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Posted on Thu, 25 Feb 2021 03:02:02 +0000

Vaccines and HD

Families around the world are being impacted by COVID-19, but hope is on the horizon in the form of revolutionary new vaccines which were developed in record time. How is the coronavirus impacting HD families, and should they be worried about any of the vaccines coming to market? Should HD patients get the vaccine? We'll unpack this below, but the short answer is - absolutely, yes!!

HD and infectious disease

Making it through everyday life for Huntington's Disease families can feel like a marathon. The stress induced by the coronavirus has made things even tougher. HD patients often struggle with isolation, and being stuck in and out of lockdown only compounds these feelings of loneliness. Accessing regular medical care to deal with HD-related issues is also much more challenging, when doctors offices and hospitals can feel very threatening and scary.

In a series of incredible breakthroughs, infectious disease scientists were able to develop a number of highly effective vaccines for the coronavirus in record time. As 2021 gets underway, we find ourselves with several vaccines that have been approved by regulators, with several more on the way.

For good reasons, HD families are nervous about anything that could impact the well-being of their loved ones with HD. So should they encourage the HD patients they love to get a vaccine? Below, we unpack some of the concerns that HDBuzz has heard from the HD community about the coronavirus and vaccines, but if you just want the short answer - our strong opinion is that anyone who is eligible for the vaccine should get it, including HD patients.

mRNA sounds scary?

One concern voiced by the community is that several of the new vaccines - tested and sold by Pfizer/BioNTech and Moderna - rely on a novel technology called messenger ribonucleic acid (or mRNA). At HDBuzz we're often talking about mRNA in the context of Huntingtin lowering trials, such as those using ASOs, which we've talked about a lot here and here. These drugs target a specific mRNA in our cells - the one that tells them how to make the Huntingtin protein - for destruction.

If drugs like ASOs target mRNA to try and cure HD, and these vaccines have mRNA in them, should we be worried? No! mRNA is one of the most common types of components of our cells, each of which contains literally tens of thousands - if not hundreds of thousands - of different types of mRNAs. mRNA messages are plentiful in almost all living things so we safely ingest mRNA all the time when we have fruits and vegetables and other foods, at much higher levels than anything that is in mRNA vaccines.

If our cells contain a vast library of mRNAs, the Huntingtin lowering drugs that we're hopeful about are like sneaking into the library, taking one book off the shelf and tearing it up. The new vaccines that rely on mRNA technology are like sneaking an entirely new book - one that teaches our cells how to recognize the coronavirus - and quietly putting it on the shelf.

How can fast trials properly assess new vaccines?

But what about the fact that these vaccines were tested so quickly, doesn't that mean that they're not as rigorously tested as other drugs? Thankfully, the answer to this is a clear no. The initial development of the coronavirus vaccines did happen very quickly, but this was in fact building upon a huge foundation of work on mRNA vaccines, prepared for by many years of work by scientists around the world who were making mRNA vaccines for other illnesses who could then apply their technology to help fight the pandemic.

All of the available vaccines have been very carefully tested and have been shown to meet very strict safety criteria determined by different independent drug agencies, like the Food and Drug Administration (FDA) and the European Medicines Agency (EMA). It is true that this happened faster than normal, but the corners cut to speed up the process were mainly bureaucratic rather than scientific. Because there was such an urgent need for the vaccine, all of the different players involved in making, testing and assessing the vaccines, worked very closely together and removed administrative roadblocks which often slow down the approval of new medicines.

The reality of HD and infections

HD is a demanding illness for families and the added complications of dealing with COVID infection for a person with HD or their caregiver can really add to the daily struggles which they might face. Although people with HD are not at any increased risk of contracting COVID, having COVID is certainly to be avoided as far as possible.

We still know very little about whether people with HD are affected by COVID infection worse than other groups of people but the data for the wider populations has shown that COVID can have devastating effects in otherwise healthy people. It is important we all do our best to stop the spread of this disease by following public health advice to stay home as much as possible, wash our hands, follow social distancing rules and wear face masks - things we are probably all too familiar with now one year into this pandemic.

Vaccines are another important part of stopping COVID infection in its tracks. COVID vaccines have been shown to be some of the most effective vaccines scientists have made to date with over 90% efficacy in some cases! There is no data to suggest that HD patients specifically should not get the vaccine, which was tested in a very broad range of people and has now been administered to huge swathes of the populations in countries like the USA and Israel. So far, the groups who are advised to hold off from getting the vaccine are people who are immunocompromised and those who have allergies to ingredients in the vaccines. This means that most people with HD have the green light to go ahead and get vaccinated.

What do the doctors say?

We spoke with some expert HD doctors to hear what they think about the COVID vaccines.

"We are incredibly fortunate to be living in an era in which medical science has advanced to the point that we have vaccines less than a year into a pandemic. I and my colleagues in the Cardiff HD centre have now been vaccinated and I’m delighted to see that our local HD community are starting to be offered the vaccine. COVID-19 is a nasty condition and, especially considering what we now know about its impact on the brain in some individuals, it is clear that having the vaccine is far safer than catching COVID-19." - Professor Anne Rosser PhD FRCP

"To be vaccinated is to be given a superpower - the ability to defeat an enemy you haven't even met. I volunteered for the clinical trial of the AstraZeneca vaccine and have been spending all my free time since Christmas eve vaccinating the people of London. The choice to consider isn't between the vaccine and nothing, it's between the vaccine and covid, which is the biggest threat currently facing the HD community. The vaccines are safe, incredibly effective, and pose no special risks to people with HD now or in the future. We need to do everything we can to get all our HD family members protected and safe from covid, so that we can get back to fighting HD together." - Professor Edward Wild MA MB BChir FRCP PhD

"Patients and their families are asking about Covid-19 and Huntington’s disease. We are learning more and more about the pandemic and the vaccines to prevent the infection. There is a lot that we know and a lot that we do not know. Covid-19 is a potentially fatal condition. There are risk factors that make it more dangerous including older patients and those with other medical problems. Patients with Huntington’s disease are more likely to become sicker due to Covid-19 if they become infected. We do not have data about this in detail, but most physicians agree that HD patients should do everything that they can to prevent infection. I encourage all my patients to get approved vaccines when they are available. There are some risks to the vaccines, but these are minimal compared to getting the infection. There is no indication that taking medications for the treatment of HD will make someone more susceptible to the infection or make their condition worse. There is also no indication that any of the investigational drugs that are being tested for HD either for symptomatic improvement or reducing the rate of progression will make HD patients worse or increase the risk of getting Covid-19. In balancing risks and benefits, In summary, get vaccinated as soon as possible." - Mark Guttman MD FRCPC

""The science supporting the approved COVID vaccines is compelling. They are safe and effective, and while not tested specifically in the HD population, I would still encourage people in HD families to consider being vaccinated if they are offered." - Professor Victor Sung MD

The bottom line

The science shows very clearly that the COVID vaccines are safe, effective and our best chance at combating this pandemic.

From: HDBuzz (English)

Posted on Thu, 11 Feb 2021 23:14:49 +0000

GPR52: Exploring a new way to lower huntingtin

Scientists have found new leads for how to reduce the levels of the Huntington’s disease (HD) protein by targeting a protein called GPR52. A team of researchers working in Shanghai, China developed small drug-like molecules which lower huntingtin protein levels in HD tissue culture models and in HD mouse models. Treatment with their molecules was also shown to improve the HD mouse symptoms.

New avenues for huntingtin lowering

Huntingtin-lowering therapies are heralded by many researchers and clinicians as a very promising avenue for treatment of HD. People with HD have a longer or expanded CAG number in their HD gene, huntingtin. This means that throughout the body and brain they make a different, longer form of the huntingtin protein. This expanded protein is thought to be responsible for many of the symptoms we observe in people with HD.

The idea of huntingtin-lowering therapies is that if you reduce expanded huntingtin, you might also get rid of its toxic effects. There is evidence in lab HD models that huntingtin-lowering can slow or improve HD symptoms, but we await the results of ongoing clinical trials before we can be sure that the same effect will be observed in patients.

As many HDBuzz readers probably know, there are already lots of different companies and academics working on huntingtin-lowering either in the lab or the clinic. We have profiled many of these companies recently and you can read the latest updates on how their therapies are progressing in this article and this article. Many companies at the front of the field such as Wave, uniQure and Roche are using genetic approaches such as gene therapy or antisense oligonucleotides, which are very large molecules. They must be administered directly into the brain or spinal cord in order to reach the nerve cells in our brains that are most affected by HD. Other companies are working to find “small molecules” which might also lower huntingtin levels. The hope is that small molecule huntingtin-lowering therapies could be taken as a pill, making them more accessible to patients.

What has GPR52 got to do with huntingtin lowering?

GPR52 is part of a family of proteins called G-protein coupled receptors that sit on top of cells and receive messages, similar to a satellite dish. These types of receptors are commonly targeted by FDA-approved drugs. This gives scientists optimism that using new medicines to target members of this receptor family, like GPR52, could be safe and effective.

GPR52 was first identified by scientists as a protein of interest for HD in a genetic screen. A genetic screen can be thought of as a scavenger hunt, where scientists look at different genes one-by-one to see how they might, in this case, change signs of HD. Scientists then used genetic tricks in the lab to delete the GPR52 gene or to lower the levels of GPR52 protein, and this helped to improve signs of HD in cells and flies. A team of researchers in Shanghai, China, recently took this one step further and tried reducing the levels of GPR52 in mice. In this recently published research, they show that reducing GPR52 reduces the levels of huntingtin, indicating that GPR52 would be a good candidate to target with small molecules for huntingtin-lowering therapies.

Targeting GPR52 with small molecules lowers huntingtin and improves symptoms in HD lab models

The scientists describe the development of small molecules which stick on very tightly to GPR52 but not other proteins in our cells. These type of properties of a small molecule suggest that down the road this potential therapy could be very specific and avoid other unwanted effects. The best or lead molecule identified in this study, called Comp-43, was then used in a variety of different experiments to test how well it worked for huntingtin-lowering and reducing signs of HD-related damage and improving behaviour.

They first showed that Comp-43 could reduce huntingtin levels and preserve the health of mouse nerve cells in a dish. Following this exciting result, the scientists went on to test Comp-43 in HD mice. Critically, Comp-43 could cross the blood brain barrier in mouse models and lower huntingtin levels in some brain regions. This suggests that if Comp-43 was developed into a medicine in the future, people with HD might take it as a pill. Mice treated with Comp-43 had improved symptoms when tested on laboratory tasks that measure their movement and coordination, like a log-rolling exercise called the Rotarod or their ability to cross a balance beam. They also showed that mice treated with Comp-43 had more and healthier brain cells.

So, what’s next for GPR52 in HD research?

All of the data available in the literature to date indicates that GPR52 is a very promising drug target for huntingtin-lowering therapies but there are still many hurdles to cross before we are treating patients with GPR52 targeting molecules. Many therapies work well treating HD in cells in a lab dish or in different animal models of HD but don’t necessarily go the distance in safely treating people with HD.

It is not yet apparent what additional effects targeting GPR52 might have, beyond changing huntingtin levels and HD symptoms. GPR52 has important jobs to do in our nervous system and may play a role in dopamine signalling, chemical messages that affect mood, movement, and motivation. Sustained targeting on GPR52 by this type of huntingtin-lowering therapy might have side effects which we just haven’t yet observed in the shorter treatment experiments completed to date.

It should also be noted that targeting GPR52 lowers the levels of both normal and expanded huntingtin. We know that targeting both forms of the protein with other therapies such as Roche’s tominersen, which is also non-selective, is safe in the trials completed to date, but targeting expanded huntingtin while preserving normal huntingtin is still the goal for many researchers.

Nonetheless, small molecule targeting of GPR52 represents an exciting new way to lower huntingtin levels and we expect to see answers to many of these outstanding questions in future studies.

From: HDBuzz (English)

Posted on Fri, 8 Jan 2021 06:54:17 +0000

Updates from the EHDN Plenary Meeting 2020

In September, the European Huntington’s Disease Network (EHDN) hosted a virtual webinar event which comprised presentations on some of the latest scientific research as well as clinical studies of Huntington’s disease (HD). Researchers, doctors, patients and other interested folks, tuned in for an afternoon of talks as well as question and answer sessions to learn and discuss some of the recent developments in Huntington’s disease research.

The Science Sessions

Lesley Jones (University of Cardiff, UK) chaired the first session which covered some of the latest research from labs around the world working on Huntington’s disease.

Frederic Saudou (INSERM, France) kicked things off with a talk about the function of the huntingtin protein. This is the protein encoded by the huntingtin gene which is mutated in patients with HD. This protein is one of the largest made in our bodies and it sticks to lots of other different proteins in the cell which makes it tricky for scientists to study. The Saudou lab is interested in the role of the huntingtin protein in moving capsules called vesicles in nerve cells, a process which is critical for brain function. Using “brain on a chip” technology, they can look at how vesicle movement changes in patients with HD as well how brain cells connect and work together in their HD models.

Next, Darren Monckton (University of Glasgow, UK) presented an update on his group’s research on somatic expansion. As HDBuzz recently wrote, somatic expansion is associated with the severity of HD and the increase of the CAG repeat length in the huntingtin gene in certain cells and tissue types can lead to earlier onset of symptoms. Recently, scientists have found that certain small changes in the code of DNA repair genes can affect the amount of somatic expansion that occurs. This makes sense of the genome-wide association study data which shows that these small variations in sequence of DNA repair genes can cause symptom onset to start earlier or later for patients. Understanding the precise mechanism and which genes are involved could open up lots of opportunities to develop new therapies for HD.

Hilal Lashuel (EPFL, Switzerland) next presented his lab’s recent findings which implicate a gene called TBK1 in HD. TBK1 is able to mark the huntingtin protein with a special label called phosphorylation. When the huntingtin protein is marked by TBK1, nerve cells survive much better in laboratory models of HD and this effect is reversed if the activity of TBK1 is blocked. If we could activate TBK1 in HD patients, this could be a new way to treat HD.

The final talk of the science session was from George McAllister (CHDI Foundation, USA) who spoke about promising new oral therapies for huntingtin lowering. Although not yet in the clinic, there are a number of companies, including Novartis and PTC, who are developing huntingtin lowering drugs which could be taken as a pill. This would mean avoiding the intrathecal (spinal tap) or intracranial (injection into the brain) methods of delivering the medicine which is what many of the huntingtin lowering therapies currently in clinical trials use. Researchers hope that this would make it easier for patients to take the medicine. Having an oral therapy would also mean that the whole body could be treated, not just the brain, which would have the bonus effect of making it easier to measure how well the drug is working by measuring in blood for example. The effects of the medicine would also be reversible if treatment was halted. However, there are lots of potential issues which scientists need to carefully consider such as whether targeting the whole body is appropriate or is there would be off target effects. Preclinical and clinical studies will hopefully provide answers and we look forward to reporting on these exciting new therapeutics in the coming year or so.

Clinical Study and Trial Updates

The next session of the day was chaired by Jean-Marc Burgunder (University of Bern, Switzerland) and focussed more of the clinical studies currently underway to find new treatments for HD.

This session started with a talk from Sarah Tabrizi (UCL, UK) which presented insights from the open label extension of Tominersen, the huntingtin lowering therapy developed by Roche. This extension study looks at the long-term safety of the treatment in a small group of premanifest HD patients over the course of 15 months. One of the key findings of the study was that waiting longer periods of time between doses of Tominersen still lowered huntingtin sufficiently, and that the more spaced out treatment regimen also resulted in fewer negative side effects for the treated patients. This 8-week treatment regimen will now be used in the GENERATION HD1 trial which will evaluate whether Tominersen treatment improves outcomes for HD patients. We know that this drug lowers huntingtin levels when we measure a treated patient's spinal fluid, which clinicians use as a proxy for measuring huntingtin in the brain. Now the scientists need to work out if the huntingtin lowering is sufficient to improve patient symptoms. The trial is now fully enrolled and we are grateful to the 791 HD patients from around the world who signed up for this critical clinical trial. Despite the COVID-19 pandemic, Roche states that it is working hard to mitigate any effects to the ongoing trials whilst keeping patients, clinicians and HD families safe.

Next, Anna Heinzmann (ICM Institut du Cerveau, France) presented an update on the PRECISION-HD study, another huntingtin lowering therapy developed by Wave. Wave’s therapy specifically targets the mutated form of the huntingtin gene which could be a preferred approach as it leaves the unmutated huntingtin levels intact. However, this treatment is only available to patients that have a specific barcode in their DNA as this is how the drug targets the mutated version of HTT so not every patient is eligible. So far, the scientists at Wave have shown that their therapy is safe in patients but will follow up with more findings in the first quarter of 2021 which we hope will indicate how well their drug is working to lower the mutated from of HTT.

The following presentation gave an overview of the SHIELD HD natural history study, which is being run by Triplet Therapeutics. Anne Rosser (University of Cardiff, UK) explained how this study will lay the groundwork for future clinical trials which aim to target DNA damage repair pathways. Triplet have shown in the HD mouse models that reducing the levels of certain DNA damage repair proteins can halt the process of somatic expansion. By targeting somatic expansion in this way, Triplet hopes to treat the underlying pathology of HD. They are running this natural history study in order to inform the design of a future clinical trial and to work out what measures they might need to take of patients to find out if their therapy is working. The HD patients enrolled in this study will be assessed by a variety of methods over the course of 2 years by clinicians and both the data and samples (such as blood) taken from the patients, will be critical for scientists to better design the future clinical trials.

Bernhard Landwehrmeyer (Ulm University, Germany) gave the next talk about PROOF-HD which will assess the potential for treating HD patients with the drug Pridopidine. Scientists have recently made headway in understand how Pridopidine might be working and think its acts through a type of nerve cell receptor called the sigma 1 receptor. Activating this receptor, as Pridopidine is believed to do, is thought to have a variety of downstream effects which are hoped to improve HD patient outcomes. Although earlier trials for Pridopidine had disappointing results, this new trial hopes that by looking at treating early manifest patients for much longer they may see better outcomes for patients.

Ralf Reilmann (George Huntington Instititut, Germany) presented an update on the Uniqure AAV gene therapy which also aims to lower huntingtin. Uniqure’s AMT-130 therapy is delivered in a one-shot brain surgery and this virus-based approach irreversibly alters the patient’s DNA resulting in reduced HTT levels. Scientists have been able to show that this treatment is both safe and effective at lowering HTT in both small and large animal models of HD such as rats, pigs and monkeys. The current AMT-130-01 study will look at how this translates into humans and whether the drug is still safe in the small number of patients who will receive it. 26 patients will receive the therapy by brain surgery and will be monitored at specialist HD clinics around the world. Enrollment is ongoing in the US for the study.

Anne-Catherine Bachoud-Levi (INSERM, France) gave a talk about the MIG-HD clinical trial. This trial investigated the use of stem cells in treating HD in a long clinical study spanning more than a decade. Although the treatment tested in this specific trial was not successful in treating HD, the scientists learnt a lot about best practises for this type of stem cell transplantation treatment. Since the trial, there have been huge breakthroughs in our understanding of stem cells. Bachoud-Levi and team are hopeful that new stem cell-based therapies may help HD patients in the future.

The final talk of the day was from Hugh Rickards (University of Birmingham, UK) who discussed the Huntington’s equal access to effective drugs (HEATED) project. As there are an increasing number of very exciting drugs in clinical trials, many people in the HD research community expect there to be a few which might be approved for use in HD patients. However, it is likely that these might be very expensive meaning that not all HD patients would be able to access them immediately. Rickards is working to understand the challenges of HD drug affordability and accessibility to ensure as many patients as possible are able to access therapies when they become available.

Rewatch online

You can watch all of the talks on the EHDN website. To find out more about the current HD clinical trials, visit HD Trial Finder.

From: HDBuzz (English)