CRISPR-based drugs: one giant leap for mankind

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.

Making babies: having a family, the HD way

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:

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.

Steady progress from uniQure – promising data to end the year

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.

Putting it in print: GENERATION HD1 study results published

The outcomes of the GENERATION HD1 trial have just been published in a scientific journal, nearly three years after the study was halted. In March of 2021, the HD community was hit with the difficult news that the GENERATION HD1 study of Roche’s huntingtin-lowering drug, tominersen, faced a halt in dosing. Since then, the data has been analysed, the findings have been shared, and based on what was learned, a new study continues to recruit globally, called GENERATION HD2.

Today marked another milestone in the history of tominersen’s development: the results of GENERATION HD1 were published in a widely-read scientific journal. The conclusions remain the same, but peer review and print documentation are immensely important for the progress of science. In this article we’ll recap the key messages, explore the impact of published research, and talk about what’s next.

What was GENERATION HD1?

Tominersen is a drug being tested in people to see whether it can help slow or stop symptoms from worsening in adults with HD. It is a type of genetic therapy, known as an antisense oligonucleotide – ASO for short – that is delivered with spinal injections. From an earlier trial we knew that it could lower huntingtin, the protein thought to be harmful to the brain in HD. GENERATION HD1 was a longer, larger Phase 3 study, in which people received a high dose of tominersen every 8 weeks or every 16 weeks.

Unfortunately, the trial had to be halted, in March 2021, when an independent safety monitoring committee found that the safety risks outweighed any potential benefits. In fact, those who got tominersen every 8 weeks seemed to have worse symptoms than those who got no drug at all, by some measurements. Since then, Roche analysed the data and presented it to scientists, doctors, and the community as new information was unearthed.

The most important finding came from an after-the-fact investigation known as a “post hoc” analysis. It seemed that people who began the trial at a younger age, with less severe symptoms, may have benefitted from tominersen. For this reason, a new trial of tominersen was designed, called GENERATION HD2. This trial began in 2023, and is testing tominersen in a younger population with earlier HD symptoms.

Today’s news: a published study

If you’re thinking “all this is old news,” well, you’re not wrong! The latest breaking research is presented at conferences, like the annual CHDI HD Therapeutics conference that HDBuzz tweets and summarises. This allows scientists to get critical research out to the world as soon as possible. All previous updates about GENERATION HD1 thus far have come from scientific conferences. Published research takes a bit longer; after it’s written up, it goes through a process of “peer review” where the data and findings are scrutinised by an outside group of experts.

Peer review keeps science unbiased, fair, and balanced. However, it also causes a bit of a delay, which is why published results from GENERATION HD1 are just coming out now. A new publication in the New England Journal of Medicine details all of the findings from GENERATION HD1. The main message remains the same: GENERATION HD1 did not reach its primary endpoints, tominersen wasn’t safe or effective at a high, frequent dose, but there might be some promise at a lower dose, in folks at earlier stages of HD.

What’s in the new paper?

The main body of the paper presents these key findings, and a massive appendix gets into the nitty gritty on the methods and the statistics. Some new, formal speculations are made about the connection between measurements of different substances in the blood, and changes observed in symptoms. However, the early halt and the variability of the data make it difficult to draw definite conclusions.

The study authors think that tominersen itself may not have caused direct damage or “shrunk” brain tissue. Instead, they theorise that these side effects could have instead been due to the high dose, which caused some inflammation. People with earlier signs of HD may have had more resilient cells, which is why some may have got some benefit from the huntingtin lowering effects of the drug.

Why is scientific publication a milestone?

Roche chose to make their findings public and accessible to the research community and HD families during the course of the long period of data analysis that led to this paper. And we’re not intending to reopen old wounds by bringing up the disappointment surrounding this trial.

Publication of clinical study results in a medical journal is a big deal. It means that other scientists and doctors, outside of Roche and those who ran the study, were tasked with rigorously looking through the data, evaluating the approach, and recommending ways to improve how it was presented.

This process of “peer review” is key in science: it can lead to new, better experiments, clearer explanations, and more minds thinking about a difficult problem. When a clinical study of Huntington’s disease appears in a well-known journal like this one, the science and the community gets more visibility from scientists and doctors and news outlets.

What’s next for tominersen

Ultimately, the best way to determine whether tominersen has potential as an HD treatment is to test the theory put forth in this publication. GENERATION HD2 does just that – the study is testing tominersen at a lower dose in people who are most likely to benefit from it. It’s a smaller, “dose-finding” study designed to determine what amount of drug is safest.

There are a few other differences between GENERATION HD1 and HD2.

  • Loading dose: In GENERATION HD1, participants were given a dose of tominersen initially before the first dose to boost levels of the drug in their bodies. GENERATION HD2 doesn’t include this “loading dose.”

  • Amount of drug: GENERATION HD2 is testing a lower dose of tominersen. While GENERATION HD1 tested 120mg, GENERATION HD2 includes a high dose of 100mg and a low dose of 60mg.

  • Frequency: Tominersen is given less frequently in GENERATION HD2. While GENERATION HD1 tested tominersen given every 8 and 16 weeks, participants in GENERATION HD2 receive tominersen every 16 weeks.

The trial, open since early 2023, continues to recruit people with early HD symptoms, ages 25-50, at study sites all over the world.

Steady strides towards HD therapies made possible because of community participation

Importantly, the publication of this manuscript is also a chance to reflect upon and recognise the contributions of the nearly 800 participants, supported by their friends and family, who selflessly enrolled in the GENERATION HD1 trial. Clinical trials are extremely complicated experiments without guaranteed outcomes, and the brave contributions of all the trial participants have substantially moved HD research forward.

Many critical advancements in HD research have only been possible thanks to the steadfast contribution of HD community members. The gene that causes HD was discovered through the participation of HD families from Venezuela – 18,000 people that spanned 10 generations! The genetic modifiers that contribute to differences in age of onset were discovered thanks to the 4,000 people with HD in the Gem-HD Consortium study. Now, advancements in the age of clinical trials are being made thanks to selfless study participants. It’s encouraging that the results of the GENERATION HD1 study have been added to the growing scientific literature.

Regulating repetition: Gaining control of CAG repeats could slow progression of Huntington’s disease

“Somatic expansion” is a hot topic in Huntington’s disease research. Somatic expansion is a process in which CAG repeats lengthen in some cells during aging. It’s thought to control how early HD symptoms appear. A group of researchers from Toronto, Canada recently identified proteins that may play an important role in regulating this process. Understanding how these proteins regulate somatic expansion in Huntington’s disease may hold the key for unlocking therapeutics for CAG repeat diseases.

Repetition is (the) key

Huntington’s disease (HD) is referred to as a “CAG repeat expansion disease” – it’s caused by an increase in the number of CAG repeats in the huntingtin gene. Everyone has the huntingtin gene – in fact, everyone even has a repetitive CAG sequence within their huntingtin gene. It’s just that people who will go on to develop HD have more CAGs within the huntingtin gene compared to people without HD.

But HD isn’t the only disease caused by CAG repeats. There are over 70 different diseases associated with nerve cell breakdown that are caused by repetitive DNA tracts! In a way, this is good, because we can look to the research in these other diseases and find similarities to learn more about HD.

One thing in common with many of these diseases caused by repetitive DNA tracts is something called “somatic instability”, also called “somatic expansion”. This is a biological phenomenon where a repetitive DNA track gets bigger in some cells as the person ages. This ongoing expansion of the disease-causing CAG tract in HD is thought to contribute to accelerated disease progression. HDBuzz recently wrote about somatic expansion, which you can read about here.

For HD, somatic expansion of the CAG repeat tract in the huntingtin gene preferentially happens in brain cells. Specifically in brain cells that are vulnerable to dying as someone with HD ages. Emerging scientific research seems to suggest that if we can get a handle on the perpetual expansion of CAGs in the huntingtin gene, we may be able to keep brain cells healthy and delay when symptoms appear. In a perfect world, even pushing that into the realm of never. But to do that, we first have to understand the intricate biological details behind somatic expansion in HD.

How exactly do CAGs get added?

DNA is made up of 2 complementary strands of genetic material, creating a double helix. This may conjure up images of a gently turning, intertwined ribbon from 8th grade biology. Each strand contains letters of the genetic code – C, A, G, or T – that interlock with the genetic code on the complementary strand like Lego pieces.

When cells need to make a protein coded by a certain gene, the DNA strands are unwound, and the Lego pieces are unlocked. After the protein is made, the DNA strands snap back together, with complementary strands finding their original alphabetic partners.

However, when the DNA contains a repetitive sequence, like a long strand of CAGs repeated over and over, it can be difficult to discern exactly which Lego piece went where. This can cause some of the genetic code to misalign and match with the complementary strand ahead of where it should. This creates a loop-out structure – one strand is nice and straight, and the other has a looped-out piece of DNA with no mate. This is a big no-no in cell biology…

There’s a reason your mind conjures the smooth-sided, intertwined ribbon when “double helix” is mentioned. DNA strands always bind to their complementary mate. DNA is never single stranded. When it is, proteins immediately intervene, chopping out or adding DNA to the looped-out structure that threatens the elegant, softly twisted natural form of DNA.

Often, to ensure that DNA strands once again perfectly match with their alphabetic mates, additional letters are added – like adding additional Legos to make sure each aligns with the matching pieces on the other side. This ensures that both DNA strands have matching mates on each side. For the huntingtin gene, this can mean that additional CAG repeats are added, and the CAG repeat expansion gets longer. The result is often earlier onset of HD symptoms. Understanding how the cell decides whether to chop or add DNA letters to a loop out structure could be the key to understanding somatic expansion, and to controlling it.

Cellular editing decisions defined

Researchers at the Hospital for Sick Children (SickKids) in Toronto, Canada recently identified proteins that play a key role in the cellular decision process of chopping or adding DNA to loop outs. This work, spearheaded by Dr. Terence Gall-Duncan and led by Dr. Christopher Pearson, was recently published in the prestigious scientific journal Cell. The work from the team at SickKids adds to our understanding of somatic instability in HD while identifying proteins that could be targeted for therapeutic gain.

The team broke down the science behind a protein called RPA – replication protein A. The job of RPA in the cell is to bind to DNA when the helix is unwound and it’s single stranded. There’s a different version of RPA that is unique to humans and monkeys, creating an alternative version of RPA called Alt-RPA. Both versions, RPA and Alt-RPA, bind to DNA loop-outs, like the ones that are created when CAGs in the huntingtin gene can’t find their mate when DNA strands are separated.

The experiments in this new paper show that when cells have more Alt-RPA, CAG expansions get bigger. But when the standard version of RPA is present, fewer CAG expansions are added. So it seems that Alt-RPA controls the cellular decision to add DNA to loop-outs while RPA decides to chop!

Something else interesting about this finding is that Alt-RPA is only found in monkeys and humans, with very strong levels found in humans – the only species to have HD. This may be a start to understanding why HD specifically and only affects humans.

The team did a large-scale interaction study to identify other proteins with which RPA and Alt-RPA were interacting. They found that Alt-RPA specifically interacted with proteins that regulate CAG repeat instability! One of the most striking proteins identified that specifically interacts with Alt-RPA was MSH3.

MSH3 is a major regulator of age of symptom onset in HD and was originally identified from samples given by thousands of HD families for a study called Gem-HD. Having lots of samples from HD families, from studies like GeM-HD and Enroll-HD, has rapidly advanced the identification genes that modify age of symptom onset, like MSH3. This new work from the group at SickKids may be the link for understanding how MSH3 helps to control somatic expansion in the huntingtin gene.

The team tested the effect of changing levels of RPA in mice that model a disease similar to HD – spinocerebellar ataxia (SCA1), which is also caused by a CAG repeat. When they increased levels of the standard version of RPA, the SCA1 mice’s symptoms improved, including the instability of its CAG repeats.

What does this all mean for HD?

There are several companies currently working on drugs as a treatment option for HD that target MSH3 as a modifier associated with somatic instability. Voyager Therapeutics is working to develop a harmless virus that targets MSH3 that can be injected into the blood to reach the brain. LoQus23 Therapeutics is working to target MSH3 using small molecules that could be taken as a pill. Pfizer has also jumped on the MSH3 bandwagon and is testing drugs to move toward clinical trials.

These new results from the team at SickKids don’t mean that we’re ready to add RPA or Alt-RPA to the drug lineup just yet though. This work still needs to be tested in mice that model HD to see if changing these proteins can improve behavior and molecular effects associated with HD. However, they do get the research world closer to understanding the precise mechanism that controls somatic instability. Knowing exactly how the cell makes the decision to add or chop DNA when a loop out structure is formed opens the door for designing more drugs to test in trials, not just those that target MSH3.