going on in HD. Although this type of study can feel a bit granular, it is actually very important to help us understand exactly what goes wrong in HD. It also helps us identify new genes and proteins which might be good targets for future drug discovery efforts.

Tony Reiner: patterns of huntingtin clumps

The final talk of the morning came from Tony Reiner, who is based at the University of Tennessee Health Science Center. His team have been looking at where the disease form of the huntingtin protein is found in HD human and mouse brains.

Tony first reminded us about the specific parts of the brain which are most vulnerable in HD. The striatum, which is at the very center of the brain, is one of the most affected brain regions, but nerve cells in the cortex and thalamus are also affected. The regions of the brain that make a lot of huntingtin protein are not necessarily those most affected in HD. Regular huntingtin is really found everywhere, so this does not seem to explain why cells in the striatum are so vulnerable.

Huntingtin proteins come in lots of different flavours – expanded, fragmented, clumped, and others. Tony’s group uses antibodies as tools to visualize the different forms of the huntingtin protein in the brain. They started by looking in HD mouse brains, and tried to match that up with tissue from people with HD who generously donated their brains to research after passing away. This selfless act has been critical for generating data that lets us know what’s going on with HD in human brains.

If you’re interested, you can learn more about brain donations from the Brain Donor Project (https://braindonorproject.org/), HDSA, HSC, HD organizations in your home country, and through local academic institutions.

We can measure lots of changes in brain cells over time but which changes are actually causing cells to get sick is still not very clear. Tony’s work shows that increased protein clumps and other measurements don’t always seem to match up with the cells we know get sick. Work from Tony’s lab and others really get into these measurements at the level of different cell types that might one day help us better understand cause and effect.

Targeting the DNA Repair Machinery to Modulate Somatic Instability

Session 2 of the conference focused on ways to combat the expansion of CAG repeats. This happens in some cells as HD symptoms worsen. Lots of new evidence points to the lengthening of CAG repeats as an important driver of cell loss in the striatum, pushing symptom onset earlier. Using blood donated by thousands of individuals with HD, scientists have been able to perform large genetic studies (known as GWAS) to determine other genes that affect HD onset. Notably, many of these genes are involved in something called DNA repair.

DNA repair is a process where little molecular machines repair mistakes or changes in the spelling code of DNA. One of those changes that happens in HD is the increase of the CAG repeat. Some people have DNA repair machines that are great at catching mistakes, while others have machines that aren’t so good. When the DNA repair machinery fails, the CAG repeat can lengthen in some cells over time.

Many HD scientists now believe that by targeting DNA repair genes, it could be possible to slow down the lengthening of CAG repeats in vulnerable brain cells, ultimately delaying onset or slowing the worsening of HD symptoms. More and more scientists and companies are now seeking, confirming, and testing different players within the machinery that repairs DNA, to determine what goes wrong when CAG repeats get longer, and try to prevent it.

We’ll be throwing around lots of acronyms and names of proteins known to be involved in the DNA repair process. These proteins work together to repair DNA in different ways and may go awry in HD. Scientists are developing genetic drugs to increase or decrease their levels and stop CAG expansion.

Maren Thomsen: the shape of DNA repair machines

The afternoon’s first speaker was a structural biologist, Maren Thomsen from a company called Proteros Biostructures. She is studying the shape of a protein called MutSꞵ which is involved in DNA repair. Using special microscopes they can see exactly how the protein is organised in 3D space which can help scientists figure out how it works.

Ideally we would like to stop the activity of MutSꞵ, and there are different ways to do this. Maren uses the analogy of trying to stop the movement of a bicycle: you could stop the pedals, or put a barricade in front of it, or block the wheel from turning. Knowing the details of the MutSꞵ structure allows them to come up with different ways to stop its activity.

Cool microscopes allow Maren and her team to figure out precisely where each atom of the protein is, and how this changes as MutSꞵ goes about its job sliding along and repairing DNA. With this high resolution of information, they can create a super detailed model of how this molecular machine works. It can really move, gripping and opening around DNA like a clamp! When Maren’s team makes changes to the MutSꞵ machine, this changes its grip and motion, and they are learning more about which parts of the protein stick to other players in the DNA repair process.

Maren is also investigating a protein called FAN1, along with its “dance partners.” FAN1 is also involved in DNA repair, and her group has been able to visualize it in new ways with the goal of harnessing it for drug development. With these detailed insights into how all these molecules work together, we can begin to understand why certain mutations found in GWAS might delay or hasten the age of onset of symptoms in HD.

Structural biology techniques illuminate the shape and movement of critical molecules so that we can better understand where and how to intervene in the faulty biology of Huntington’s disease and design drugs that precisely target proteins like MutSꞵ.

Wei Yang: MutSꞵ and long CAG repeats

We heard next from another structural biologist, Wei Yang, who is based at the National Institutes of Health, and is also studying MutSꞵ. The MutSꞵ molecular machine acts on all kinds of repeating DNA sequences, not just CAG repeats. Wei’s team worked to figure out exactly how MutSꞵ binds to these repeating DNA letters using structural biology approaches.

An interesting conundrum is why there is a threshold of CAGs at which the repeats continue to expand over time. Understanding this requires neat experiments looking at CAG repeating DNA and how it binds onto MutSꞵ. Wei and her team found that MutSꞵ much prefers binding onto longer CAG repeats than shorter ones. In fact, if the CAG stretch is long enough, more than one MutSꞵ molecule will bind onto the CAG DNA.

When they look at the CAG DNA stuck to MutSꞵ, they see that MutSꞵ contorts the CAG repeating DNA to look like non-repeating DNA. It works like a vice to bend the DNA into this different shape. Unsurprisingly, this requires a lot of energy. But what does this all mean for HD? Well, when the CAGs repeat enough, like they do in folks with HD, more and more MutSꞵ molecules bind on. Wei thinks this may unintentionally encourage CAG expansion.

Structural biology studies help us confirm findings from people that have revealed the importance of DNA repair in HD. We are learning more about the genes and machinery involved in somatic instability and how it might be linked to symptom onset. Armed with this kind of knowledge, drug hunters can work to find ways to stop MutSꞵ from making mistakes that lengthen CAGs, with the goal of slowing or stopping HD.

In fact, Wei and her team have identified a compound which changes how MutSꞵ sticks onto CAG DNA. Although this molecule is not likely to be a drug, it could be a helpful starting point for drug hunters.

Sarah Tabrizi: exploring DNA repair in human cells

Next up was the legendary Sarah Tabrizi, a physician and scientist from University College London who is involved in lots of basic and clinical HD research. Sarah is using human cells grown in a dish to further test many of the genes identified as important for DNA repair and CAG repeat expansion. There are lots of DNA repair proteins which look like good targets for therapies.

Sarah and her team are using genetic techniques like CRISPR to lower the levels of DNA repair proteins that go awry in HD. Then they see how this affects the levels of other genes, to tease out relationships among the DNA repair machinery. After changing the levels of different DNA repair proteins, Sarah’s team then looked to see how this affected CAG repeat expansion. They targeted genes called MSH2 and MSH3. Lowering these (and others) reduced the level of somatic expansion.

In stem cells coaxed to become brain cells, lowering of one specific DNA repair gene called MLH1 reduced somatic expansion by 78% – wow! She’s also exploring other targets, including a gene called MSH3, which she calls “an ideal therapeutic target.” Her work highlights two repair proteins called MLH1 and PMS1 as potentially interesting drug targets. Working on targets beyond the MutSꞵ complex could be really handy to increase our odds of finding drugs that work.

Nonetheless, Sarah reiterates that MSH3 is her favourite drug target, as knocking it out seems to slow CAG repeat expansion. Furthermore, depleting this protein does not seem to have too many bad side effects, at least in models. Sarah’s lab uses ASOs to lower levels of MSH3, the same type of drug that some companies (like Roche) are using to lower huntingtin. When they lowered MSH3 levels, this slowed down somatic expansion. When they completely removed MSH3, CAG repeats got smaller. This did not affect other DNA repair proteins, which is positive news for MSH3 drug discovery.

Nearly all of this work was done in nerve cells in a dish, which had been created from a blood sample generously donated by a young patient that Sarah was treating before they passed. These discoveries and many others in the realm of somatic instability would have been impossible without the dedication of HD families and their willingness to participate in research. Sarah’s team are continuing this work in a mouse model to see how their MSH3 ASOs fare in a more complex system. Watch this space!

Ricardo Mouro Pinto: exploring DNA repair genes as potential targets

Ricardo Mouro Pinto is based at Massachusetts General Hospital & Harvard Medical School. His team also studies somatic expansion. Patients with increased somatic instability start to have HD symptoms earlier. The genes that influence the onset of symptoms are known as genetic modifiers. Ricardo and others are testing the theory that changing the levels of these modifiers can delay or stop the onset of HD.

Ricardo is using CRISPR to change levels of these modifiers in mice that model HD. He’s screened 60 different genes in mice – that’s a lot of work! What all that work found is that DNA repair genes have a large effect on the length of CAG repeats. This confirms what many others in the field have found. Anytime results are replicated in various labs across the world it strengthens the field’s confidence in that data.

He then moved to human cells grown in a dish to confirm their own and others’ data. They found that lowering MSH3 slows the rate of expansion and lowering FAN1 increases it. They also found that reducing levels of MLH3 and PMS1 halt expansions. Ricardo is also working to check these modifier targets in other diseases. HD isn’t the only disease affected by somatic expansion. So he’s screening the targets he identified in HD in mice that model other diseases, like Frederich’s Ataxia.

Targeting the same protein that is involved in multiple diseases not only benefits more people, but could speed up trial enrollment and drug development. But before we get ahead of ourselves, these targets have to be tested more to ensure they’re having the effect we want! One point researchers have to be aware of is that DNA repair genes are also involved in cancer. Ricardo is being mindful of this and choosing potential drug targets with the lowest chances of leading to cancer in people.

One target Ricardo’s team is particularly interested in is called MLH3. They did some detailed studies to see exactly what part of the MLH3 gene is responsible for somatic expansion in HD. Knowing exactly what part of the gene is responsible for influencing CAG length lets researchers know which spot they would need to target if they designed a drug against MLH3.

Using cool genetic techniques, Ricardo is able to make cells that produce a version of MLH3 that excludes the part of the code that leads to CAG repeat expansion. When he did this, he was able to suppress CAG expansions. He’s now working to use CRISPR to change a single letter in the sequence of MLH3. This is a precise approach that will stop MLH3 from increasing the CAG number while leaving the rest of the MLH3’s functions alone.

This is important because proteins in cells have lots of different functions. Targeting a single function reduces the chances of having unintended consequences. Something that’s critical for drug design! Ricardo’s next steps are to use his new CRISPR approaches to alter MLH3 in mice and human cells in a dish. For this, Ricardo was recently awarded a $1,000,000 grant from the Hereditary Disease Foundation!

Karen Usdin: somatic expansion in other diseases

Karen Usdin from the National Institutes of Health spoke about her team’s work looking at somatic expansion in different types of diseases caused by DNA repeats, beyond HD. There are many diseases caused by repetitive sequences of DNA. Karen’s team primarily focuses on one of those diseases called Fragile X, which is caused by a repeating CGG. However, she’s now also beginning to focus on HD. Woohoo!

Fragile X also has somatic expansion controlled by DNA repair genes. Karen has used mice that model Fragile X to identify which DNA repair genes are important for this process in Fragile X. Karen has focused on parts of the DNA repair machinery called MutL complexes.

Her lab eliminated a piece of the MutL complex, called PMS2. Lowering PMS2 levels stopped repeat expansions in human cells and mice with other genetic diseases. She found similar results with another part of the MutL complex called PMS1. Lowering levels of PMS1 reduced expansions in Fragile X. Combined with data from other diseases, this suggests that PMS1 plays a role in expansion across repeat diseases.

Now Karen is getting to the good stuff – her work in HD! She made a mouse model that had genes for both HD and Fragile X. With this mouse, she was able to look at repeat expansion in both genes at the same time. She wanted to know if expansion of one gene affected expansion of the other gene. Put simply – no. Expansions of the HD gene didn’t influence the gene for Fragile X and vice versa.

She suggests that expansions depend on the balance between different types of DNA repair machinery in different cells. Some of the ideas she is putting forward are purely theory, but she welcomed other scientists to engage in conversation about it over a beverage! Conferences like this one are a fantastic place to exchange ideas.

Rgenta Therapeutics: oral drugs targeting DNA repair

The final talk of the day came from Travis Wager of Rgenta Therapeutics. Travis told us about drugs his team is developing which can be taken by mouth to target the modifier PMS1, with the aim of slowing down somatic expansion in human clinical trials.

Rgenta has spent the last 4 years thinking about how they can go after targets that have traditionally been considered “undruggable”. Others have tried to target genes that control somatic expansion, like PMS1 and MSH3, in the past without success. Rgenta’s drugs act like glues that create a stronger bond between disease-causing RNA messages and the proteins that bind to them, in order to change how proteins are made, or to get rid of a faulty message or protein.

Travis highlighted the various diseases that they’re trying to target with their drugs against genes that control somatic expansion. This includes HD, myotonic dystrophy, Fragile X, and Fredreich’s ataxia: all repeat expansion diseases. Rgenta’s interest in HD is driven by the availability of huge amounts of data from both humans and animals, a testament to the collaboration and dedication of scientists and HD families. The HD field draws many companies for this reason.

Rgenta has targeted PMS1, because higher levels of PMS1 in people are associated with earlier HD symptom onset. Using mice, they’ve shown that changing levels of PMS1 seems safe and isn’t associated with cancer. Rgenta tested thousands of different chemicals known to change levels of RNAs, then measured which ones were best at changing the levels of PMS1, their target. So cool!

Their drug molecule that targets PMS1 is something called a “splice modulator.” It works by altering the PMS1 message molecule, which results in lower levels of the PMS1 protein. They’ve shown their drug works in lots of different cell and animal models. They then tested their PMS1-targeting drug in HD cells grown in a dish. In theory, lowering PMS1 should reduce somatic expansion. And that’s exactly what they found! Lowering PMS1 by about 90% essentially halted somatic expansion.

Rgenta’s compound also appears to only really target PMS1 levels without affecting other proteins. They also shared data which suggests that the compound works well in animal models, and does a good job getting into the brain. Right now Rgenta only has data showing that lowering PMS1 reduces somatic expansions in HD cells in a dish. But they’re marching forward with this approach, planning to test their drug in other models of HD. However, this is exciting news as it means there is another promising drug in the pipeline which might one day make it into the clinic if the animal studies continue to look good.

We are very happy to end Day 1 after reporting on so many cool things happening in labs at universities and companies around the world! Stay tuned for Day 2, coming shortly!

You’ve likely heard of CRISPR. By now, you also may have heard that CRISPR has been used to produce a revolutionary new treatment for Sickle Cell Disease. Just 4 years after the Nobel Prize for the discovery of CRISPR was awarded, we have an approved treatment using this technology. This may have you wondering if this approach is being used in Huntington’s disease (HD) research and when a similar drug for HD might come to the clinic. Let’s discuss!

Genetic scissors transform science

CRISPR is short for “clustered regularly interspaced short palindromic repeats” – quite a mouthful! That’s essentially just science-speak for short strings of DNA letters that break up repeating parts of genetic code. These so-called CRISPR sequence interruptions were first noticed in bacteria. The unique strings of DNA letters which make up these sequences appear to have come from viruses, which scientists think might be part of an immune system that protects bacteria against viruses that they previously encountered.

The real secret sauce that transformed CRISPR into a powerful tool with the potential to treat many diseases are proteins called Cas – “CRISPR-associated sequence” proteins. If the CRISPR system as a whole is thought of as “genetic scissors”, the Cas proteins are the scissors themselves – they are the enzyme that actually cuts the DNA. The CRISPR sequences are the guide that show where the DNA should be cut. For this discovery in 2012, Drs. Emmanuelle Charpentier and Jennifer Doudna won the Nobel Prize in Chemistry in 2020 for the use of the CRISPR/Cas system to precisely edit DNA. An all-female Nobel team!

The CRISPR system wasn’t the first tool that allowed researchers to cut DNA, but it took off like wildfire throughout research labs around the world because it was easier, cheaper, and more accurate. Having an easy to use system to precisely edit DNA has revolutionized how researchers work in the lab. It can not only be used to turn genes on or off, but can also edit their DNA letter code. This holds a lot of promise for genetic diseases like HD where changes to the DNA letter code are the root cause of the disease.

Targeting Sickle Cell Disease with CRISPR

Once scientists knew how easy it was to edit DNA with the CRISPR system, lots of different companies began working with the technology to target various diseases. So why did the first approved CRISPR-based treatment focus on Sickle Cell and what exactly is it? Let’s focus on what Sickle Cell Disease is first.

Sickle Cell Disease is a blood disorder that gives red blood cells a sickle shape, like the letter “C”. Genetically, this is caused by mutation of a gene called hemoglobin that allows red blood cells to hold oxygen. If red blood cells aren’t carrying oxygen to parts of the body where it’s needed, this can lead to a stroke. The sickle-shaped red blood cells get all clumped together, leading to clogged blood vessels. With fewer red blood cells, people with Sickle Cell Disease are anemic, experience swelling of the hands and feet, and extreme fatigue. Sickle Cell Disease is recessively inherited. This means that both parents must have a faulty copy of the gene to pass the disease on to their kids, who have a 25% chance of inheriting the condition.

Drug discovery companies looking for a way to use CRISPR in the clinic focused on Sickle Cell Disease for several reasons:

• 1) The genetic cause is known. Sickle Cell Disease was first described all the way back in 1870. Hemoglobin as the cause was first noted in 1927 and the genetic basis was first described in 1949. So it has a long history!

• 2) The cure is already known! Increasing levels of hemoglobin essentially erases symptoms of the disease. So companies already knew what they had to do to treat the disease.

• 3) It affects red blood cells, which only live for about 120 days and new ones are constantly being made by the body. Additionally, red blood cells are made in bone marrow. Bone marrow transplants have a long medical history and have been well studied.

• 4) Genetic editing can be done outside the body. Because bone marrow transplants have been successful for other applications, researchers planned to take bone marrow stem cells out, treat them with CRISPR technology, and then put them back again. This is a lower risk approach than treating cells still inside the body because they could start over if something went wrong with the CRISPR editing process, and no one would be harmed.

How the drug works

With a disease in their targets, CRISPR Therapeutics and Vertex Pharmaceuticals tested their first CRISPR-based treatment for Sickle Cell Disease in a person in 2019. The drug, Casgevy, received approval in the United Kingdom and United States in November and December of 2023, respectively.

Once a patient is identified, bone marrow stem cells are removed. They are taken back to a lab where they are edited using CRISPR therapy. This editing modifies the faulty hemoglobin gene that prevents red blood cells from holding their shape and carrying oxygen. After editing, the cells have to be “grown” in the lab – essentially scientists feed them nutrients and watch over them closely to take care of them while they multiply, allowing the few cells they edited to divide into many cells.

With Casgevy-treated cells in hand, the cells are then returned back to the patient using an infusion. Now the Casgevy-treated cells can attach and turn from stem cells to red blood cells, producing new cells that have the corrected version of hemoglobin.

The good, the bad, and the ugly

As with all drugs, there will be pros and cons. The pro here (and it’s a big one) is that this is the first ever lifetime or one-shot treatment for Sickle Cell Disease! Casgevy is essentially a cure for Sickle Cell Disease which is a fantastic achievement for this community. However, even when a drug is the first or best in class, there can still be large drawbacks. In this case, Casgevy is complex to manufacture, will have a slow roll-out, and is very expensive.

Editing and growing the bone marrow stem cells has to happen in a specific facility with very strict manufacturing rules in place. These rules also require scientists with very specific training and skill sets. This reduces how fast the treatment can be produced and increases costs associated with the drug. The overall treatment takes about 6 months.

Prior to the infusion of the Casgevy-treated cells, the patient has to undergo high-dose chemotherapy in preparation of receiving the treatment. This can cause lots of side effects, like exhaustion, hair loss, and nausea. Chemotherapy is needed to remove blood stem cells that are left in the bone marrow. With the old blood cells gone, only the Casgevy-treated cells will be able to produce new red blood cells.

There are limitations on how fast this type of treatment can be rolled out. For instance, in the United States, there are currently about 25,000 bone marrow transplantations performed every year, but there are 100,000 people living with Sickle Cell Disease in the US. The current transplantations will still need to take place along with the new Casgevy treatments. So there is an issue with scaling up this treatment and finding the capacity to add to the current system.

Lastly, and perhaps most importantly for many people, Casgevy is very expensive. With the intense hands-on processing that Casgevy requires, it has a hefty price tag – $2.2 million according to Vertex. High price tags are likely to be the norm for one-shot drugs.

With all that in mind, Casgevy is still a massive leap forward for the Sickle Cell community and science as a whole. The first patient to be treated in the 2019 clinical trial was going to the hospital every 4 to 6 weeks for blood transfusions and her kids started struggling in school because they were worried about her dying if she didn’t receive treatment. After treatment with Casgevy, she no longer needs blood transfusions and her blood counts are stabilized; she’s essentially cured.

Where do CRISPR-based drugs stand for HD?

Sickle Cell and other blood disorders aren’t the only diseases that pharmaceutical companies are eyeing for CRISPR-based treatments. Any disease with a known genetic cause is a candidate for a CRISPR approach. This includes HD.

There is lots of work currently being done in cells and animal models to test CRISPR therapies that target various aspects of HD. Some researchers are directly going after the HTT gene that causes HD, while others are going after modifier genes that control age of onset. Having a diversity in approaches is a great thing!

There are also pharmaceutical companies that have committed to using a CRISPR-based approach for treating HD. Life Edit Therapeutics is a company that is working to use harmless viruses to deliver CRISPR machinery that will target only the expanded copy of HTT to lower expression. So far, they’ve tested this in different kinds of mice that model HD and have looked at different drug doses. While many people are currently working on CRISPR-based treatments for HD, none of these are currently in clinical trials.

Why aren’t CRISPR trials for HD in the clinic right now?

Having commercial approval for a CRISPR-based drug paves the way for similar drugs for other diseases, like HD. However, treating a blood disease is very different from treating a disease that primarily affects the brain. There are many aspects of Sickle Cell Disease that made it the perfect candidate for the first ever CRISPR-based drug. The other side of the coin is that there are many aspects of HD that make it a challenging disease to treat with CRISPR.

A major difference is that Sickle Cell Disease affects red blood cells while HD primarily affects brain cells. Blood cells are easy to access and blood sampling can be used to let doctors know if editing was successful. Brain cells can’t be sampled to get a picture of how the treatment is going.

Sickle Cell affects bone marrow that’s comparatively easy to manipulate and there’s lots of precedent for successful bone marrow transplantations. HD affects the brain, which requires invasive procedures to access and we don’t have a similar precedent for successful treatment of the brain.

Sickle Cell is caused by the lack of a protein, which many studies have shown can be added back to erase symptoms. We don’t yet know what will erase symptoms of HD. Researchers also have to weigh targeting both copies of HTT or only the expanded copy.

While this is a massive leap forward for using CRISPR to treat disease, we also want to manage expectations about when CRISPR-based treatments will be available for HD. Companies went for the low hanging fruit first with Sickle Cell Disease. However, none of this is to say that CRISPR won’t work for HD! On paper, this is a great strategy, HD fits the genetic requirement for such a treatment, and scientists love a good challenge. CRISPR-based treatments for brain diseases are certainly heading toward the clinic, but we have various other hurdles to clear first before they can be applied to HD.

For people at risk of Huntington’s disease, having a baby who might inherit HD can make decisions around planning a family extremely difficult. This article explains the options available, and how modern reproductive science can make a difference right now to families touched by HD.

Content warning This article describes issues of fertility, tough choices, and medical procedures including termination of pregnancy.

Not all techniques described here are available everywhere, and in some countries, they can involve major expense. So, if you’re thinking about any of them, we recommend you contact a specialist genetic counsellor for individual advice. The earlier you do, the more options you’ll have.

Introduction

Many people with Huntington’s disease, or at risk of it, would like to know if there are ways to have children without passing the disease on to the next generation. The short answer is yes!

Genetic science and reproductive technologies mean that several choices are available to people who are at-risk of Huntington’s disease, to ensure that future children won’t be at risk of developing HD. This includes people who have had testing and carry a HD gene expansion, but there can also be options for some people who choose not to have a HD genetic test themselves.

First things first: nothing has to change

Although a lot of this article focuses on the options for having HD-free children, it is important to know that having a child without doing any genetic testing is very much an option for parents at risk of the condition.

As every HDBuzz article confirms, scientists are making real progress towards finding treatments for Huntington’s disease. While we cannot guarantee anything or promise a firm timeline, we firmly believe a time will come when at-risk children are born into a world where HD is a treatable condition.

Additionally, there is always a chance that the child won’t inherit HD gene expansion in the first place, and therefore will never develop HD.

Some people may want to guarantee HD-free children, but options may not be available to them, for example based on location, financial support, or religious beliefs.

Having a child at risk of HD is something that can be a point of discussion and debate within the HD community. While people may not agree with the decisions that others make, it is important to remember that everybody has the right to be respected when making their own decisions.

The Huntington Disease Youth Organisation has some resources available to help discuss HD and genetic risk to children in an age-appropriate way:

• Info for kids
• Info for teenagers
• Info for young Adults

Some people feel that they don’t want to take any chances and would like to avoid the risk of passing on HD at all. That’s where genetic testing techniques come in. These options are available whether it is you or your partner who is at risk of HD.

What are my genetic testing options?

Thanks to genetic testing. we can identify the risk of HD for a fetus during a pregnancy, or in embryos in the lab.

Testing a fetus during pregnancy is called prenatal testing. Testing embryos in the lab is a form of in-vitro fertilisation or IVF, and is called pre-implantation genetic testing or PGT.

If you or your partner have had genetic testing that confirms you carry an HD gene expansion, you would be able to have direct testing during pregnancy or via PGT, to confirm whether or not the pregnancy or embryo has inherited the HD gene expansion.

Some people want HD-free kids without getting the gene test themselves. There are options for this, too! They involve more complicated versions of the same methods. So first we’ll discuss how it works for couples where one partner has already had a positive HD gene test.

Pre-implantation Genetic Testing (PGT)

Pre-implantation genetic testing is one way of having an HD-free kid without having to consider terminating a pregnancy. It can be a long, challenging and expensive process though.

PGT involves using eggs and sperm to create embryos in a lab, then performing the HD test on the embryos, and putting only the HD-negative embryos into the womb.

The PGT Process

PGT is IVF with an added step of genetic testing. IVF is a medical procedure which involves a hormone medication to cause the egg provider to produce more eggs than normal. Hormone medication can involve injections to deliver the medications into the body.

The eggs are then collected and fertilised using a sperm sample.

The fertilised eggs develop into embryos, which are grown in the laboratory for up to five days until they are a small bundle of cells. One or two cells are removed from each embryo at this stage and sent for genetic testing while the embryos are frozen and stored. Removing cells at this early stage of development doesn’t affect the way the embryo develops.

Any embryos found to be not at risk of developing HD will continue to be stored. Depending on the country you are in, one or two of these risk-free embryos are then transferred to the womb.

About two weeks after the embryos are transferred, a pregnancy test is run on a blood sample. If the transfer has been successful, pregnancy then carries on like normal.

The downside of PGT

The process of stimulating egg release, collecting eggs, fertilising them outside the body and returning embryos to the womb – is always a time-consuming and exhausting process. It can also be dangerous, carrying risks of the person becoming unwell.

Various things can go wrong, like not enough eggs or embryos being produced. There’s also more chance of having twins with PGT, which is harder work and riskier.

On top of the risks of the procedure, things can go wrong with the genetic bit of PGT. Embryos can be damaged when cells are removed, and sometimes the HD test doesn’t work because there isn’t enough DNA. Bad luck can mean that all the embryos have the HD mutation.

In the end, sometimes only one embryo is available for implantation – and sometimes none at all. To top it off, a pregnancy can fail after implantation. Overall, each attempt at PGT gives a 20-30% chance of an HD-free pregnancy. This success rate varies per PGT centre and is dependent on a number of factors.

Women under the age of 35 have the highest success rates – another reason to think ahead about fertility. Unfortunately, the chances of success over the age of 40 are small.

How much does PGT cost?

PGT is expensive. The cost is somewhere in the region of US $20,000 (£15,000 or €18,000) for each attempt.

Health insurance usually doesn’t cover the cost of PGT/PGD. In some countries the public health care system will fund some PGT attempts – for instance, three attempts in the UK – but even this can vary within individual countries, and may be limited to couples with no existing children.

Any additional embryos that are not at risk of HD may be stored. However, this also comes with a cost that varies depending on the length of storage.

If this is an option you are considering, we recommend contacting your local genetic service to have a discussion regarding eligibility, referral, and associated costs.

Testing during Pregnancy

It is possible to perform a genetic test during pregnancy to see whether the developing baby (fetus) carries the gene expansion that causes HD. This is called prenatal testing.

Deciding whether to test a fetus is a difficult decision. It is important to understand that prenatal testing in HD is only performed on the understanding that if the result showed that the fetus carries the HD gene expansion, the pregnancy will be terminated. This is an immensely challenging and personal choice.

It’s important to think carefully about prenatal testing for HD, and how you feel about pregnancy termination, in advance of getting pregnant.

Once pregnant, there is very little time to absorb the information about the prenatal test and make these important decisions, as the testing has to be carried out early during a pregnancy.

Testing a pregnancy, but not going ahead with a termination after a positive test result, would take away the child’s right to choose whether to have the genetic test, later in life. After all, most people at risk of HD choose not to have the test before they develop symptoms. We know that big problems can occur when a child is identified, from birth, as someone who will develop HD.

In addition, most testing in pregnancy can only be done if tests have been carried out on the couple or other family members beforehand. Often, there is not enough time to do this background work when a pregnancy has already started.

Invasive Prenatal Testing

Most commonly and reliably, a procedure called chorionic villus sampling or CVS is performed during early pregnancy to test the fetus. CVS involves collecting a small sample of the placenta which represents the DNA in the fetus.

CVS is a quick procedure in the outpatient clinic, and in some countries, it is done under local anaesthetic. Depending on where the placenta is attached to the wall of the uterus, a very fine needle is passed either through the cervix or through the skin of the abdomen, using an ultrasound scanner to guide it. A small sample of cells is then collected from the placenta.

These cells can be used to test for the HD gene expansion. Some genetic centres will also offer testing for three common chromosome syndromes as part of the CVS genetic test.

CVS is usually carried out between 11 and 12 weeks into a pregnancy but no later than 15 weeks. An early dating scan is often required prior to a CVS taking place.

The main complication of this procedure is a small risk of miscarriage. Each centre will have specific information on the risk of miscarriage following a CVS. Please contact your local centre if you wish to learn more.

An amniocentesis is another type of invasive prenatal testing technique, similar to a CVS, but takes a sample of amniotic fluid rather than placenta. This can be carried out from 16 weeks. This therefore provides a result at a much later gestation and can make decisions around termination of pregnancy even more challenging.

If the genetic test is positive, a termination can usually be carried out under general anaesthetic until about 12-13 weeks depending on the country’s laws. Unfortunately, there can sometimes be a waiting list for this procedure.

In some countries termination of pregnancy may be carried out later on by inducing labour; however the availability of this option is again dependent on the country’s laws.

Non-invasive Prenatal Diagnosis (NIPD)

Non-invasive Prenatal Diagnosis is a newer way of testing in pregnancy without doing an invasive test, and so avoiding the small risk of miscarriage. Instead of an invasive test that takes a sample from the placenta or amniotic fluid, NIPD takes a blood sample from the parent carrying the pregnancy. This test looks for tiny bits of DNA from the fetus that float around in the parents’ blood.

NIPD can take place from around 10 weeks of pregnancy. NIPD usually involves some workup by the lab in advance of a pregnancy. It requires samples from the couple looking to extend their family and may require a sample from an affected relative. Therefore, it is important to plan in advance if you think this might be the right option for you.

NIPD may not be available or reliable everywhere. At the moment, an NIPD result indicating a pregnancy is at risk of HD may still be followed up with an invasive test to confirm the test results, before booking a termination. There are a few reasons why NIPD would not be appropriate, for example during twin pregnancies.

What if I don’t want to get the gene test myself?

There are ways to have HD-free kids without the at-risk partner getting tested themselves.

They use the same basic methods we’ve described – prenatal testing or PGT – with a genetic twist to identify ‘high risk’ pregnancies or embryos without revealing the HD gene status of the at-risk partner.

The twist is a couple of methods called exclusion testing or non-disclosure testing. These involve more preparation and planning, and there are some situations where it isn’t possible, so if this sounds like the right option for you: get expert advice early.

How does exclusion testing work?

Exclusion testing involves at least three blood samples. One each from the couple wanting to extend their family and ideally one each from both the mother and father of the person at-risk of developing HD. This technique may sometimes not be an option without a blood sample from the parent affected with HD.

We know that each of us will inherit one copy of the HD gene from each parent. The affected grandparent will have one normal copy of the HD gene and one expanded copy of the HD gene. We can label these genes ‘AA’. We do not know which one of these has been passed onto their adult child – and that person does not want to get tested to find out.

The unaffected grandparent will have two normal copies of the HD gene. We can call these ‘BB’.

The adult at risk will have some combination of A and B, with the A gene having a 50% chance of carrying the mutation.

If they wish to have a family without having genetic testing to determine their own risk, we can use exclusion testing during a prenatal test or PGT to identify if the fetus or embryo has inherited an A-gene from the affected grandparent, or a B-gene from the unaffected grandparent. This tells us whether the pregnancy would be high-risk or low-risk.

Crucially, exclusion testing identifies the grandparent of origin, without telling us whether the expanded HD gene has been inherited. If we found out the answer to that, it could tell us the results of the at-risk parent – which is what we are trying to avoid!

The flip side of this is that some high-risk embryos don’t carry an HD mutation, which would mean potentially ending a pregnancy or discarding embryos that may not have been at risk of HD in the first place.

Non-disclosure PGT

Non-disclosure is a twist on PGT that enables at-risk people to have HD-free children without finding out their own genetic status. This option is not available in every country, so it is important to contact your local genetic service to know if this is an option that is available in your area.

If an at-risk couple opt for non-disclosure PGT, the blood sample of the at-risk person would be tested for the HD mutation. The at-risk person would not be told the result of this test, and neither would any of the healthcare professionals that the at-risk person meets – only the professionals at the fertility lab would know the result.

The PGT then begins, with egg collection and generation of embryos. If the at-risk person’s ‘secret’ test result showed they had a HD gene expansion, the embryos are the tested for HD, and only those without the HD gene expansion are transferred for a potential pregnancy.

The couple isn’t told how many eggs are harvested, how many are successfully fertilised, or how many embryos are implanted. If there are no embryos without a HD gene expansion, the cycle stops there, and the couple are told that the fertilisation failed, but not why.

IVF can fail for many reasons, so a failure to get pregnant can’t be interpreted to mean the at-risk person has the HD gene.

Other options

One way to have HD-free kids is to use donor eggs or sperm instead of those of the at-risk person. Deciding to have a child with the help of a donor is a difficult decision but avoids the need to consider termination of a pregnancy. It can be done for people who’ve had a predictive test showing they carry an HD gene expansion, as well as those at risk who don’t want to be tested themselves.

Like all choices, this is complicated. The child won’t be genetically related to the at-risk parent, and careful thought will need to be given to how and when to share the information with the child. A parent doesn’t need to be genetically related to their child in order to fulfil a complete and loving parental role. There is plenty of support available to people who decide to go down this route, and this can be discussed before deciding to embark on the process.

Many couples think about adopting children. In many places, couples with one partner at risk of HD may have difficulty adopting a child. This is due to the disease being in the family and the adoption agency have to ensure the child has a stable home to go to. However, each case is individually assessed, so it is worth looking into adoption as an option. If you have been turned down for adoption, at-risk couples may be able to be foster carers for children as this is often a short-term option, caring for children over weeks or months at a time. The time you spend with foster children while short, can still often have a positive impact on the child’s life.

What about LGBTQIA+ people?

All the options discussed above are likely to be available for LGBTQIA+ couples, with a family history of HD, that are looking to start a family. There would be the additional step of finding a sperm or egg donor as well as a surrogate, if necessary, which will come with its own additional cost and legal paperwork.

In many countries being LGBTQIA+ is unlikely to prevent you from accessing the family planning option that’s right for you and your partner. There will be specific information for the family planning techniques available in your country for LGBTQIA+ couples that wish to have a family.

Summary

There are a number of options available to people at risk of HD who wish to start a family.

Not everyone chooses to go through genetic testing to start a family, and this is a completely valid option.

For those who wish to remove the risk of their child inheriting HD, they may not need to know their own risk for HD. Direct testing can take place when we know the result of the at-risk parent and they are shown to have the HD gene expansion. Whereas exclusion or non-disclosure testing can be carried out for at-risk couples who do not wish to find out their own test results.

Direct and non-disclosure testing can take place during pre-implantation genetic testing (PGT) where embryos are created in the lab and tested for their risk of developing HD, or a fetus can be tested during pregnancy. Testing in pregnancy can be invasive via chorionic villus sampling (CVS) or non-invasive (NIPD), but both of these are only options for those who would consider ending a pregnancy at risk of developing HD.

There are other options available for at-risk couples that include using donor eggs/sperm or adoption/fostering of children.

Expert advice, in the form of genetic counselling, will help you understand the exact options available to you locally and help explore which option feels right for you. Your country’s HD Association can tell you how to get in touch with a genetic counsellor. As with so many things in life, forward planning and understanding all the options in advance is key.

With the holidays approaching, welcome news arrived on December 19th in a press release from uniQure. The latest data from the HD-GeneTRX studies of AMT-130, an experimental huntingtin-lowering gene therapy, shows that the drug still appears to be safe over the course of a few years. Since the number of participants is very small, we cannot yet draw conclusions about the effectiveness of AMT-130 to treat HD, but there are early, promising signs that AMT-130 holds potential to stabilize some symptoms. This means that the trial can safely continue and will hopefully expand in future.

A refresher on the HD-GeneTRX trials

First, let’s talk about the history of the first gene therapy for HD. Developed by uniQure, AMT-130 involves a harmless virus packaged with genetic material that is designed to lower the amount of huntingtin protein in the brain. We’ve covered a bit more on the science of this in a 2019 article. It was first thoroughly tested in many different animal models of HD before the current human safety studies, known as HD-GeneTRX-1 and HD-GeneTRX-2, began in 2020.

AMT-130 is delivered via a single surgery into the fluid-filled spaces of the brain, known as ventricles, with the goal of permanently lowering levels of huntingtin in brain cells. Across the two studies in Europe and the USA, there have been 39 participants who underwent surgery. We’ve talked more about the different groups involved in the study in a previous article. Overall, most have received AMT-130, with some receiving a low dose, some a high dose, and a few undergoing a “sham” surgery as a control. After 1 year some of those in the “sham” surgery group also received a high dose of the drug.

As the trial has unfolded, uniQure has periodically shared data along the way. HDBuzz covered these releases, discussing positive 12-month data in 2022, a [safety hiccup]https://en.hdbuzz.net/329 that led to a pause in high-dose surgeries, and then the resumption of the trial late last year. In mid-2023, the trial was continuing to proceed smoothly with some positive data emerging. Today, some of the participants have been followed up to 30 months, and the data continues to look promising.

The latest data release

uniQure issued a press release and held an investor call to share the latest data from the trial. Let’s break down the news into digestible chunks related to AMT-130’s safety, potential impact on participants’ symptoms, and biomarkers.

Safety

This is a small study that is designed mainly to test safety and how well people tolerate AMT-130. There are definite risks following a major brain surgery, which we saw with the study pause last year. But with longer monitoring after the surgery and the prescription of anti-inflammatories, these risks are now better controlled.

Additionally, bloodwork, vital signs, heart rhythms and other measures of health were largely normal. Overall, this means that for up to 30 months after the surgery, AMT-130 seems to be safe and well tolerated at the low dose, and there are good options for managing potentially dangerous side effects.

Impact on symptoms

Although this study wasn’t designed to determine if AMT-130 can actually slow or stop symptoms, there are many clinical measurements built into the study that can begin to give us a picture of whether this drug can change the course of HD. Because the control group for the HD-GeneTRX studies is so tiny, uniQure also used data that was collected separately through a big observational study that did not involve a drug, called TRACK-HD. They were able to compare data from those who got AMT-130, with data from people at a very similar disease stage who didn’t receive the drug. These observational study participants were also followed over the course of at least 30 months.

The studies involved tests that measured movement, day-to-day function, ability to switch thinking tasks, and more. The main positive takeaway here is that those who received the high dose of AMT-130 seem to retain their functional and movement abilities for 18 months, as they performed better on all the tests than the TRACK-HD participants who didn’t have the surgery. The data for the low dose extends to 30 months, and these participants showed preservation of movement and function on some measurements.

All that said, much of this data describes a trend and the statistics don’t yet allow uniQure to draw a definite conclusion about how well AMT-130 works to slow or halt the signs of HD. There are too few people so far to tell – just 5 or 6 in the low dose group have reached the 30 months mark after their surgery.

Biomarkers

Another important thing that uniQure shared was measurements made in the spinal fluid of participants. Neurofilament light (NfL) is a protein released from brain cells when they are damaged. This is one measurement that scientists use in HD drug studies to get a clearer picture of whether the treatment could be helpful or harmful. After a brain surgery, NfL levels naturally go way up, but the hope is that they return to normal or “baseline” after a while (sometimes this takes quite a long time). If NfL levels dip even lower, that is one sign that the drug is safe and could even be helping to preserve brain health.

The latest NfL data from this study show that after the surgery, there is a big spike in this biomarker, but in the group that got a high dose of AMT-130, the levels seem to have returned to baseline after 18 months. In the low dose group, NfL levels are below baseline at 30 months – a good safety sign and one piece of the puzzle to show a possible benefit for the brain. Once again, we’re looking at trends in data from a very small group of people.

Since AMT-130 is designed to lower huntingtin, uniQure also wants to understand whether the treated participants have lower levels of huntingtin – but this has proven to be very tricky, not only in this study, but across the HD research field. They weren’t able to get reliable measurements from the spinal fluid for many of the study participants. Scientists at uniQure also suggested that it’s not yet clear whether looking at levels of huntingtin in spinal fluid is the most accurate way to measure the effects of a drug delivered directly to the brain. Still, any positive clinical signs will always outweigh measurements of a biomarker.

What can we take away from the latest data?

Above all, it’s important to remember that this study was designed to test safety and not efficacy, and so far it seems that AMT-130 is safe and tolerable for up to 30 months. It’s also a very tiny data set, and the comparison group was taken from a separate, observational study.

Despite all these caveats, there is reason for some excitement around the latest data shared by uniQure. This is the first time ANY HD study has shown genuine positive signs that a drug has the potential to stabilize symptoms, with safety and side effects that appear to be manageable.

Overall, this is what uniQure hoped to see at this point in the study. There is reason for it to move forward, and to hope that a larger study will be designed to test efficacy. So – no miracles, but a solid body of data that continues to grow. We expect another data release in around six months, in mid-2024.

HD is a slowly progressing disease, and for an unprecedented gene therapy like AMT-130, it’s about the long game. Ensuring that a novel approach is safe and effective can be frustratingly slow, but we are encouraged by the latest data and we will continue to report on any new results that are shared.

In the meantime, we are doing a cautiously optimistic happy dance, and we wish all HDBuzz readers a happy and healthy holiday season.