In this article, we’re bringing you advice from the 2024 Lancet Commission on dementia prevention, intervention, and care – a group of experts who have combed through massive amounts of previous research collected over decades to highlight 14 risk factors associated with dementia. The good news? Those 14 factors are things that can be modified. So making lifestyle changes around the factors identified here can help improve brain health, and potentially keep people that have the gene for Huntington’s disease (HD) healthy for longer.

Dementia vs HD

While HD and dementia may have different root causes, underlying factors that are beneficial for one will be beneficial for the other. Dementia is a general term for a reduced cognitive ability – the ability to think, remember, and reason.

A reduction in cognition is only one component of HD, which is caused by an inherited expansion of the genetic code in the huntingtin (HTT) gene. HD also affects a person’s mood and has a movement component similar to Parkinson’s disease, called chorea.

While there are currently no disease-modifying treatments for HD, there are several very promising ongoing clinical trials, such as those by uniQure, Wave Life Sciences, PTC Therapeutics, and Skyhawk Therapeutics. These companies are directly targeting the cause of HD, aiming to lower the HTT message. There are also companies with ongoing trials for drugs that would treat the cognitive aspect of HD, like Sage Therapeutics.

But we want to make sure that folks with the gene for HD stay as healthy as possible until we do have a disease-modifying treatment for HD in hand. So what active changes can people make to ensure that happens?

14 factors that affect brain health

1. Less education

People who have more childhood education and those who go on to attain higher education have a reduced risk of developing dementia. This could be because these groups are more likely to obtain more cognitively stimulating jobs, challenging their brain more frequently. Less education is considered a risk factor from early life that if rectified, would reduce the cases of dementia by 5%.

2. Hearing loss

It seems like a strange correlation, but the Commission found an association between dementia and hearing loss. While this is a factor typically associated with older people, age wasn’t the variable contributing to the risk of dementia here since they accounted for age. The authors think there could be social factors at play, such as isolation due to the inability to hear in social situations, leading to low mood and motivation. They also floated the idea of biological factors, such as vascular disease that could affect both the cochlea of the ear and the brain. However, none of those theories relating hearing loss to dementia have been proven. Hearing loss is considered a midlife risk factor, and eliminating it, for example with hearing aids, would reduce the number of dementia cases by 7%.

3. High blood pressure

People with untreated high blood pressure, aka hypertension, have an increased risk of dementia. However, this risk is lost when hypertension is treated with medication. The study specifically notes that risk of dementia increases when systolic pressure (the top number) is over 130. So getting blood pressure in check by age 40 so that it’s closer to 120/80 is good for your brain. Hypertension is a midlife risk factor that accounts for a 2% increase in dementia cases.

4. Physical inactivity

Exercise is tricky to measure since it varies so much across a person’s life, between cultures and socioeconomic status, and occurs at different intensity levels. However, the study shows that physical activity, particularly sustained physical activity across a person’s life, is associated with better cognition by the age of 69. The thought behind why exercise is so good for us is that it improves blood flow and reduces blood pressure, which could improve brain plasticity and reduce brain swelling – certainly things that could be beneficial for HD! Eliminating this midlife risk factor by living more active lifestyles could reduce the number of dementia cases by 2%.

5. Diabetes

While there’s a correlation between diabetes and increased risk for dementia, this appears to only be the case for diabetes acquired in midlife, not later than age 70. No one is sure why there is a correlation between diabetes and dementia, but they think it may be because of the effect that diabetes has on blood vessels, which run throughout the brain. It could also be because the brain requires insulin for metabolism and insulin resistance can lead to brain swelling. Improving health to eliminate type 2 diabetes in midlife could reduce dementia cases by 2%.

6. Social isolation

Infrequent social contact shows an increased risk for dementia. Criteria that counted toward social isolation were living alone, visits with friends and family less than once per month, and lack of participation in weekly group activities. Studies have found that socialization can improve the brain’s resilience to damage, promote healthy behavior, lower stress, and reduce inflammation. Eliminating social isolation in later life could reduce the number of dementia cases by 5%.

7. Excessive alcohol consumption

The report finds that heavy drinking comes with an increased risk for developing dementia compared to light drinking. Interestingly, not drinking at all had a higher risk for dementia than light drinking. A reason to imbibe?! Probably not. The jury is still out on how sound those findings are since various factors could be at play here, like not drinking because of alcoholism or other non-related health issues. Reducing alcohol consumption by midlife could reduce dementia cases by 1%.

8. Air pollution

Air quality is determined by the amount and size of particles in the air. Fine particles equal to or smaller than 2.5 μm are notoriously dangerous. The report found that sustained breathing of particles that are equal to or smaller than 10 μm increases the risk of developing dementia. Since there is a strong link between air quality and socioeconomic circumstance, developing policies and regulations around clean air will be important for reducing this risk for people from various social and geographical backgrounds. Having access to healthy air to breath later in life accounts for a 3% reduction in dementia cases.

9. Smoking

We now have an overwhelming amount of data to show that smoking is unequivocally bad for your health, and that includes your brain. Smoking increases the risk of dementia, with a higher risk for those who start smoking earlier. The good news is that this risk is only associated with current smokers; there was no increased risk of dementia between ex-smokers and people who had never smoked. Quitting smoking habits by midlife can reduce the cases of dementia by 2%.

10. Obesity

While obesity is associated with increased risk for dementia, this is a tricky factor to measure. Obesity is associated with other factors on this list, such as physical inactivity, diabetes, and high blood pressure. So it’s hard to tease out which is the factor really associated with dementia risk. However, most studies adjust for these other factors and obesity is still associated with higher dementia risk. Even a modest weight loss of 5 pounds improved cognition, suggesting that keeping an eye on your weight is good for your brain. Maintaining a healthy weight by midlife would reduce dementia cases by 1%.

11. Traumatic brain injury

Perhaps unsurprisingly, a bad knock on your noodle is bad for your brain! The study found that people who got a traumatic brain injury at younger ages were more likely to develop dementia. Avoiding traumatic brain injuries by midlife could reduce the number of dementia cases by 3%.

12. Depression

The report noted that the correlation between depression and dementia was bidirectional – that depression could be both a cause and consequence of cognitive changes. Theories about how depression could affect cognition relate to less self care and social contact, as well as biological factors like increased levels of the stress hormone cortisol that could affect the brain. Encouragingly, seeking treatment, like therapy, for depression by midlife could reduce dementia cases by 3%.

13. Vision loss

Vision loss was a new factor added since the 2020 Commission report. Specifically, they found an increased risk for dementia related to untreated vision loss. For conditions like cataracts where people sought treatment, there was no increased risk. But for people who had cataracts or diabetic retinopathy and didn’t seek treatment, there was an increased chance they would develop dementia. The report specifically noted the correlation wasn’t seen for other eye conditions, like glaucoma or age-related macular degeneration. Getting a handle on preventable vision loss by late life could reduce dementia cases by 2%.

14. High cholesterol

High LDL cholesterol is also a new addition since the 2020 report. Since then, studies have been done to show that high cholesterol is indeed associated with an increased risk for dementia. Taking a lipid-lowering drug, like statins that are widely prescribed to lower cholesterol, was not associated with an increased dementia risk. So the correlation seems to be with untreated high cholesterol. High LDL cholesterol is a midlife risk factor that if eliminated could reduce dementia cases by 7%.

What wasn’t included?

Notably absent from this list is sleep. HDBuzz has previously written about the importance of sleep for managing HD, tips and tricks for a good night’s sleep for people with HD, and biological reasons for why people with HD might have trouble sleeping. We also recently heard about sleep issues caused by HD and new drugs being developed for treatment at the Hereditary Disease Foundation conference.

However, there doesn’t yet seem to be a conclusive link between sleep disturbances and an increased risk for dementia. So far, studies haven’t been able to tease out how the risk for developing dementia might be associated with various facets of sleep, like duration compared to quality of sleep.

Diet was also not included as a risk factor in the report. While diet heavily plays into several factors on the list, like obesity and diabetes, there isn’t yet enough evidence for specific diets like the Mediterranean diet. However there’s lots of evidence that reducing consumption of ultra processed foods is good for overall health, so opting for an apple over chips will always be a good decision!

Surprisingly, even genetics can be overcome

The more surprising findings from the report are that developing dementia can be modified even for people who are at an increased genetic risk. The paper states that, “for the first time, it is clear that risk can be modified even in people with increased genetic risk of dementia.” It’s likely that these findings can be applied to HD as well – even if someone has the gene for HD, modifiable lifestyle choices could delay onset, increase healthy years, and reduce disease burden.

Since the previous report in 2020, the field has seen a massive expansion in the use and utility of biomarkers – biological changes that track with a disease and can be used to measure progression. Shockingly, there are many older people who have biomarkers of dementia, like amyloid plaques within their brains, who never go on to develop dementia. These findings strongly suggest that brain changes associated with dementia don’t mean that the disease is inevitable, supporting the 14 modifiable factors highlighted here.

Unsurprisingly, being healthy is good for you

This report from the Lancet Commission on dementia can not only be used by individuals to improve their own brain health, but it’s also used to guide policy changes at the national and international governmental levels. This could take the form of prioritizing early education across socioeconomic backgrounds, destigmatizing and encouraging seeking help for mental health, and enacting helmet laws for contact sports and bicycles.

Overall, the report shows what people certainly already know – living a healthy lifestyle and being kind to yourself will give you more healthy years. Things that are good for your brain, like education and preventing brain injury, will keep your brain healthy. And things that are good for your heart, like exercise, not smoking, and less alcohol, are also good for your brain.

You may have also noticed that each of these factors is relatively small by comparison – a few percentage points here or there, with the highest being 7%. So even if someone can’t check off every factor on the list, their chances of developing dementia are still low. It’s when health issues compound that the risk for developing dementia really increases. The take home message here is take care of – and be kind to – yourself.

Today, on International Ataxia Awareness Day, we’re bringing awareness to a group of brain disorders known as Ataxia, which can take many forms. Like Huntington’s disease (HD), Ataxia is degenerative; it damages brain cells, causes changes in movement, and involves complex symptoms that worsen over time. HD and some forms of Ataxia have a shared genetic origin, and we’ll talk about medical and research overlap.

What is Ataxia?

Like HD, Ataxia is a rare form of neurological disease. It can lead to a variety of symptoms including lack of coordination, slurred speech, and difficulty walking – this can appear similar to the effects of alcohol. Ataxia is usually caused by damage to a part of the brain that coordinates movement, known as the cerebellum, which is located at the back of the head right above the neck.

The symptoms of ataxia can vary a lot by the person, and they can also vary by the type of Ataxia. Some forms are passed down from one parent, as with HD – just one copy of the faulty gene causes disease. This is known as autosomal dominant inheritance. Other forms of Ataxia are passed down only when a person inherits two copies of a faulty gene – the parents don’t have ataxia, but they are each a “carrier” of the gene. Ataxia can also be caused by a brain injury or infection (acquired), or have unknown causes (idiopathic/sporadic).

Why should the HD community be aware of Ataxia?

Ataxia can refer to a group of disorders, but it can also simply refer to uncoordinated movements. If you’ve ever had too much to drink, you’ve likely experienced alcoholic ataxia. And many people with HD experience ataxia at some point over the course of their disease. Ask many healthcare workers with HD expertise, and they’ll tell you that when you’ve seen one person with Huntington’s disease, you’ve seen one person with Huntington’s disease. We all know that HD is complex and that symptoms can vary from day to day, let alone between individuals. Symptoms of ataxia can affect people with HD, especially in later stages.

HD affects the part of the brain that is important for voluntary movements, and it is more likely to cause chorea, which can appear jerky and dance-like. Ataxia affects the part of the brain that coordinates movement, and it is more likely to cause movements that appear unstable or slow. Both diseases worsen over time and cause people to have difficulties with speech, walking, and day-to-day tasks. There are even case reports where a person with HD was misdiagnosed with ataxia because their early symptoms involved difficulties with balance and coordination.

The genetics of HD and Ataxia

The greatest area of overlap in HD and Ataxia research is within a group of Ataxias that is caused by the same genetic error. We know that HD is inherited dominantly (from one parent), and that it is always caused by the expansion of CAG repeats within a gene called huntingtin. Some ataxias are also inherited dominantly, including a group of disorders known as spinocerebellar ataxia (SCA), and several of these are also caused by the expansion of CAG repeats.

In HD, the extra CAGs are found within the huntingtin gene, whereas SCA is caused by CAG repeats within other genes. Some examples are ataxin-1, ataxin-3, and ataxin-7, but there are a whole family of genes with CAG repeat expansions that are known to cause rare Ataxias (among other diseases). We recently heard about research into SCA from Dr. Harry Orr at the Hereditary Disease Foundation conference, which we covered.

New genetic causes of Ataxia have been discovered very recently, including ones caused by triplet repeats. In fact, in 2024 a new 5-letter DNA repeat was revealed as the cause of many hereditary Ataxia cases. Like the discovery of the gene that causes HD in 1993, this is a huge step forward for folks who have this type of Ataxia! Bill Nye the Science Guy, a well-known science communicator (and source of inspiration to us at HDBuzz) has family members who have this form of Ataxia, known as SCA27B. He has partnered with the National Ataxia Foundation in the USA to create several videos about this condition.

Historical research overlap

Historically, genetic research in HD and Ataxia has followed a similar path. There were initial efforts in the 1980s and 1990s to narrow down the “neighborhood” followed by the exact location of the genes that led to disease. There followed the creation of animal models in the 1990s and 2000s allowing scientists to study the development, progression, and treatment of HD and hereditary Ataxias. These paths involved similar laboratory techniques that built upon one another across fields.

Importantly, research developments in the HD and Ataxia fields involved similar collaborative efforts between researchers and family members who agreed to donate their time, samples, and brain tissue for the benefit of future generations.

Research today

The shared nature of the CAG repeat in HD and several hereditary Ataxias means that researchers can continue to learn from one another, working together and in parallel, and employing a shared set of tools and ideas. Bi-annual international conferences continue to gather global scientists studying CAG repeat disorders, and many labs work on HD in addition to hereditary Ataxias like SCA. The phenomenon of CAG repeats getting longer in some cells (somatic expansion) holds true for these Ataxias in addition to HD, knowledge that can be leveraged towards treatments.

What’s more, we’re already reaping the benefits of shared insights in drug research. The development of ASOs for huntingtin-lowering has led to similar efforts in the Ataxia field, which also involves an extra-long, clumpy protein. Similarities between diseases in how CAGs repeat themselves has even led to the development of a drug by VICO Therapeutics that may be used to treat people with Huntington’s disease, SCA1, or SCA3. Stay tuned for a deeper dive into the recent positive momentum of that human trial, which involves participants with all three disorders.

The takeaway

Ataxia and HD share many similarities. It’s productive for researchers to gain insights from one another across disease fields, especially those with common genetic features. And it’s gratifying to know that other families challenged with an inherited disease have built their own supportive networks whose parallel efforts drive clinical research and advocacy.

HDBuzz is proud to acknowledge the Ataxia community on Ataxia Awareness Day. We’d also like to give a shout-out to Dr. Celeste Suart at the National Ataxia Foundation (NAF) for her input. The NAF hosts SCAsource, a site similar to HDBuzz which provides plain-language research news written by scientists. If you’re interested in learning more, SCAsource is a great place to start.

Disclaimer: I have written this piece from a position of privilege – as an HD family member that has been fortunate to receive an education that allows me to deeply understand the nuances of Huntington’s disease. I know what it means not only at the biological level, but also at the family level. I am profoundly aware of the desire for a disease-modifying drug. But my hopes are tempered through the privileged lens of understanding complex scientific data and interpretation. Here, I report facts and my opinion of those facts with no vested interest in any specific therapeutic approach. If Prilenia feels errors have been made, they are invited to reach out and any factual corrections will gladly be made.

Recently, there have been a few press releases from Prilenia Therapeutics about their advancement of the drug pridopidine toward regulatory approval for the treatment of Huntington’s disease (HD). There’s also been mixed messaging about findings from pridopidine clinical trials and statements made by the company. Let’s break down what the research really says and what the recent press releases mean in the bigger picture.

MermaiHD Trial

We’ve written about the long and storied path of pridopidine before. It’s been tested in a number of different clinical trials, by a few different companies. Over the years, the use of pridopidine has shifted. Once thought to have utility for helping to regulate movements associated with HD, it’s now being tested for potentially slowing the disease course.

In 2008, pridopidine (previously called Huntexil) was tested in a European Phase 2 trial called MermaiHD. Back then, the company running the trial, NeuroSearch, thought the drug could be used to help with changes in movement control caused by HD.

Specifically, they thought the drug could help people control their voluntary movements that get more stiff and rigid as HD progresses. While people on pridopidine had slight improvements in movement control, the effect wasn’t large enough to determine that it was caused by pridopidine, and the trial failed to meet its endpoints.

HART Trial

Around the same time, NeuroSearch also carried out the HART study in America. Again in this study, there wasn’t a conclusive improvement in voluntary movements associated with stiffness and rigidity.

After the HART study, they pooled that data with the MermaidHD study to find that with this combined dataset, there did seem to be an improvement on voluntary movements. However, both the US FDA and European EMA determined that a larger trial was needed to conclude what effect pridopidine was truly having on HD-associated movement changes.

PRIDE-HD Trial

After this, the rights and ownership for the drug changed hands. The new owners, Teva Pharmaceuticals, wanted to test if a higher dose of pridopidine was needed to see a positive effect on HD movements. Enter the 2013 trial called PRIDE-HD.

In PRIDE-HD, a key goal was to see if pridopidine could improve total motor score – a robust collection of tests that assign a numerical value to movement symptoms associated with HD. Unfortunately, again, pridopidine failed to meet its primary endpoint and did not show an improvement in total motor score.

A change in direction

At this point, scientists went back to the drawing board to try and better understand the drug. They did more experiments and when they emerged, they had a new model for how pridopidine might improve brain health.

Now, the idea was that pridopidine might not just control HD-associated movements, but might modify disease course. This would mean pridopidine isn’t just treating the symptoms of HD, but is treating the disease itself – a huge difference.

New goal for PRIDE-HD

With this new theory, the drug developers added a few new goals mid-way through the PRIDE-HD study. The primary endpoint of testing movement was the same, and wasn’t met, but they also added a second test – total functional capacity, or TFC.

TFC is measured through a collection of tests that determine how well someone functions day-to-day. Things like the ability to hold a job, manage finances, and perform domestic chores. These abilities decline as HD progresses.

So did pridopidine improve TFC in the PRIDE-HD study? Kind of. Out of the 4 doses tested, only the lowest dose showed improvement on the TFC scale. These results were inconsistent, TFC wasn’t a primary endpoint of the trial, and there wasn’t enough data to draw a firm conclusion – so for the drug to have a chance of getting licensed, yet another trial would be needed.

Big conclusions were drawn – too big

Despite these inconsistent findings, Teva interpreted the results from PRIDE-HD to mean that the drug was slowing the progression of HD. This was a big message for the data that was generated. Quite frankly, too big of a message. This conclusion cannot be substantiated with the results from this trial.

Why not? It’s important to understand that improving or stabilizing TFC does not necessarily mean that something has slowed HD progression. For example, successful treatment of depression in a person with HD could enable them to resume work, improving that person’s TFC by 1 or 2 points – but not because the underlying progression of the disease has been slowed.

To be clear, a drug that improves the ability of people with HD to function would be fantastic. And a drug that slows the progression of HD would be super fantastic! But there is a clear distinction between those two.

Improvements in function cannot directly be interpreted as slowing HD progression – that requires much more solid evidence, from direct measures like MRI scans or biomarkers that can tell us whether something has rescued brain cells, or from much longer-term improvements in symptoms.

PROOF-HD Trial

Following the results from PRIDE-HD, pridopidine changed hands again, this time to Prilenia Therapeutics. Another trial was begun to test the ability of pridopidine to modify disease course of HD. This new Phase 3 trial began in 2020 under the name PROOF-HD.

This time, the primary endpoint was TFC, which it did not meet. People who took pridopidine in the PROOF-HD trial did not show any improvement in day-to-day functioning as measured by TFC. Again, this was a negative pridopidine trial. The trial also failed to meet its secondary endpoint, an overall assessment of HD severity called the composite Unified Huntington’s Disease Rating Scale (cUHDRS).

However, one would be hard-pressed to understand this, based on the headlines about the PROOF-HD trial. Again, there were controversial interpretations that have touted PROOF-HD as a success.

Drug interactions

Previous results had suggested an interaction between pridopidine and drugs that reduce dopamine activity in the brain. Dopamine is a chemical that helps control movement, memory, and mood. The interaction between pridopidine and these dopamine-altering drugs is perhaps unsurprising, given that pridopidine was originally designed to alter dopamine activity to help with HD movements.

Drugs that reduce dopamine activity in HD include commonly-used medications like tetrabenazine for chorea, or ‘neuroleptic’ drugs like olanzapine and risperidone, which are used to help control some of the most difficult symptoms of HD like aggression, impulsivity, paranoia, delusions, or suicidality. Physicians don’t take prescribing these medications lightly, and often do so to reduce the risk that a person with HD will harm themselves or others.

Prilenia decided, in advance, to do a ‘subgroup analysis’ of the PROOF-HD trial results in people who were not taking any of these dopamine-altering drugs. This group had only 79 people with HD compared with the full trial population of 499 people with HD. They reported that this subgroup had benefited from treatment on cUHDRS and one measure of cognition, but not the TFC.

A troubling narrative

Of the drug, Prilenia CEO Dr. Michael Hayden is quoted as saying, “Pridopidine has delivered consistent efficacy benefits across multiple key measures of HD”. We at HDBuzz do not agree that the data collected to date support this interpretation.

Pridopidine has been tested in more trials than any other drug in the HD landscape, and has consistently failed to deliver the benefits anticipated by the companies running the trials. Apparent improvements seen in one aspect of HD have not been replicated when tested in subsequent trials.

What if it’s true that pridopidine works in people not taking neuroleptics? That would be good news! But to make this claim and have the regulatory agencies believe it, another clinical trial would generally be needed, focusing exclusively on this group and enrolling enough people to test this robustly. This is a valid scientific hypothesis, and it’s reasonable to test it with such a trial.

However, that’s not what Prilenia are planning.

We were troubled by an announcement from a recent, non-peer-reviewed poster summary supported by Prilenia where the authors claimed to show links between neuroleptic treatment and the progression of HD. This is a very difficult thing to prove with existing data and statistics, since neuroleptics are generally given to people whose HD symptoms are worse, or whose HD is progressing more rapidly.

It is certainly important to study how different medications might impact HD progression. But when a company whose unapproved drug may rely on people not taking neuroleptics, starts supporting research into whether neuroleptics may be bad for people with HD, we worry about what conclusions HD families might draw, and we worry especially about people stopping medicines that are protecting themselves and others from harm.

Hope vs. hype

At HDBuzz, we’re less worried about the science around pridopidine – in every trial, the results are what you get, and continuing to test theories based on those results is reasonable, if the sponsor thinks there is a real effect to be found in a particular group of people. This process is what needs to be done until we get better drugs for HD.

What troubles us is the message being put out about pridopidine, downplaying the big things it has failed to do, and emphasizing less compelling findings in subgroups or individual endpoints. We worry that people from HD families – families like mine – could end up with a much more favorable impression than is warranted of pridopidine being the first disease-slowing drug for HD. Unfortunately, all the evidence so far does not support that hope.

Hope that a drug will work is useful – but only when that hope is grounded in truth.

We want people from HD families to participate in trials for drugs with a good chance of working. Drugs that have strong scientific reasoning and solid evidence to support asking people and families to make the sacrifice of time, effort, and risk.

We have the right to expect that trial results will be presented plainly and understandably. Trials that fail to meet their outcomes should not be presented as positive, and companies with vested interests should be extremely careful about commenting on how HD clinicians and their patients choose from currently available treatment options.

Getting an application accepted for review

Most recently, we’ve heard news from Prilenia about advancing pridopidine through the European regulatory agency, the EMA. Their recent press release titled, “Prilenia’s Pridopidine for Huntington’s Disease Accepted for European Marketing Authorisation Review” is notable for its use of the word “Accepted” considerably earlier than the word “Review”.

What the press release actually says is that Prilenia has put together the paperwork to ask the EMA to consider the results from pridopidine to date, and the EMA has accepted the submission of their application.

Getting applications accepted for consideration is a process that every approved drug goes through. But it’s also a process that every refused drug goes through. Applying to get into a university is very different from being accepted. We’re reliably informed by an expert familiar with EMA procedures that this step is not that big of a deal.

Most of the time, we don’t hear about when companies go through these minor steps. Press releases generally aren’t issued for these commonplace steps throughout the regulatory process. While it’s broadly good that Prilenia are ensuring the HD community gets regular updates on where they are in the regulatory chain, we want to make sure that the news isn’t causing undue hype. We’re more keen on seeing the full, peer-reviewed results of the PROOF-HD trial in a scientific journal.

What we know

Pridopidine has been tested in various clinical trials with various primary endpoints, all of which have sadly failed to be met. Regardless of the messaging being put out from Prilenia, thus far pridopidine has produced negative results from every major endpoint in every trial. Period.

We’re not even remotely happy about this: we love drugs that work, and we love trials that prove it. We even love negative trials – when the results are presented clearly, without spin, and give a scientifically-grounded path ahead, whether that’s planning another trial or calling it quits.

The goalpost for the intended use of pridopidine continues to shift: to control movements, to modify disease course, to modify disease course for those not on neuroleptics. It’s fantastic that Prilenia continue to study pridopidine in the lab! It’s in everyone’s best interest that researchers understand medicines from as many angles as possible. However, we need to make sure the intended use of a drug is shown through positive clinical trial results.

An application has been submitted to the EMA for consideration. So far, this doesn’t mean much. An application was submitted. It will be reviewed.

Seeking truth

Scientists are truth seekers. At HDBuzz, we believe researchers have a duty to accurately relay scientific findings to the patient communities seeking answers for a cure. For truth.

If hope that a drug will work becomes so blind that it turns to hype, something has gone wrong. Results from clinical trials, by design, are not subjective. Reporting results should also not be subjective. Messaging matters. Headlines matter. Ensuring that the patient community receives and understands the full, balanced truth matters.

The team at HDBuzz honestly does hope that pridopidine delivers on everything Prilenia says it does, and more! We all want a drug that makes a positive difference to people with HD, but right now there is only data from 79 people to support moving this drug forward. In our opinion, that isn’t sufficient for regulatory approval – time will tell whether the regulators have the same view or are persuaded otherwise.

Until we get there, HDBuzz will be here to report the truth and tease out the hope from the hype. We’re sorry if our take is disappointing, but we make no apology for keeping openness, frankness, and science at the heart of our reporting.

Stem cells grown in 3D in a research lab can mimic some features of Huntington’s disease (HD). They also hold promise for transplantation studies to potentially add back cells that are lost in HD. But what would happen to those new cells? Would they get along with the cells still in the brain that have the HD gene? And what can this system teach us about ongoing clinical trials aimed at lowering the HD-causing message in only parts of the brain? Read on to find out!

The power of stem cells

Stem cells hold a certain mystique. They can either retain their “stemness”, remaining a stem cell, or to turn into something else altogether. Contained within each one is the ability to become almost any cell type in the human body. Scientists can coax them into becoming a heart cell, or a muscle cell, or even a brain cell, providing scientists with a powerful research tool that can be used to answer questions about people’s brains in health and disease.

For brain diseases like Huntington’s disease (HD), there’s a second powerful potential application for stem cells – transplantation. As a neurodegenerative disease, HD causes the gradual loss of brain cells. This primarily happens in a central portion of the brain, called the striatum, and in the outer wrinkly bit of the brain, called the cortex.

Several groups of researchers are exploring approaches that would allow them to harness the power of stem cells to replace cells that are lost over the course of HD. We recently wrote about the work Dr. Leslie Thomspon is advancing for stem cell transplants from our coverage of the Hereditary Disease Foundation conference. But what would happen to the new cells? Would they adopt features of HD?

Dr. Elena Cattaneo and her team from the University of Milan, in Italy, recently published a study aiming to answer some of these questions. Elena’s lab are world leaders in using stem cells to research HD. In this new paper, they sought to better understand the effect that cells with the gene for HD have on cells without the HD gene. This might help inform future cell transplantation studies and trials aimed at lowering the disease-causing message since those drugs are unlikely to hit every cell in the brain equally.

Mini brain in a dish

Typically, when cells are used in lab experiments, they’re grown flat on the back of a dish. But if you’ve ever seen another person, you know that people aren’t 2D! So more sophisticated technologies allow researchers to grow cells in 3D.

The fancy term for these 3D cells is “organoids”, aka “mini brains”. We’ve previously written about these lab-grown brains and what researchers have learned from them. While mini brains can adopt some of the cellular features of a brain, such as connections between different cells, they don’t actually have the ability to transmit thoughts and feelings.

While these mini brains look deceivingly unsophisticated on the outside (like a little whitish, pinkish snot to be honest!), they’re elegantly complex on the inside. The cells form intricate networks between brain cells that can be seen communicating with one another under the microscope. These mini brains give researchers a way of understanding in 3D how HD affects connections and communication between different cells.

Scientists know that in a human brain, HD reduces the ability of cells in the outer cortex to communicate with the inner striatum. This communication breakdown leads to a loss in those connections over time. When those connections go unused for extended periods of time, it can create an unhealthy environment for the brain cells, and they may eventually die.

A positive influence

Elena and her team see something similar in their mini brains that have the HD gene. At the molecular level, brain cells communicate across a very small gap called the synapse. This is where the tips of brain cells meet to send bubbles of information back and forth to one another. In HD, the number of bubbles is reduced over time. In this new paper, the team sees the same thing in HD mini brains – there is less communication at the synapse than in mini brains without the gene for HD.

A key experiment in the new paper from Elena’s lab asked what happens to cells in mini brains when cells without the gene for HD are combined with cells that have the gene for HD.

The team performed a very detailed analysis of the genetic messages contained in the mixed population mini brains, seeing that they more closely resemble the mini brains without the HD gene rather than the ones with the HD gene. This suggests that the cells without the HD gene have a positive influence on those with the HD gene. Good friends to have around!

They also looked at the synapses in these mixed population mini brains. They found the communication being sent from the synapse was greatly improved! It more closely matched the mini brains without the gene for HD. This suggests the cells without HD might be helping the cells with HD to communicate better.

The team also identified some features that weren’t totally rescued by the presence of the cells without the gene for HD. In the mixed population mini brains there were still some changes at the genetic message level. Additionally, the number of cells that died in the mixed population mini brains wasn’t totally rescued. This suggests that while cells without HD help the mixed population mini brains, they can’t overcome every feature caused by the HD gene.

Informing ongoing and future trials

Overall, this type of research can help determine the therapeutic potential for using stem cells to slow progression and treat HD. It is also informative for ongoing trials that lower levels of the disease-causing genetic message.

While the goal for some of those trials is to lower the message by about 50%, that won’t occur in every cell in the brain. Because of that, those cells with reduced HD genetic message will exist in a mixed population with cells that have more of the HD genetic message. Data from studies like those highlighted here help researchers understand exactly what may happen at the molecular level when such mixed populations of cells with and without the gene for HD exist.

An important point the research team was able to tease out in this paper is that the cells without HD have a positive influence on the cells with the HD gene. But the opposite is not true. The cells that have the HD gene don’t seem to alter programs in the cells without HD. This is important for future transplantation studies because it suggests cells without HD that are added may have a positive effect, but the cells already in the brain with HD possibly won’t have a negative effect on the new cells. A win, win!

Moving treatments forward

While stem cells and mini brains are super cool, there are some limitations to their use. Firstly, they don’t truly mimic what’s happening inside a human brain in a living person. Nothing in a lab dish can. This is why it’s important to study potential treatments in a functioning brain, like in a mouse, and eventually run clinical trials in people.

Additionally, the mini brains that contained cells with and without the gene for HD were mixed before they were made. Meaning the mixed population was there from “birth”. In the case of a person with HD, the cells or treatment would be added after the person had a fully formed brain.

Despite the caveats, this work represents a cool approach for better understanding how cells without the gene for HD may act if they were added to a brain with HD. It also sheds light on what may happen in a brain when some cells have the gene for HD while others have less of that message.

The human brain, both inside a lab dish and out, is incredibly complex, so knowing as much as possible about how HD affects cellular and molecular features will help move treatments forward.

We’re back for the last day of the Hereditary Disease Foundation conference!

Serendipitous finding?

Up first is HDBuzz co-founder and editor emeritus, Jeff Carroll. Jeff’s lab studies HD in mice and cells in a dish and investigates different potential treatments.

The first story Jeff is telling us about is developing tools that lower HTT. He’s using something called an ASO, or antisense oligonucleotide. You may have heard of these if you followed Roche’s trials since tominersen is a HTT-lowering ASO.

Jeff’s team saw that when they lowered HTT with ASOs, the degree of somatic instability seemed to go down. But it turns out this is not because of the reduced amount of HTT protein, but a strange quirk of how ASOs work to target genetic message molecules. This doesn’t mean that HTT-lowering ASOs will reduce somatic instability in the key cells HD researchers are targeting. The doses would have to be crazy high to achieve this and then there might be unwanted off target effects. Still, an interesting observation – science is weird!

The ability of the ASOs to influence somatic instability got Jeff curious if other tools that lower HTT also affect somatic instability. So he repeated his experiments with another tool to lower HTT called zinc finger proteins, or ZFPs. These work in a completely different way to ASOs, binding the CAG repeats in the DNA molecule itself, not the genetic message molecule (RNA).

Again, they see that ZFPs decrease the amount of somatic instability in the mouse models they studied. Jeff speculates that this could pave the way for new approaches to think about treating somatic instability, by decorating the HD gene DNA with things like the ZFP molecules.

The second story Jeff is telling us about is his work with ASOs to specifically lower the expanded copy of HTT. He’s collaborated with Wave Life Sciences on these experiments.

He’s being mindful of the super toxic HTT1a fragment we wrote about yesterday from a talk by Gill Bates. Since these are the form of HTT that causes sticky protein clumps, Jeff looked to see if those were affected in mice treated with these ASOs. And they were! The HTT clumps in mice treated with the HTT-lowering ASOs were dramatically lower.

They also see that the changes to which genes are switched on or off more in HD are restored when the mice are treated with the ASOs. Jeff thinks that treatments that affect genes turning on or off might also have an added bonus of influencing somatic instability.

He finished with a call to arms to look into this idea more and encouraged drug developers to ensure that they’re also hitting HTT1a with their drugs.

Beyond the barrier

Up next is Nick Todd who is going to talk to us about using focused ultrasound to do a better job of getting drugs into the brain. The brain has a protective barrier that keeps things from the blood out that could cause harm to the delicate brain cells.

This barrier is also a headache for drug hunters as it often keeps out drug molecules from getting into the brain – this is why HTT-lowering ASOs, like those from Roche and Wave, are delivered by spinal tap, as they are too large to get across this barrier.

Focused ultrasound can cause this barrier to open temporarily, potentially allowing drugs to get from the blood to the brain. Nick is showing that he can control this system to a very fine level of detail to open up the barrier in very specific areas for defined timeframes.

This approach has already been tested in 30 clinical trials – wow! So far, these have primarily been in cancer, but are moving to neurodegenerative diseases, like Alzheimer’s and Parkinson’s. Nick and a collaborative team from Boston are hoping to apply this technology to HD.

Right now, Nick and his team are testing this approach in mice that model HD to work out if it is feasible and if there are any safety issues that need to be figured out. Once this is done, they want to start testing the delivery of gene therapies in mice with this technology. This approach looks very promising in other models and for other diseases, so we’re excited to have Nick using this approach for HD!

A new upcoming trial (!) to replace lost cells

Up next is Leslie Thompson – a total rockstar in the HD space. She was part of the team that went to Venezuela to help identify the gene that causes HD and runs a productive HD lab that works on various aspects of HD. One of the models she uses to study HD is stem cells.

For a long time now, one idea people have had to treat degenerative brain disease like HD, is to replace the cells that are lost over time – something called cell therapy. There are a lot of different ways scientists are researching this approach, including adding cells back with surgery.

There has been success with this approach in other disease fields, like a type of epilepsy. A cell therapy recently received FDA approval for people that live with this type of epilepsy, 60% of whom in the trial went from having 5-6 seizures a day to none. Impressive and exciting!

A global team of expert HD researchers have been working together to try and get a cell replacement therapy off the ground. This is no mean feat: they need to make the right type of cells that have certain markers and that are able to survive and thrive after transplant.

So far, Leslie and her team have tested this approach in mice that model HD with great success. The motor and movement symptoms of the mice improved after they were given the stem cell therapy. They also saw increases in molecules that are known to be protective for the brain and reduced amounts of sticky HTT protein clumps. They also saw restoration of other molecular markers indicating that the brain has more healthy neurons. Very cool!

Having healthy cells in the brain after transplant is one thing but, ideally, you want to see these new cells making connections with other nerve cells in the brain. Using cool imaging methods, they could see new connections formed between the transplanted and existing brain cells!

Leslie and her team are advancing this stem cell therapy toward the clinic and are gearing up to start a Phase ½ trial. She and her team are being ultra-cautious so that the stem cells that will get transplanted won’t cause tumors. So far, all tests indicate tumors won’t form.

The great news is the team have approval to start the trial. Once they receive funding, the trial will get underway under the name REGEN4HD. Participants will receive one dose of the therapy and different amounts of the cells will be tested to find the amount which works best.

The aim of the trial will be to check the safety of this therapy in people. Although they have done lots of testing in different animal models, there are still many possible risks with a therapy like this, which adds cells to the brain and is delivered by brain surgery.

HDBuzz will keep you updated as we learn more about this new trial using a totally different approach! We have many irons in the fire now for HD therapeutics which is giving the HDBuzz team lots of hope.

Improving ASO technology

Next up is Holly Kordasiewicz from Ionis Pharmaceuticals. Ionis is the company that initially developed the HTT-lowering ASO that is now called tominersen and is being tested in clinical trials by Roche in the ongoing trial GENERATION-HD2.

GENERATION-HD2 is happening across more than 70 sites in 15 different countries and is now at ~75% enrollment of trial participants. This trial is a huge undertaking with lots of complicated logistical considerations.

Holly is giving the crowd details on how Ionis develops their drugs and how they’ve been modified over time for improvements. If you loved your organic chemistry classes, this talk is for you! Lots of chemical structures are being shown.

Different chemical decorations on ASOs can really impact how well they work as drugs, as well as the possible side effects they might cause. ASO chemists are constantly improving these molecules to give the drugs the best chance of delivering the desired effects.

These small changes also help to improve how long the drugs stick around in the body, so spinal injections are needed less frequently. The chemical decorations also affect how the drugs spread through the body, including getting across structures like the blood-brain barrier.

Ionis are testing out technology where a small protein molecule is tacked onto the ASO. They give this modified ASO to mice by regular injection into their bloodstream. The protein handle helps the ASO move from the bloodstream into the brain tissue – very exciting!

This could mean that ASOs for brain diseases, like HD, could eventually be delivered by regular injections, not the more arduous spinal tap procedure. This would put less burden on folks receiving these drugs and be a real game changer.

Somatic instability as a therapeutic target – MSH3

Our next speaker is David Reynolds from LoQus23. LoQus23 is one of the companies working to target one of the HD modifiers, called MSH3. By stopping the actions of MSH3, LoQus23 believes this will potentially slow down HD signs and symptoms by halting somatic instability.

Unlike many of the approaches we have heard about so far today, they are making small molecules that target MSH3 and stop it from working. The challenge with this approach is that MSH3 has many lookalikes in the cell, so they wanted to ensure that any molecules they made ONLY target MSH3. So far, they have found molecules which look very promising on this front.

They are using special microscopes to look at exactly how and where their molecules bind onto MSH3. These molecules work by handcuffing the MSH3 protein molecule. That locks MSH3 in place, preventing it from doing its job in the cell, which leads to CAG expansions.

The scientists at LoQus23 use cells in a dish to see if their molecules alter somatic instability. A challenge with this is that somatic instability is a slow process, making these experiments quite long. LoQus23 has optimized this and can get a readout in just 2 weeks.

In this system, they only need to add a very small amount of their drug to see a big impact on somatic instability – great news! They use all kinds of chemistry tricks to show this is an “on target” effect i.e. it is happening because the molecules are hitting MSH3. They’re currently working to test these molecules in mouse models of HD and hope to be able to share if the molecules work at the next big HD scientific conference.

Somatic instability as a therapeutic target – PMS1

Up next is Travis Wager from Rgenta. He will be telling us about his team’s work creating drugs that target PMS1, which works to drive somatic expansion in HD and other diseases.

People whose bodies make more PMS1 tend to get HD symptoms earlier, whereas other people who make a less effective form of PMS1 get symptoms later. This points to the fact that PMS1 could be a great drug target to treat HD.

Rgenta’s approach is to target the message molecule of PMS1, causing it to get jumbled which will lower the amount of the PMS1 protein that is made. It looks like Rgenta has done a great job of finding molecules which do just this, with very low doses needed to see the reduced PMS1 levels.

Next, they looked at how changing PMS1 levels with their molecules affected somatic instability. They saw a significant slow down in this regard – which is great news.

PTC’s trial is ongoing

Now we will hear from Amy-Lee Bredlau, from PTC therapeutics. They have developed a small molecule, called PTC-518, which works to change the way the HTT message molecule is processed, causing it to get sent to the cell’s trash can, and reduce the amount of the HTT protein that is made.

PTC-518 is under investigation in a Phase 2 study, and we wrote about their interim update a little while ago.

The headline from that update is that things look very promising for PTC-518; it is effective at lowering HTT in the blood and in the central nervous system, and also appears to be generally safe. Great news!

We look forward to seeing the final results of this trial and learning more about PTC’s future plans for this drug. We will keep you all updated on all fronts.

Aggressive behavior in HD

Our next speaker is Amber Southwell, who will be telling us about a new mouse model she’s created to better study and understand aggression that some people with HD experience. Amber tells us that there are different kinds of aggression. Reactive aggression, that occurs after a trigger, even if seemingly small, is the type of aggression that’s been described in people with HD, and also in mice that model HD.

Amber does lots of experiments with mice. She noticed that some of her HD models had aggressive behavior even with normal handling. So she dug into this observation more to try and figure out if that was caused by HD, or perhaps by something else.

There are lots of different mouse models of HD, all of which differ in the forms and amounts of the HTT protein that they make. Amber thinks that these differences are likely why certain traits and signs of HD are observed in some mice, but not others.

Amber controls interactions between mice in several scenarios, films them, then scores their behavior data. It turns out her hunch was right, one type of HD mouse does seem to be generally more aggressive in certain scenarios than other HD mice.

However, in other scenarios, there was little difference between different types of HD mice and the control mice. One thing which did seem to hold true, is that HD mice are not very good at assessing perceived threats and are easily triggered to exhibit aggressive behavior.

Amber eloquently highlights that for a long time, many psychological symptoms people with HD experience were thought to be a reaction to the hardships of living with HD. But increasingly, we are finding out that depression, aggression etc. are in fact symptoms of the disease itself.

There are regions of the brain attributed to these type of behaviors in people and some scientists have observed changes in these regions in brain scans of people with HD. Amber and her team are now investigating these brain regions in their mouse models.

A prescription for sleep

Our next speaker is Zanna Voysey, who studies sleep in HD to see if there’s a link between problems with sleep and disease onset and progression. Zanna is also interested in using medication to treat this aspect of HD.

For people with HD, many experience insomnia or fragmented sleep. Similarly, people often move around a lot even whilst they are sleeping. This can really impact people’s quality of life and exacerbate other symptoms, so research into this is very welcome.

These sleep symptoms actually start very early in HD and people may be unaware of the extent of their symptoms. This is why we need specific sleep studies, as just asking how well someone slept does not always give a complete picture.

Beyond improving quality of life, sleep seems to directly impact many signs and symptoms of HD, at a molecular level and at a clinical level. So treating sleep issues could help people think more clearly and even help slow down symptoms of HD.

The Cambridge HD-Sleep study has now been running for 12 years! They have collected all sorts of data from more than 40 people, with and without HD to see how HD impacts sleep over the course of the disease. They confirmed that poor sleep tracked with HD progression, and the scientists could even predict who was more likely to progress to the next stage of HD based on sleep symptoms.

Interestingly, they found that people with HD who had worse sleep had more trouble thinking and increased amounts of NfL, suggesting poor sleep is having a very real effect on the health of their brains.

Melatonin, a chemical that causes us to fall asleep and stay asleep, increases in deep sleep, but people even at the very early stages of HD were shown to have altered melatonin levels in this study. This indicates that sleep issues are an early sign and symptom of HD.

The good news is that there are now many options for treating sleep with a new series of drugs which target a molecule in the brain called orexin. These drugs seem to have very limited side effects and have shown great promise in different diseases, including Alzheimer’s. Zanna and her colleagues in Cambridge are keen to see if these drugs might help people with HD, and possibly even slow down disease. They’re setting up a clinical trial to measure these questions in a controlled way.

Excitingly, Zanna’s work shows us that there are things that people can do TODAY to help with signs and symptoms of HD. So grab your pillow and get to bed early!

Communication breakdown

Next up is Chiara Scaramuzzino who studies how molecules move along the long, thin branches of neurons. This process doesn’t work so well in HD so Chiara is trying to get into the details of exactly what is going wrong. Molecular messages travel throughout cells and between cells in little bubbles. The transfer of these bubbles and capture of them by neighboring cells doesn’t work as well as it should in cells affected by HD.

Chiara’s lab has made a cool way to study this in the lab. Using 3D printed micro structures, they grow neurons on a chip, where the nerve cells make connections with other cells in a similar way to how they do in the brain.

Using this system, they can do all kinds of imaging of the nerve cells. This includes measuring the transport of individual cargos in cells moving along the length of the nerve cell – Chiara is sharing super cool videos with the crowd!

Comparing regular and HD nerve cells on a chip, they can see that some of this transport is impaired in HD. They also looked at connections between different combinations of HD and regular cells, seeing that networks that start with HD cells are the most impacted in their function.

They followed up on these cargo transport issues by doing some experiments in mice. With some very cool imaging technologies, they were able to “see” the movement of the cargo in the mouse brain. Chiara is hoping that this work will help her and her team identify new targets to develop potential therapeutic targets that might help regulate communication within and between brain cells, which could help improve thinking, movement, and mood in HD.

Systematic screen for somatic instability

Our next speaker is Ricardo Mouro Pinto, who was awarded a $1,000,000 Transformative Research Award from the HDF in 2023 for his work on targeting somatic expansion using CRISPR to develop new drugs for HD.

Ricardo’s lab are some of the many talented folks investigating genetic modifiers that influence age of onset of HD symptoms and how they impact somatic instability of the CAG repeat in the HTT gene. Ricardo’s team systematically looked at every genetic modifier (60 in all!) in HD mice to see how they impacted somatic instability. This found many of the usual suspects, like FAN1 and MSH3, as some of the genes with the most influence on somatic instability.

They looked in different parts of the mice, including the liver and the striatum, the part of the brain most impacted by HD. This showed that some modifiers, like PMS1, seemed to have more of an impact in the brain than in the liver. Identifying genes, like PMS1, that have a stronger effect in one tissue over another suggests some tissue-specific effects with this process.

Other modifiers, like MLH3, seemed to have an impact at different timepoints of the life of the HD mouse. Together, this shows us that somatic instability is a complicated process that happens in different phases with many different proteins playing a role.

Interestingly, some drugs that lower HTT also seem to hit somatic instability-related genes. We recently wrote about this idea. The drug branaplam not only lowers HTT, but it also targets PMS1 to reduce somatic instability.

Ricardo and his team are looking through all of the different modifiers to see which might make the most sense to target with drugs, to slow somatic instability, and potentially treat HD and possibly other repeat expansion diseases like SCA1.

They are looking into CRISPR tools to try and edit some of these modifiers, with the aim of slowing somatic expansion. A very exciting potential future treatment for HD. While they’re only in mice right now, their plan is to move toward the clinic, so we’ll keep you posted as Ricardo’s work moves forward!

Improving gene therapies for HD

The final talk of the conference is from Beverly Davidson, who also was also awarded with a $1,000,000 Transformative Research Award from the HDF in 2023 for her work advancing gene therapies for HD.

Bev’s lab works on the problem of gene therapy delivery and are working to optimize technology that will allow scientists to move from treating a mouse brain to a human brain. She doesn’t just work on HD, but many different genetic diseases, all in need of new drugs.

In current gene therapies under investigation right now, like that of uniQure, multiple injections of the drug are needed in brain surgery at relatively high doses. Bev’s team is trying to rethink this process, making it less laborious for surgeons and arduous for patients.

Gene therapies are generally packaged in harmless viruses called AAVs. Bev’s team is testing different AAVs in animal models to see which work best at getting into different regions of the brain. Bev’s team have identified AAVs which, at very low doses, are able to really get into the center of the brain. This will be a great tool for HD gene therapies which aim to target the striatum, which is right in the middle of the human brain.

She shared beautiful images of a monkey brain showing that her lead AAV candidate, with only one injection, gets to deep structures of the brain and lights up lots of cells there. They’re working on producing a very potent drug delivery system!

Bev is also sharing a story about developing a new technique that allows them to mix samples from different mice, barcode the different cells, then analyze them as a group. This has massive advantages – saving time, money, and resources in the lab!

After the data is analyzed, they can work out which genes and how much of each are expressed in every cell from each brain that they pooled together. It’s a very innovative approach called SPLiTseq.

Up next on Bev’s to-do list is to package HD-targeting drugs into their potent AAV. She promises an update at the next big HD conference!

That’s all from us for HDF’s 2024 conference! Thanks for following along. You can also find other updates in the near future about the conference from Ken Serbin, aka Gene Veritas at his blog. We’ll be back in Boston in 2026 to bring you more updates!