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Posted on Tue, 10 Jul 2018 23:48:23 +0000

First Dolly, now Piglet; a new Huntington’s disease pig knock-in model confirmed

Exciting news for the HD research field this month as a new genetically faithful model has been created in pigs. Using a combination of cutting edge DNA editing tools researchers were able to generate HD pigs that not only replicated the selective brain cell death seen in HD, but also a broad range of symptoms observed in HD.

Animal Models

Neurodegenerative diseases like Huntington’s disease (HD) are particularly tricky for researchers to study, because unlike liver or kidney disease for example, the organ that’s damaged (the brain) isn’t exactly available to take samples from. Therefore, we have to make do with the next best thing, which are animal models produced to replicate the damage and symptoms we see in human patients.

The majority of the information we have on HD so far has been gathered from such models, particularly studies completed in mice. Safe to say if we didn’t have these wonderful tools, HD research would be several decades behind where we are currently! Having said that, a mouse is a mouse…not a human; we have differences in brain structure, size, lifespan and the list goes on and on. Therefore not everything that's been discovered in HD mouse models has been found in the human condition.

And now, pigs

What we really need is a middle ground, a larger animal that has more commonalities to humans, a stepping stone or piggy in the middle (known as Keep Away across the pond) if you will. As luck would have it, this is literally what we now have thanks to the combined efforts of an American-Chinese team.

Researchers from Emory University and Jinan University's Guangdong-Hongkong-Macau Institute of CNS Regeneration have generated a genetic model of HD in pigs using two very cool techniques which rely on genome editing. This is a nifty process where scientists can go into the DNA of a cell, and edit it, sometimes to correct the errors that nature has made – think of when you hand in a paper, you normally do a first draft right? Well in this case, nature is the first draft, and scientists are the proof-readers. The techniques used in this particular study are called CRIPSR/Cas9 (see https://en.hdbuzz.net/244) and somatic nuclear transfer - the latter is the same technique used to clone Dolly the sheep back in 1996.

So how exactly does this work? Is it quite technical and tricky to do? Essentially yes, but it's super cool science and as this study shows, it is doable!

To put it simply, we can take the pig version of the HTT gene, cut part of it out and directly swap it for the human version which causes HD - this is the ‘proof-reading’ bit. The authors did this in pig skin cells, but then (and this is the really cool part) took out the nucleus of the cell, which contains all the DNA, and put this nucleus into what would become a pig embryo. Using a surrogate pig, they then bred several generations and found that the alteration was successfully passed down from parent to child in the same way HD is in humans. For those that don’t know, a group of piglets is called a drift, and that’s exactly what these researchers had; a drift of piglets, some of which had HD.

Benefits of the pig model

As if that wasn't cool enough, the truly exciting result of this new work was that the pigs themselves had very dramatic symptoms, which appeared to mimic what’s seen in human HD patients much more closely than in rodents. The movement abnormalities, or chorea, that patients experience was replicated as the pigs developed walking and running difficulties with age. Videos of the pigs reveal very clear movement abnormalities that really do resemble a human HD patient. Surprisingly, no rodent model of HD has this type of movement problems, which has been a big problem for testing new therapies in mouse models of HD.

In terms of brain changes, remarkably the HD pigs had a lot of the same damage as HD patients. You may have heard about medium spiny neurons before in the context of HD (no puns here, they really are spiny). These neurons are the first casualties in HD patient brains, and die very quickly in the course of the disease, which probably explains the movement problems that happen early in HD.

Researchers have been pretty flummoxed as to why this selective loss of cells happens, and despite decades of research we still don't really know why the spiny ones are so sensitive! We may not be too far from a light bulb moment now however, as in these pigs, the researchers found selective loss of spiny neurons as well as many other neurological features of human HD.

Similar to what happens elsewhere in the body, when there is an injury in the brain you get an immune response. In the brain, specialised cells are 'switched on' when damage occurs in a process called gliosis. This immune response is found in the brains of human HD patients; however previous animal models have typically struggled to replicate this feature of disease. Here the knock-in pig model prevails once again, with the researchers finding marked evidence of gliosis occurring in diseased pigs - this study really brought home the bacon!

On a different note, what you may not know about HD is that the majority of patients don't pass away from the actual brain damage itself, but instead the knock-on effects. If you think about it, the brain controls all of our conscious decisions, as well as everything we do without thinking about it, like breathing.

When we lose a large part of the brain, everything in our body suffers as a result, and it's actually breathing difficulties and pneumonia that claim so many HD patient lives. Critically, this has never before been shown in a HD animal model, but the knock-in pigs in this study developed the exact same breathing difficulties that patients experience, which is pretty groundbreaking.

All of these things together made for a very exciting read as a HD researcher, as it seems we finally have a model that replicates the journey of a HD brain and body from start to finish. The excitement doesn't stop there though; due to the physical size of pigs we will be able to test potential treatments and specialised drug delivery routes that have previously been impossible.

For example the potential treatment in the headlines currently, ASO mediated HTT lowering. This has to be delivered by lumbar puncture i.e. injection directly into the spine. I challenge those of you even with the steadiest of hands to attempt that on a mouse...it's not going to happen - a pig however, much more feasible.

What's that mean for us?

With that said, nothing in life is perfect and this study is no exception. With increased animal size, comes increased costs in terms of housing and feeding, plus it takes longer for the animals to develop and reach adulthood which could really hinder how quickly new discoveries are made. This undoubtedly contributed to the number of animals used in the experiments discussed here, which were on the low side. The authors did own up to this however and admitted that more rigorous testing would be required, and was in the pipeline.

Issues aside, this new model is pretty incredible and should open many doors for future HD research and therapeutics ventures, so on behalf of HD researchers across the globe, 'that'll do pig, that'll do'.

From: HDBuzz (English)

Posted on Thu, 10 May 2018 23:48:25 +0000

New collaboration seeks to speed Huntington's disease drug licensing

Recently the Critical Path Institute announced a new effort - the Huntington's Disease Regulatory Science Consortium, or HD-RSC. This collaboration with many international partners aims to speed the development of new HD treatments. What's all this about, and how could it help HD patients?

What is C-Path?

The Critical Path Institute is likely new to most Huntington's disease community members, but they're not new to the fight against human diseases.

In 2004, the US Food and Drug Administration (FDA) launched an effort to modernize and speed the development of new therapies. As a result of that effort, in 2005, the FDA and partners founded and funded the Critical Path Institute (or C-Path) with a goal of speeding the development and reducing the costs of bringing new drugs to patients who need them.

To do its work, C-Path brings together teams of organizations that are working on a specific problem. These C-Path consortia work to streamline drug trials in their area of interest, as well as developing new tools to improve the quality of trials.

As an example, C-Path has a consortium focused on Alzheimer's Disease which they call Critical Path for Alzheimer's Disease, or CPAD. This consortium of regulatory agencies, drug companies, researchers and advocates focuses on developing new tools to accelerate the development of new therapies for Alzheimer's Disease.

What does C-Path do?

How do groups like CPAD work to improve or speed clinical trials? As an example, CPAD has developed a sophisticated computer model that tracks the progression of Alzheimer's Disease by compiling huge amounts of existing information about Alzheimer's Disease patients. Alzheimer's Disease clinical trials are done by a number of different individual organizations, and the data is not always shared between trials.

This is where C-Path comes in - they specialize at pulling together information about the disease stored with drug companies and academic researchers around the world. Based on real data from dozens of drug trials, C-Path's computer model allows organizations thinking of developing a new Alzheimer's Disease model to essentially do a practice run of their trial in a computer simulation.

This allows any organization with a new Alzheimer's Disease drug to plug in a few numbers about how well they think their drug will work, and get feedback about how likely a given trial design is to be successful. That can be enormously powerful for trying to figure out how many patients to enroll in a study, and how to divide the people in the study between the arms of the study.

C-Path's consortia have also worked on other critical roadblocks to rapidly completing trials. Several of their consortia have focused, for example, on helping researchers develop a new biomarker to simplify or shorten clinical trials.

There are a few kinds of biomarkers, but ultimately they are precise measurements that serve to tell us about how a disease is progressing in a human - say, a brain scan for HD. They can also report on how well a drug is doing based on changes that drug leads to in body chemistry or other measurements.

Because of their history and membership, C-Path understands how regulators, like the FDA and the European Medicines Agency (EMA), think about drug approval. This puts them in a great position to translate the science that researchers generate, into the measurements and outcomes that regulatory agencies need, to prove that drugs are safe and effective.

C-Path's Newest Consortium: HD-RSC

Recently, the official launch of C-Path's newest consortium was announced - the Huntington's Disease Regulatory Science Consortium, or HD-RSC. The consortium was launched in partnership with the CHDI foundation, a non-profit dedicated to rapidly developing meaningful treatments for HD.

The HD-RSC involves a huge range of players in the HD world beyond C-Path and CHDI, including drug companies (ten in fact, including Roche, Sanofi, Teva, Wave Life Sciences and others), regulatory agencies and patient advocacy organizations (including the HDSA, HSC and EHDN). These diverse organizations all have their own expertise and interests, but all of them are committed to developing new therapies for HD patients.

Last November, representatives from all these organizations came together in Silver Spring Maryland for a kickoff meeting. Your humble HDBuzz author attended to get a sense of what to expect from the HD-RSC. Over two days of meetings (program available at the link), dozens of participants talked about how best to speed clinical trials for HD.

Excitingly, the attendees included very high-ranking members of the FDA, including Eric Bastings (Deputy Director), and Billy Dunn (Division Director, Division of Neurology Products). These are the folks that are in charge of the review of new HD drugs being tested. Far from standing on the sidelines, the FDA attendees sat front and center in the first row, taking notes and asking a number of questions. It seems that these regulators get HD, and they're interested in trying to speed the safe development of new therapies for HD families. This consortium sums up the collaborative spirit of the HD community and our determination to make progress as quickly and efficiently as possible.

By the end of the meeting, the organizations comprising the HD-RSC had organized themselves into 5 working groups. Each of these smaller groups is focused on helping solve a specific problem - developing new biomarkers, for example.

Another exciting goal embraced by the HD-RSC is the problem of how to design trials of drugs for presymptomatic HD mutation carriers - meaning people who carry the HD mutation, but who don't yet have HD symptoms.

Stopping HD symptoms before they start is the goal for everyone working on HD, but it's complicated to understand how we would design a trial and monitor people who don't yet have any symptoms to measure. Excitingly, this working group suggests that some really savvy folks think this is an important problem and have agreed to spend time working on creative solutions.

Take home message for families

We're entering a new phase in the fight against HD. Incredible drugs, designed specifically for HD, have moved from labs around the world into the clinic. The feeling many in the community had that "no one cares about HD" is being replaced by the realization that HD is a very hard, but solvable, problem.

Groups like the HD-RSC are great news for us because they mean that smart people are working hard, that they're collaborating and most importantly - that all these organizations feel that HD drug development is an exciting place to work. Stay tuned for exciting new ideas from the HD-RSC.

From: HDBuzz (English)

Posted on Thu, 26 Apr 2018 23:48:27 +0000

HDSA’s Q&A on the latest huntingtin-lowering update from Ionis and Roche

Earlier this week, Ionis Pharmaceuticals put out a press release after presenting data from the HTTRx (RG6042) Huntingtin-lowering clinical trial program at a scientific conference. Ionis’ partner Roche also released a community statement. Our friend at Huntington’s Disease Society of America, Dr Leora Fox, has prepared this Q&A in response to community questions received after the release. We liked it so much, we decided to reproduce it here, by kind permission, for the benefit of HDBuzz readers.

What did the press release say?

Mainly, it restated what we already know: the drug is safe, and it lowered levels of huntingtin, the protein that harms brain cells in HD. The newest information, presented on April 24th, is that overall, participants with lower huntingtin levels also did a bit better on clinical exams that test HD symptoms. However, the study was only designed to be sure of safety, not efficacy, so a larger trial still needs to be conducted.

So are they saying that the drug worked?

It’s not possible to draw that conclusion right now. All we know is that it’s safe and landed on the genetic target it was designed to hit. The clinical findings shared by Ionis are exploratory – the trial only involved 46 participants in total, which is not enough to be sure it could help with symptoms. Even though the overall conclusions are very promising, the statistics have not yet shown a clinical benefit.

What’s next? Does this knowledge change anything going forwards?

Nope. Ionis is passing the torch on to Roche Pharmaceuticals, a larger company that is invested in the HD community. In the United States, the company is called Genentech. An experienced international team has been assembled and is tasked with the planning and coordination of a global Phase 3 clinical trial. You can read their most recent message to the community here. In the meantime, we’re encouraged that the analysis of the Phase 1/2 data continues to show promising results. We’re also really excited that these results are being given the spotlight at international research conferences. This will positively impact families by raising awareness of HD among medical professionals worldwide.

If it’s so promising, what’s the holdup?

Ensuring that drugs are safe and effective is a time-consuming and heavily regulated process. Roche-Genentech has a lot of work to do, including designing the trial with care, identifying the medical teams and facilities that will take part, making sure that professionals are equipped and trained to administer the drug, producing the drug itself, and sorting out funding and regulations at different agencies worldwide. All of these steps require planning, paperwork, and patience. Rest assured that there are smart and compassionate minds involved, including HD patients and families, working to bring this drug to the clinic as quickly as possible.

Can I sign up to be in the trial, or put my name on a list?

Unfortunately, no. The way that clinical trials usually recruit is through existing doctor-patient relationships, where the doctor decides if a patient might be eligible, and makes a referral. That’s one reason why HDSA encourages people [in the USA] to see an HD expert at an HDSA Center of Excellence or other HD clinic with a research interest, and to join Enroll-HD.

There’s been an outpouring of folks who are ready to take a big leap and participate. The trial is not up to that stage yet, and HDSA is not in control of any aspect of the design, participation, or eligibility. There will be many fewer “spots” than willing participants, which will understandably lead to some disappointment. We do not encourage people to consider a big life shift (like moving) based on their desire to participate in a trial.
However, we are thrilled about the community’s engagement and we’ll continue to provide and interpret any new information we hear.

There may be other research opportunities near you, as well – check out HDTrialfinder for details.

What is HDSA doing to support the trial and the community?

HDSA staff are working very closely with members of the Roche-Genentech team to ensure timely and proper information about this trial will be shared with the community as soon as it becomes available. HDSA is also a founding member of the Huntington’s Disease Coalition for Patient Engagement (HD-COPE), which helps industry teams connect directly with patients and families. HD-COPE will help companies like Roche to make sure that trial planning, measurements, and participation requirements seem reasonable to the real experts – people with HD and their loved ones.

Finally, we continue to provide trial details and contact information for participating in open research studies on HD Trialfinder. Because the upcoming trial has not yet begun, it is not listed there.

When do you think this drug will be available?

That’s extremely difficult to answer. Trials can take several years, and a lot of care must be taken with this one, because it’s so important and so different from drugs that address just the symptoms of HD. We’d love to be able to say there’s a definite timeline, but this is uncharted territory and we simply don’t know. The first step is to see whether it can improve symptoms or slow down HD, and that’s the focus of the Phase 3 trial.

What can I do right now?

Make sure you’re under regular care with a doctor or team who has experience with HD, particularly one with a research interest (like an HDSA Center of Excellence or university HD clinic). Follow the news at HDBuzz, on HDSA’s weekly research blog, or on HDSA’s social media pages. Check out HD Trialfinder for research opportunities. Above all, take care of yourself and those around you!

In the fight against HD, family is everything.

From: HDBuzz (English)