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Posted on Mon, 30 Aug 2021 02:08:00 +0000

Another tool in the box: Creation of a molecular “dimmer switch” advances gene editing

A team of scientists recently created an innovative genetic system where a drug taken by mouth could be used to control the action of a gene editor, like those used in CRISPR systems. This has useful applications for research studies in cells and animals, and perhaps most importantly, could lead to improvements in the safety and accuracy of future gene therapies in humans. The technology can be applied broadly for studying genes and diseases, and was developed by researchers with HD expertise, incorporating a drug that is relevant to HD. Though actual clinical trials are a long way off, the company that has recently licensed the technology has an existing interest in HD.

Improving the control of gene therapy

Although the methods for delivery of gene therapies have improved vastly in recent years, it hasn’t yet been possible to control the actions of those therapies once they reach their targets in the brain or other parts of the body. Ideally, when modifying human genetics, we’d want to be able to fine-tune things like the location of the genetic change, the amount of change that occurs at once, and the ability to stop the change in surrounding cells if it proves harmful – those last two have proved to be a particular challenge in gene editing, until now.

A recently developed genetic switch system, dubbed X<sup>on</sup>, addresses some of these challenges in a novel way. It was created by a team of scientists led by Beverly Davidson at the Children’s Hospital of Philadelphia, joined by researchers at the pharmaceutical company Novartis. The idea behind X<sup>on</sup> was to create a gene editing technology that could be precisely delivered and then controlled over time using a drug that acts like an on/off switch.

How does it work?

Imagine a red traffic light that is on all the time, and can only be disabled with a special tool. There’s no way to move forward until the red light turns off. With the X<sup>on</sup> system, scientists can put a stoplight in front of any gene, by inserting the gene and the stoplight together into a genetic package and delivering it to cells in a dish or in a living animal. The new gene is present but inactive, meaning it can’t produce messages or proteins, until the stoplight is removed. But when a particular drug reaches the cell, it acts as the tool that turns off the genetic stoplight, activating the gene.

The reason that this is an exciting scientific innovation is that the X<sup>on</sup> system allows researchers to insert a gene and turn it on and off by simply adding a drug to a dish of growing cells, or by giving the drug to a research animal. This could be a new way to understand what happens when there is too much or too little of a given gene or protein, or to create a disease model to easily explore genetic interventions at different time points during aging.

In a recent publication in the journal Nature, Davidson’s team tested the technology using a variety of genes involved in neurodegenerative diseases and cancers to show that their levels could be controlled based on when and how much of the stoplight-disabler drug was given.

Combining X<sup>on</sup> with CRISPR gene editing

Even more interesting is the potential application of the X<sup>on</sup> system to technologies like CRISPR and the future of gene editing as a therapeutic. This recent paper demonstrates the ability of the X<sup>on</sup> system to be combined with CRISPR-Cas9 technology, for more precise control of CRISPR editing using a drug fed to mice. Davidson’s team demonstrated this using an artificial gene that can make a mouse’s liver cells glow green. But ultimately the hope is that it could be applied to human therapies.

A system that can help us gain better control of CRISPR gene editing is an exciting prospect because it provides more hope of safely adapting this technology for future medicines. This is not currently possible for most diseases, because direct, irreversible changes to human DNA can have drastic consequences. We wrote recently about the first ever successful safety trial of a CRISPR drug for a human disease that commonly affects the liver. Although it would be marvelous in theory to cut out or correct the HD gene in people, the knife-like CRISPR system almost always leads to additional unwanted changes in other genes. This is why we’ve so often emphasized that gene editing needs to come a long way before we can apply it to the treatment of human brain cells, which can’t be regenerated like cells in the liver.

Coupling X<sup>on</sup> with a CRISPR-Cas9 system that targets a disease gene (like the HD gene) would mean that an oral drug could turn the gene editor on and off. The dose could also be adjusted to control the amount of gene editing – not just acting as a tool to disable the red stoplight, but also acting as a “dimmer switch” for precise regulation. Most importantly for safety, if anything went awry, the treatment could be stopped to prevent further changes to their DNA. Right now this is all theoretical, because the X<sup>on</sup> system and other gene editing “dimmer switches” are in early developmental stages. Nevertheless, this publication hints at the possibility of applying it to therapies in people, and Novartis has licensed the X<sup>on</sup> technology.

So why has this innovation made HD research news?

First and foremost, we know that HD is caused by a change to a single gene, so it has always been a prime candidate for genetic therapies, and dozens of researchers and companies worldwide are developing innovative solutions to treat HD at its source. HDBuzz (and HD researchers) always have an eye out for new technologies that improve upon existing methods. Furthermore, the leaders of the team that published the recent Nature paper are respected HD researchers who have devoted much of their careers to the development of gene therapies.

However, the main reason this publication has popped up as news for the HD community is that the X<sup>on</sup> system actually relies on an existing drug to flip the gene editing switch – and that drug is none other than branaplam. Yep, branaplam, the oral drug developed to treat children with SMA, which Novartis will soon be testing in clinical trials for adults with Huntington’s disease.

This does not mean that X<sup>on</sup> gene editing has any part in upcoming trials for HD. It simply means that branaplam, a drug with genetic cut-and-paste abilities, forms part of an elegant new system that can be adjusted to control the activity of any gene scientists want to study. “Dimmer switch” systems for gene editing could potentially be designed to use a completely different drug, but in these early experiments, X<sup>on</sup> and its precise control with branaplam has stood up to many tests of flexibility and accuracy.

The take home message

The X<sup>on</sup> system is a really cool early-stage technology, and though it’s not ready to be applied to human treatments, it is a novel element of the gene editing toolbox. Furthermore, it was created by researchers with HD expertise, and has now been licensed by a major pharmaceutical company which is already invested in HD therapeutics. That bodes well for its continued development in the study and potential treatment of HD and related genetic disorders.

From: HDBuzz (English)

Posted on Mon, 16 Aug 2021 02:10:28 +0000

Unpacking recent gene therapy press

A recent announcement from Voyager Therapeutics outlined a shift in the company’s strategy towards an exciting new technology for gene therapy delivery. Unfortunately this also means that in the short term, they have dropped previous plans to test an HD gene therapy in people with HD. While this news is disappointing, the decision to embrace a novel approach now could potentially lead to a safer, more accurate, and less invasive HD therapeutic in the longer term.

This news provides an opportunity for the HDBuzz team to talk more about the current landscape and share the latest news from the gene therapy pipeline.

A brief genetics recap

Before we get into the HD gene therapy pipeline, let’s review some basic genetics. With the advent of RNA-based COVID vaccines, we’ve all been hearing a lot about RNA. But how does RNA differ from DNA, and what does it mean if we alter either of these?

You can think of DNA like a blueprint – it's the master plan at the genetic level for every cell in your body. To ensure that master plan stays in pristine condition, cells make copies of DNA to work from when they make proteins. That copy of the DNA is RNA. Because RNA is just a copy, it can be well-used without much care if it gets a bit tattered. If it does, the cell can just make another RNA copy from the DNA blueprint, and voila! The cell has a fresh RNA copy that can be used to produce more protein.

Scientists have leveraged this knowledge to come up with clever ways to get cells to produce more or less of the proteins they’re interested in.

Applying this to huntingtin-lowering

In the case of Huntington’s disease, we’re interested in reducing production of the huntingtin protein that damages cells – referred to as huntingtin-lowering. That could be done in 2 ways:

1) Destroy the RNA copies as they are produced, but leave the DNA blueprint intact. This is the strategy behind antisense oligonucleotides (ASOs), like those that were being tested in trials by Roche and Wave.

2) Modify the message of the DNA blueprint, so it either can’t be copied into RNA or contains new instructions to help destroy the RNA. This approach is what we refer to when we say “gene therapy” – it changes what is made from the blueprint without altering it.

While both of the strategies above ultimately lower huntingtin protein production, they are different for several reasons. The primary difference is that destroying only the RNA copy requires repeated doses. Because the cell still has the original DNA blueprint for the huntingtin protein, it will continue to make more RNA copies. So unless the copy is constantly destroyed, the huntingtin protein will still be produced. While the repeated doses may seem like a nuisance, this type of approach means that the effect of any drug that targets only the RNA will eventually wear off – an added safety benefit.

Gene therapy approaches for huntingtin-lowering, like those being pursued by uniQure and Voyager, target huntingtin with a one-time delivery of genetic instructions to cells of the brain. These instructions then tell the cells to continuously produce RNA molecules that can interfere with the making of huntingtin, leading to lower protein levels. This is a one-and-done type of approach – no repeated doses necessary. But something to consider is that this approach also means that if there are other effects because of huntingtin-lowering, there’s no going back.

It’s important to note that even though DNA is being added in these gene therapy approaches, a person’s DNA is not being edited. This means that while the gene therapy will have benefits in the person being treated, it won’t be passed to future generations. That would require a gene editing strategy like CRISPR.

Current gene therapy strategies for brain diseases like HD would require brain surgery since these DNA-altering drugs can’t get past the barrier of the brain. This major limitation is something Voyager wanted to get around.

What did Voyager share?

On August 9th, 2021, Voyager Therapeutics issued a press release about their finances, recent leadership transitions, and importantly, a major shift in their scientific pipeline. The announcement had a lot of corporate and investor information, but the science content centered around an improved gene therapy delivery system and a proprietary discovery platform, which in combination could allow Voyager to develop less invasive methods of delivering gene therapies for rare diseases like HD.

Like previous genetic therapies developed by Voyager (and other companies, like uniQure), delivery involves packaging genetic drugs inside a harmless virus called an AAV. In the field of HD gene therapy, AAVs are used to deliver genetic instructions that cause cells to divert one tiny wing of their machinery towards producing a genetic “antidote” to the expanded HD gene.

Voyager has developed a proprietary new AAV packaging and has collected evidence from monkeys that these AAVs can be delivered with greater safety, potency, and accuracy. They have also invested in a new discovery system for identifying and improving upon AAVs for additional diseases and drug targets.

What does this mean for HD gene therapy?

Whereas AAV delivery of HD therapies has so far required a brain surgery, drugs developed using Voyager’s new platform can be designed for delivery through an injection into the blood, so there is potential for less invasive delivery to the brain.

The press release shared that Voyager will shift its focus to the new technologies and away from older existing ones. The upside is the next-generation technology; the downside is that this means that Voyager will no longer be pursuing the therapy that they had previously developed for HD. This drug, VY-HTT01, was meant to be the focus of a planned clinical safety trial called VYTAL, which would have begun later this year. No participants had yet been recruited – it was still in early planning stages.

Although the loss of a gene therapy that was approaching the clinic is a significant short-term setback, Voyager’s shift in focus now to accommodate a new scientific development provides a new and potentially better therapeutic avenue for HD.

Other gene therapies in the pipeline

Luckily, there are other companies working on gene therapy approaches, who have also provided recent public updates on their ongoing or upcoming trials for Huntington’s disease. We’ve provided brief summaries for each of these below; stay tuned for additional updates as these efforts advance.

The first company out of the HD gene therapy gate was uniQure, who are developing a viral therapy known as AMT-130, which has the goal of delivering instructions to brain cells for the making of a special kind of RNA that will find and destroy the RNA for the huntingtin gene. In this way, gene therapy can be used to permanently induce huntingtin-lowering. After many years of careful work in animals, uniQure launched their safety study, and as of this summer they have excitingly been able to complete surgeries for 12 of the planned 26 patients. A strictly regulated schedule has allowed the team to carefully monitor any safety worries, and none have emerged so far.

Additional companies in the preclinical stages of development of virus-based huntingtin-lowering gene therapies include Spark, Sanofi, and AskBio.

Another gene therapy approach to huntingtin-lowering relies on a novel tool known as a Zinc Finger. We’ve been writing about this approach at HDBuzz since 2012, and more recently (2019) about a large scale study of the tools in HD mice. Recently, the Japanese drug company Takeda has taken over the HD program from Sangamo Therapeutics, who initially developed the drugs. A key benefit of the Zinc Finger approach for huntingtin-lowering is that it allows selective silencing of just the mutant huntingtin gene, while sparing the normal copy that nearly every HD patient has.

Strategies that target the RNA copy

We mentioned the multiple-delivery strategy which was used by Roche and Wave in the trials that concluded unsuccessfully this spring. Despite these setbacks, ASOs and other RNA-based strategies are still being actively developed as HD therapies.

Wave Life Sciences has redesigned the chemistry of their ASO drugs, which could lead to better potency and the ability to use lower doses in people with HD. They have announced plans to launch a safety trial of a new ASO by the end of 2021. The drug is called WVE-003, and it targets the expanded form of huntingtin.

Novartis and PTC Therapeutics are developing drugs called splice modulators that also target huntingtin RNA, but can be delivered by mouth. We covered Novartis’s drug, branaplam, in a recent article; a trial in HD patients is planned to begin by the end of 2021.

NeuBase Therapeutics is developing an ASO drug called NT0100 which also aims to target only the expanded form of huntingtin.

At the end of July, a company called Vico Therapeutics received a special rare disease therapeutics status, known as Orphan Drug Designation, to develop their ASO for HD, known as VO659.

Companies like Atalanta and Alnylam/Regeneron are developing ways to lower huntingtin through RNA interference (RNAi) which, similar to ASOs, target copies of RNA and would require multiple deliveries.

Even more approaches

There are more strategies in the works, some of which also rely on gene therapy or destroying copies of RNA, like targeting the expansion of CAG repeats, which is being explored by companies like Triplet Therapeutics and LoQus23 Therapeutics.

There are also many approaches to HD drug development that diverge from genetics but focus on addressing other aspects of HD biology, like preserving or boosting connections between neurons, or treating aggression, memory issues, or movement problems. Those already being tested in human we explored in a recent clinical trials roundup. Other companies have pre-clinical programs aimed at strategies like cleaning up existing huntingtin protein that litters brain cells, suppressing inflammation in the HD brain, and more – newcomers to HD research are quite frequent (and very welcome)!

Take Home Message

Gene therapy for brain diseases is amongst the most cutting edge approaches to trying to fight HD. As with any new field, there are bound to be many ups and downs on the way to a treatment. The recent update from Voyager is a good example of this – while it’s disappointing that they’ll not be running their planned trial later this year, it’s very exciting that they’ve developed these new technologies and want to apply them to help HD families. The extensive efforts from other companies in the gene therapy space and beyond suggest that a lot of really exciting strategies are being applied to the problem of HD.

From: HDBuzz (English)

Posted on Wed, 4 Aug 2021 19:34:46 +0000

Does blood hold the key to testing treatments earlier in HD patients?

Researchers at Johns Hopkins led by Wenzhen Duan have developed a non-invasive way to track progression of Huntington’s disease (HD) which could be used before patients even start showing symptoms. Using a type of brain scan called an MRI, the researchers have shown that in mouse models of HD they can accurately measure the amount of blood in the brain. It is proposed that this could be used as a biomarker of HD advancement which could be used even before traditionally measured symptoms develop. Biomarkers are lab tests that we can do to predict the course of disease in a living patient, and they may be the key to identifying effective HD drugs.

Why do we need different biomarkers for HD?

Despite recent disappointments in ASO clinical trial outcomes, the HD research community has by no means given up hope for developing a drug which would switch off the mutated Huntington’s disease gene or slow the disease by another means. In many cases, clinical trials run to date test drugs in “manifest” patients who have clear symptoms of HD which can be monitored throughout the trial to determine if the drug under investigation is working or not.

But perhaps we need to be testing these drugs at an earlier stage of disease to stop HD in its tracks? The problem with opting to test a new drug early before patients have symptoms is working out what we could measure to see if the drug is working. This is where biomarkers come in. If we could find a biomarker which could be measured in patients without obvious symptoms, this could be very helpful for doctors to track and monitor patients and hopefully, in the future, see if medicines are helping slow down their disease progression even at very early stages.

Is blood volume a good biomarker?

Good blood flow is very important for healthy brains as it delivers oxygen and other nutrients to brain cells to keep them well-nourished and working properly. Without good blood flow or a good supply of oxygen and nutrients, brain cells can get sick and die. Surprisingly, in people with HD, the volume of blood in the brain is significantly lower compared to people with healthy brains.

In this study, Duan’s team used a type of MRI brain scan which allows them to calculate the precise volume of blood in the brains of HD mice which are engineered to have a similar mutation to people with HD. The volume of blood measured in this scan is altered over the lifetime of the HD mouse. Even when the mice were very young and had yet to show signs of HD symptoms, the blood volumes were already lower than normal. The researchers suggest that careful tracking of blood brain volumes could be useful as an early biomarker of the progression of HD.

Can blood volume measurements indicate if HD drugs are working?

The group of researchers also investigated if using CRISPR to edit the HD mutation improved signs of HD in the mouse model. CRISPR is a gene-editing technology which allows scientists to precisely alter a region of DNA sequence. In this case, CRISPR was used to silence both copies of the Huntingtin gene – both normal and disease-forms – to switch off the expression of both. This is a similar approach to huntingtin-lowering therapies currently in clinical trials being led by Novartis, uniQure and others.

Using the MRI scanning technique and other brain function tests, the researchers compared regular HD mice with those which had been treated with the CRISPR therapy. As they had expected the CRISPR therapy delayed onset of symptoms in HD mice.

Importantly however, CRISPR treated mice had their altered brain blood volumes restored even when the mice were at an age when symptoms could not yet be measured. This shows that, with this treatment, using blood brain volume as a biomarker of disease can show if early treatments are working or not.

This looks good for mice but what about in people with HD?

Whilst the alteration to blood brain volume in HD mice mimics what we know happens in the brains of people with HD, it is important to remember all of these experiments were completed in mice, not people which obviously have different brain structures. There is still a way to go yet before we can be sure that this same measure of brain blood volume will be a good biomarker in people with HD. To do this we need to validate these findings in clinical trials with people. A benefit of this new blood volume approach is that the MRI is a non-invasive procedure, so looking at this measurement would hopefully be less taxing for patients compared to spinal tap or other invasive measures currently in use.

However, this is a hopeful step forward in HD drug discovery. Scientists now have a new measure they can use in the lab to study changes in HD models before they show symptoms and to test different drugs in these models. The hope is that early intervention with good drugs in people with an HD diagnosis might delay or even stop the progression of Huntington's disease altogether. We look forward to reading more about this work!

From: HDBuzz (English)