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Posted on Wed, 21 Jul 2021 00:17:38 +0000

A first for CRISPR gene editing could have wider applications for human disease

A recent clinical trial successfully tested the safety of CRISPR gene editing to reduce the amount of a toxic protein in patients with Familial Transthyretic (TTR) Amyloidosis. Although this study is unrelated to Huntington’s disease, it’s a first for gene editing, and the results could have implications for HD and other brain disorders.


Clustered Regularly Interspaced Palindromic Repeats (CRISPR), is not only a mouthful, but also the name of a gene editing system that has taken the scientific world by storm since it was discovered in 2014. Such has been the importance of the finding that the two researchers who discovered it, Jennifer Doudner and Emanuelle Charpentier, were both awarded the Nobel prize in 2020 - the first time two women have shared the prestigious prize. The CRISPR-Cas9 system targets double stranded DNA by acting like a GPS system and a microscopic scissor. A piece of RNA acts as a guide to target the DNA that needs to be cut. The Cas9 protein then unwinds the double stranded DNA and cleaves both strands. This allows researchers to then insert new genetic information and utilize the cell's natural DNA repair mechanisms to smooth things over.

To deliver the necessary components of the CRISPR-Cas9 system to the relevant organ, researchers use a technology called Lipid Nano Particles. Lipids are simply fatty molecules, and nano particles simply very small spheres (100,000 times smaller than a human hair!). These microscopic balls of fat are able to carry and deliver a wide range of therapeutics, including the CRISPR-Cas9 system, to various parts of our bodies. For example, this delivery method has been successfully used to deliver the COVID mRNA-based vaccines.

Familial Transthyretin Amyloidosis

Familial Transthyretin Amyloidosis is a rare genetic disease, caused by a mutation, or a change, in the TTR gene. This mutation results in build-up of amyloid protein in many organs, with the symptoms varying depending upon which organs are affected. As one example, if the brain cells in the nervous system are affected, patients can experience symptoms like a loss of feeling in the limbs.

The liver is a commonly affected organ. The build-up of amyloid proteins results in loss of the liver’s ability to regulate levels of key amino acids and nutrients in the blood, eventually leaving a liver transplant as nearly the only treatment option. A short interfering RNA (siRNA) therapeutic (Patisiran) shows clinical efficacy for treating this condition, but unfortunately, Patisiran requires multiple doses a year and costs more than $100,000 per treatment. Gene editing has the potential to be a one-time cure for Familial Transthyretin Amyloidosis.

The results

The results of an early clinical study in patients with TTR amyloidosis, supported by Intellia Therapeutics and Regeneron Pharmaceuticals, provided evidence of successful gene editing inside the human body for the first time using the CRISPR system. Previously, gene editing success has come from taking the blood of patients who have a genetic blood disorder, and editing the cells outside of the patient, before reintroducing the blood back to the patient. In the TTR amyloidosis study, gene editing took place inside the body, in the liver - something that has not previously been possible.

As this is a Phase I study, its focus was whether the CRISPR system could be used safely in this way, rather than how well it edited the TTR gene. Nonetheless, these results indicate successful knockout of TTR, resulting in a decrease in the harmful TTR protein in blood. Toxicity wise the results were similarly promising, with patients reporting some mild side effects, but no severe ones. As the study sample size was quite limited, further studies will be needed to confirm the results, and identify rarer potential dangers.

Potential roadblocks for CRISPR in brain diseases

This Phase I study effectively shows that both delivering CRISPR-Cas9 machinery and achieving high levels of editing in humans is possible. In theory, altering the CRISPR machinery to target genetic diseases like HD should be achievable. However, targeting the liver, as the researchers did in this study, is known to be relatively straightforward, while the brain is widely regarded as one of the most difficult organs to target. This is because the liver is responsible for filtering many toxins, metabolites, and other substances from our blood, so it is feasible to design a therapeutic that the liver can absorb. Conversely, the brain is protected by the blood brain barrier, a highly selective roadblock for substances seeking to enter the brain. Another difference is that for these types of diseases, you do not need editing of all liver cells to get a therapeutic benefit. However, for brain diseases, every neuron that we want to save requires editing.

Challenges remain for CRISPR in HD

Although this trial is unrelated to HD, we felt it was important to cover this story because these results are exciting and unprecedented. Furthermore, the World Health Organization has recently released ethical guidelines to ensure safe limits around gene editing, and HD was featured as an example in discussions among experts that led to these guidelines. Many researchers in the HD field and beyond are working on ways to achieve safe and effective gene editing, including targeted delivery to the brain.

That said, there remain many things we do not know about gene editing. This study was a phase 1 trial, designed primarily to test the toxicity of this CRISPR-Cas9 therapeutic, and its results in this sense are very promising, with most patients reporting only mild to moderate side effects. However, there remain some major questions unanswered by this study. Will a reduction in TTR protein lead to meaningful changes in a patient’s disease symptoms? Will editing the TTR gene with CRISPR cause unintended edits in other genes, and if so, where and to what degree?

These results are encouraging, but a phase 1 trial puts safety first, and there will need to be several more phases before a therapeutic of this kind can come to market.

From: HDBuzz (English)

Posted on Sat, 12 Jun 2021 01:04:20 +0000

Scientists identify precisely how pridopidine works in models of Huntington’s disease

Pridopidine is a drug developed to treat Huntington’s disease (HD) and now scientists have a clearer understanding of how it works in the body and brain. In a series of academic papers, researchers figured out that pridopidine is working by targeting a particular receptor protein called S1R. With this new understanding, the researchers believe pridopidine could be an effective medicine to help treat neurodegenerative diseases such as HD.

Pridopidine sounds familiar?

The drug pridopidine has been investigated by researchers for a long time now to try and understand how it might be used to treat neurodegenerative diseases and specifically HD. During this time, it has been called a few different things including ACR16 and Huntexil but we’ll be sticking with its current name in this article, pridopidine.

Pridopidine was originally discovered as a medicine which might help treat the motor symptoms of HD and was thought to regulate a chemical called dopamine. Because dopamine is so important for the way our brains control movement and motivation, pridopidine was tested in a few different clinical trials to see whether it could improve motor function in people with HD. These studies included HART, MermaiHD and PRIDE-HD, and they all showed pridopidine was a safe drug to take. They also looked to see if pridopidine improved movement symptoms in hundreds of people with HD, but unfortunately no significant improvement was seen.

You may wonder why there is still interest in this drug if so far the clinical trials did not reach their key goals. Well, one of the reasons is that although pridopidine did not significantly improve motor function in people with HD, the PRIDE-HD study did indicate that a measure called Total Functional Capacity or TFC was better maintained in people with HD. TFC scores measure how well people can function at tasks like managing their households and finances, ability to work, drive, cook, and do other day-to-day activities. Similar promising TFC results were found in the open-label extensions of the HART and PRIDE trials where patients in the original trial continued to take pridopidine for a longer period of time.

There was some controversy amongst scientists when this was originally published as to whether this meant that pridopidine still held promise as a medicine which could slow the progression of HD symptoms, what is often referred to as a disease-modifying therapy.

Pinpointing the precise details of how pridopidine works

At the end of 2020, the company Prilenia began a large Phase III clinical trial called PROOF-HD to test pridopidine in a larger group of people with HD for much longer, to look for conclusive proof of improved TFC. This trial is still in the process of recruiting 480 patients and will run until mid-2023.

At the same time this series of trials has been unfolding, scientists have been busy in the lab working on pridopidine to try and better understand exactly how it might be working. These types of experiments hope to uncover the mechanism of action of pridopidine – a term used by scientists to describe the nitty gritty details of precisely how taking a medicine results in the change in symptoms we hope it provides to patients.

One thing that arose from these mechanism of action studies is that although pridopidine affects the brain chemical dopamine, it was actually having a much stronger effect on a totally different aspect of HD biology, through a chemical receiver called the sigma-1 receptor.

Early insights into these new ideas about how pridopidine works were presented last year at the Huntington Study Group meeting and EHDN conference but are now formally published in peer reviewed scientific journals. The authors of these articles hail from academic institutions around the globe as well as from Prilenia, and they argue that this new data supports the idea that treating people with HD with pridopidine should slow the course of HD.

What does pridopidine do when you take it as a medicine?

Pridopidine is shown in these new papers to target a specific protein called S1R or the sigma-1 receptor. Lots of the S1R protein is found in cells and tissues in the brain, particularly in regions important in HD. The S1R protein is important for lots of different processes which help nerve cells survive under different types of stress. Nerve and brain cells in people with HD are under a lot of different stresses caused by the mutant version of the huntingtin protein which is made because of the HD mutation. Pridopidine may alleviate some of those stresses by targeting the S1R protein, helping these nerve cells to survive.

In people with HD, we know that the energy powerhouses of the cell, the mitochondria, do not work properly, which creates stress for cells in the brain and body. In the first of this series of new academic publications, researchers investigated how pridopidine affected the way mitochondria work in different HD models. When mouse models of HD are treated with pridopidine, it was shown to target S1R which then helps mitochondria to work more normally again. The same effects were also seen in experiments treating HD patient nerve cells in a dish with pridopidine. Overall, this paper suggests that pridopidine restores normal function of mitochondria in different HD models by targeting S1R.

In the second paper, the researchers investigated whether pridopidine relieved another form of stress in nerve cells related to a part of our cellular machinery called the endoplasmic reticulum or ER. One of the ER’s main functions is to act like a factory and warehouse that can churn out proteins and fats and ship them all over the cell. In HD the ER is stressed and stops performing as it should because of the mutant huntingtin protein which slows down production. Pridopidine was shown in this study to improve ER stress in HD cells in a dish. However, if scientists eliminated S1R from the cells, the improvements seen from pridopidine treatment disappeared, suggesting that pridopidine works through S1R. The scientists went on to show that targeting S1R was critical for relieving ER stress in numerous different ways, suggesting that pridopidine was an effective way to relieve this type of nerve cell stress and restore normal nerve cell activity.

In the final paper, scientists reviewed data which shows that S1R is able to associate with cholesterol, a type of fat molecule. They suggest that when cells are treated with pridopidine targeting the S1R protein, this stops association of S1R and cholesterol. Like separating a couple of slacking employees, when S1R and cholesterol can’t associate as much, the ER’s machinery operates more smoothly. This could be responsible for the improvements seen in HD cells and mice given pridopidine.

What's next for pridopidine?

These recent papers are important in showing that pridopidine is making improvements to different indicators of stress in both cells and animal models of HD. What remains to be seen is whether these improvements observed in the lab can conclusively and convincingly be measured in patients in a clinical trial. This is obviously a much harder experiment to do, but hopefully the PROOF-HD study will give us some concrete answers.

From: HDBuzz (English)

Posted on Thu, 29 Apr 2021 00:57:26 +0000

Huntington's disease therapeutics conference 2021 - Day 3

We are back for the last day of the virtual 2021 CHDI Therapeutics conference. This article summarises our live Twitter updates on the exciting science being presented, which you can find with the hashtag #HDTC2021. The final session of the conference will provide the latest news on more Huntington’s disease clinical programs.

A new way to define the different stages of HD

The first talk of the day was from Sarah Tabrizi and Jeff Long who presented the HD Integrated Staging System (HD-ISS), which aims to redefine the different stages of HD to encompass all the complexities and variability of HD progression.

The new system is a result of lots of hard work by the HD Regulatory Science consortium, a global network of academics, industry scientists and experts in drug regulation. The HD-RSC exists to put in place a framework that lets good drugs for HD get tested and approved smoothly.

The main aim of HD-ISS is to enable clinical trials to include people before they develop movement problems from HD (motor diagnosis). These trials would aim to prevent or delay HD onset. Tabrizi pointed out that the HD-ISS framework is not a reinvention of clinical diagnostic or staging criteria - it is purely a research tool to allow selection and monitoring of patients for clinical trials - an important distinction.

Current trials use staging systems based on "landmarks" with cutoff values. The most obvious in HD is the concept of "motor diagnosis" which is what was used to diagnose HD even before we knew the genetic cause. But biologically, we now know HD is a continuum - it develops slowly, affects people very differently, and has a long period where people feel and look normal, but we can show with things like blood tests and scans that the mutation has had some effect on the brain.

For research purposes, Tabrizi proposes a new definition of HD. She conceptualises HD as 4 changes happening in a sequence: The disease (the lifelong effect of the gene); being able to detect the gene's effects (biomarkers); symptoms; and functional change (loss of ability to do stuff).

These changes are expressed as stages 0 to 3 and the transition from one stage to another is defined by agreed landmarks. Jeff Long explained that the cutoff values for each landmark were determined systematically from large datasets, for example, monitoring the volume of the caudate lobe of the brain as measured by MRI. Crunching the numbers lets Long plot trajectories showing how a person might be expected to move through the stages during their lifetime.

Tabrizi explained that this kind of modelling lets drug developers plan trials because terminology will be unified including the possibility of intervening before motor symptoms emerge. Importantly, HD-RSC sought input from non-scientist HD family members via the HD-COPE network.

Updates on the huntingtin-lowering trial HD-GeneTRX1 from uniQure

The next speaker was David Cooper who gave updates on the uniQure huntingtin-lowering gene therapy trial, testing the drug AMT-130 which we recently wrote about.

AMT-130 is the first gene therapy for HD. It is packaged inside a harmless virus and delivered to the brain via a one-time surgery. Once there it acts to inactivate the recipe for huntingtin protein. Cooper told us about how AMT-130 was tested in large and small animals and was shown to be safe and well distributed to important regions of the brain.

Next, Cooper introduced the Phase I/II study, called HD-GeneTRX1. It involves 26 people who will get one of two dose levels of AMT-130, or will undergo an imitation surgery. They will be followed closely for a year and more infrequently for up to 5 years. This is a safety study so the main objective is to make sure patients do not experience any dangerous side effects.

Participants are between 25-65 and have early HD symptoms. They also need to have a CAG repeat of 44 or more, and to meet other criteria regarding the size of certain brain areas so that the procedure can be performed safely. The criteria evolved a bit as they screened patients and learned from the first surgeries.

10 patients have now been treated by brain surgery which is performed in an MRI. This is cutting-edge science and has provided valuable lessons learned to the neuroscience community thanks to the selfless volunteers in this study. There are nine sites recruiting patients in the USA and uniQure will be starting a small study in Europe later this year, in which everyone will receive the drug (known as an open-label trial).

In the Q&A, Cooper was asked whether the Roche trial results changed uniQure’s plans for this trial. He explained that right now they are moving forward as planned, and that their surgical delivery method is different from that used by Roche.

Diving back into the data from the SIGNAL trial

The final speaker of the session was Maurice Zauderer from Vaccinex. Zauderer presented results from the recent SIGNAL trial which looked at whether the drug pepinemab helped HD symptoms. We previously wrote about this here.

In this study, around 250 people with early HD symptoms received pepinemab for over a year via a monthly IV injection, and they were monitored for safety and whether it could help with symptoms. The focus was on measuring and observing serious side effects, cognitive and movement symptoms. The drug was safe but they saw no overall improvement in patients in different cognitive tests which assess planning and memory.

When Zauderer and colleagues teased out the data, they do see some small benefits of treatment in a subset of patients who are showing early signs of symptoms but this was not the case in a patient subset not showing symptoms.

The SIGNAL trial did not meet its primary endpoint and these findings have arisen from a subsequent analysis of the trial data. Although this benefit in people with HD symptoms with early signs of disease is potentially good news, this would need further study.

Towards a more collaborative HD research community

The final speaker of the conference was Aled Edwards of the Structural Genomics Consortium, who spoke about how the HD scientific community and in particular industry researchers might better collaborate at the level of drug discovery, the process of identifying genes and pathways to target with therapeutics. Drug discovery often starts with a huge array of possibilities that get narrowed down over time as research reveals more about the biology of HD.

Edwards is a huge proponent of open science and data sharing, and he suggested that the perceived legal and financial barriers to doing this, even within the private sector, can be easily overcome and could benefit individuals with HD and many other diseases. The HD community is already so tightly collaborative that it could potentially set the bar for others by implementing some of these strategies. Excellent food for thought at the end of three packed days of sharing the latest in HD research amongst academics, clinicians, and members of industry.

Looking forward to HDTC 2022 already!

And that’s all folks! We hope this has been a helpful way for everyone to learn about all of the latest news in the pursuit of medicines to treat HD.

From: HDBuzz (English)