DAY 3: CHDI Therapeutics Conference

The 15th Annual Huntington’s Disease (HD) Therapeutics Conference was taking place in Palm Springs  from February 24 to 27. Here is a summary of the third day, put together by tweets from HDBuzz

By HDBuzz and Phylis Kitema | Photo: HDBuzz

Session: Huntingtin lowering

The topic on the third day was Huntingtin lowering – one of the major avenues to Huntington’s disease treatment. If you want some background information on the topic, HDBuzz has covered the general idea of Huntingtin lowering (previously known as ‘gene silencing’).

Ignacio Munoz-Sanjuan| CHDI 

Ignacio Munoz-Sanjuan from CHDI, discussed the timing of Huntingtin (HTT) lowering strategies. Munoz-Sanjuan is also very actively involved in patient outreach in Latin America. Munoz-Sanjuan started a non-profit organisation centered around his efforts in patient outreach called Factor H.

The brain is a really complex organ and it is important to remember that while mouse models are useful for investigating some aspects of Huntington’s disease (HD) progression, a mouse brain is not the same as a human brain. Using lots of different models of HD is key for studying how well drugs might work.

However, mice are critical for advancing HD research. Since timing of treatment is a hot topic, researchers have been following what happens to reversal of cellular effects in mice. They’ve found that while they can’t be reversed, other metrics also need to be tracked

One key questions in HTT lowering is timing – when should we be treating to stop the disease? Can we reverse any damage that has been done or can we treat at later disease stages? Researchers don’t want to give unnecessary medicines to patients if they don’t have to.

Very excitingly, researchers are finding that Huntingtin lowering in mice can prevent and reverse deficits in striatal neurons – the most affected cell type in the brain of HD patients  – which is very promising news!

CHDI Foundation

CHDI has spent a long time developing a Huntingtin PET ligand – a small molecule which specifically binds to the expanded Huntingtin protein molecule when it forms into certain clump structures. The molecule is able to cross into the brain so could be used to help track Huntingtin lowering. 

Already, CHDI and team are measuring the lowering of these Huntingtin clumps in different Huntington’s disease mouse models. They are trying Huntingtin lowering in different areas of the mouse brain and also treating mice which are different ages.

Another question scientist’s are trying answer is by how much should we lower Huntingtin protein in cells? What level might help treat patients? What levels are safe? 

We can use the Huntingtin PET ligand and other experiments to measure the lowering levels after treatment and can then see which mouse models recover at which levels of lowering. This might help translate discoveries from mice to humans.

CHDI is coordinating efforts from a huge team of scientists on this work to move things forward quickly!

Mark Bevan|Northwestern University

Mark Bevan from Northwestern University, discussed his work on lower Huntingtin in a specific brain region. The research Bevan shared focussed on how Huntingtin lowering in certain brain areas might change the way the brain works and how this could affect symptoms in patients.

Like many others, Bevan is interested in cell type-specific differences caused by Huntington’s disease. His group is finding that specific subtypes of neurons are less active, while others seem to be unaffected in Huntington’s disease mice.

By looking in Huntington’s disease models of mice, Bevan has found that there are differences in the way neurons talk to one another and is using his experiments looking at neuron-to-neuron communication to study the effect of Huntingtin lowering in these mice. By lowering Huntingtin protein in HD mice, Bevan is seeing that motor deficits are improved – the mice are able to move longer distances at a faster speed. Great news since current human clinical trials haven’t yet disclosed data regarding changes they might be seeing in symptoms.

Bevan and colleagues are continuing to look at Huntingtin lowering on other motor deficits and so forth in their mouse models. They hope their findings might inform how Huntingtin lowering therapies could be translated to the clinic.

Marcy MacDonald | Massachusetts General Hospital

Marcy MacDonald from Massachusetts General Hospital, talk was titled “the outer limits”. From the Enroll-HD study, researchers are finding there is lots of variability contributed by factors other than CAG length. While this has been a big finding in the Huntington’s disease field, it really indicates how complex this disease is even though we know the genetic cause.

While everyone has the Huntingtin gene and HD patients have a longer CAG than others, we also have other small variations in the Huntingtin gene sequence that researchers like MacDonald are interested in studying and targeting therapeutically. These are all points that companies running Huntingtin lowering trials are considering in their trial design. 

Because Huntingtin expression levels vary within the population, researchers also need to be aware that the starting levels of Huntingtin for patients in Huntingtin lowering trials may differ. So one could imagine in the future a more personalized approach may be adopted for each patient. MacDonald’s team has generated stacks of data on what can modify disease progression in HD. They are sharing all their data so that scientists all over the world can work together on it. 

Charlotte Sumner | Johns Hopkins

Charlotte Sumner from Johns Hopkins discussed the challenges associated with targeting genes therapeutically. Sumner primarily focuses on a different neurodegenerative disease called spinal muscular atrophy (SMA), there’s currently an ASO treatment for SMA so the Huntington’s disease field can learn a lot from watching what they’re doing.

Similarly to HD, we know the precise genetic causes for SMA. However, our understanding of what’s happening with the protein molecules in the cell is much hazier, so the drivers of disease are not completely clear. Because the genetics are clear, there are a number of different gene therapies which have been developed for SMA. In addition to an approved ASO therapy, there are small molecules which lower the target gene currently under review at the FDA.

A single dose or “one-shot” gene replacement therapy which fixes the DNA sequence directly has also been shown to work well in young children with SMA and work is ongoing to see if this treatment would work well for older patients.

Some patients in the SMA trials improved dramatically across various metrics that were measured. These findings are very encouraging for the field of HD research, where we hope to apply some of the successful strategies they’ve found in the field of SMA. Again, similarly to HD, SMA researchers are interested in neurofilament (NF) as a biomarker for disease progression. They are monitoring NF levels in patients who are treated with the different SMA therapies and NF levels seem to drop over time with treatment. 

Earlier in the conference we heard that researchers were interested in determining when is the best time to treat Huntington’s disease. In the field of SMA they’ve found that timing really matters, so it’s great to see that HD research is on the right track.

Anastasia Khvorova | University of Massachusetts Medical School

Anastasia Khvorova from the University of Massachusetts Medical School, talkedabout Huntingtin lowering using a technique called RNAi. RNAi-based therapeutics target the message of Huntingtin rather than the DNA or the protein, acting to destroy the middle step so that protein is never produced.

Read more: RNAi and how it differs from ASOs.

To test how the Huntingtin-targeting RNAi affects disease, Khvorova and her team first analyzed the effects in mice. The first step was to measure how widely their treatment spread in the brain. After treatment, they found Huntingtin was significantly reduced in many areas of the brain. This work targeted both expanded and unexpanded Huntingtin, but they’re also working on approaches that will just target expanded Huntingtin.

Making some clever tweaks to the  RNAi molecules, Khvorova and team were able to make their treatment selective for just the expanded Huntingtin message so that only this protein is lowered, not the unexpanded. However, it should be noted that this will only work in ~35 % patients who have a slight difference in their huntingtin gene sequence called a SNP. This allows the RNAi treatment to select for the expanded over the unexpanded Huntingtin.

Next they wanted to see how their RNAi treatment worked in larger animal models, so they moved from mice to sheep. Using sheep they tested various delivery methods for the treatment finding they could inject into the brain or CSF and it works the same.

After sheep, Khvorova and colleagues moved into monkeys and again saw that the RNAi treatment spread fairly nicely across the brain and through the spinal cord. It stays in these regions for quite a long time so they don’t expect to have to treat very frequently. In a very early safety study in these monkeys, the therapy seems safe at the dose tested. Similarly, early data from a sheep safety study showed the therapy was safe under the conditions that the scientists tested.

The exciting news is that Huntingtin is significantly lowered in these early studies in monkeys. The levels of other genes seem to be unchanged which means the off-target or side effects appear to be low in the way the scientists measured in their experiment. Nonetheless, looking for even small changes in other genes is really important so work is ongoing by Khvorova and colleagues to make sure that there are no differences and confirm the safety of this therapy.

This technology is thought to be very promising by Khovrova and colleagues, as well as the CHDI. It could be used to change the levels of other proteins in the brain such as those identified as modifiers for symptom onset in HD patients or other targets.

One of the things they’re paying attention to is cost. They’re trying to keep the cost down so it can be widely available to all HD patients. We’re really looking forward to more updates about this promising research as they move toward clinical trials! 


Astrid Valles-Sanchez from uniQure spoke about uniQure’s approach to lower Huntingtin (HTT). UniQure has a treatment called AMT-130 to lower HTT and is currently performing a clinical trial to determine the safety of this treatment. AMT-130 is designed to be a one-time injection of HTT lowering treatment into the brain. Valles-Sanchez focused on biomarkers they’re assessing to measure how effective this treatment will be to modify HD disease progression. 

Read more: Huntington’s disease goes viral as UniQure inches ahead in gene therapy race

When they look in a pig model, they find that their treatment is detected in the CSF out to 2 years. In monkeys, they detected their treatment out to 6 months, when the animals were sacrificed. Similarly to other studies, uniQure want to check that their therapy is spreading out across the brain to see where it might be working. n the pig model 12 months after treatment, they analyzed tissue from different areas across the brain to see how effectively their treatment lowered HTT. They find significant lowering of expanded HTT with the strongest lowering in brain regions most affected by HD. 

uniQure also looked at expanded HTT levels in the CSF after treating HD pig models with AMT-130, but in this particular experiment, the levels in the CSF do not correlate to levels of HTT found in the brain.Scientists at uniQure are interested in using magnetic resonance spectroscopy (MRS), a non-invasive way to look at the brain, to see whether there are any changes in chemicals called metabolites that are found in different areas of the brain after treatment. 

Roche Pharmaceuticals

Scott Schobel from Roche, shared very preliminary new results from the Roche trial. These results come from a 15 month open label extension in manifest (symptomatic) HD patients, we should cautious in interpreting this data as it’s still very early days.

Read the results here.

RG6042 now has a new name! Its called tominersen which is what the therapy will be called moving forward.

Patients in the original safety study were kept on an open label extension which means that after the safety trial ended, they continued to receive the therapy and the data we will see today is what scientists have found since the end of the safety stud

From the safety study, it looked as though Huntingtin (HTT) protein levels could be reduced with tominersen in a dose-dependent manner. This means that the protein was lowered more in patients who received more of the treatment in the small number of patients tested.

Because they found the less frequent dosing was effective in lowering HTT, they modified the strategy for the next arm of the study (Phase III) to reduce the number of doses and test dosing every 16 weeks – much less demanding for patients! Next they looked at how much of the drug they should give per dose. They found that NFL levels have an initial rise, but amounts seem to decrease and even out by the 15-month mark.

The open label extension tested 2 dosing strategies – participants either were dosed either every month or every other month. This type of design is critical for determining how often patients would need to take tominersen.