HD Therapeutics Conference 2013

HD Therapeutics Conference 2013 Updates: Day 1 09 aprile 2013 13:28

Our first daily report from the annual Huntington’s Disease Therapeutics Conference in Venice, Italy. We’ll be bringing you live updates via Twitter over the next two days. You can tweet @HDBuzzFeed, comment on Facebook or use HDBuzz.net to send us questions, comments and queries.

9:00 – Buonasera from Venice, where HDBuzz will be tweeting the latest Huntington’s disease research news from the annual therapeutics conference

9:08 – Huntington’s disease therapeutics conference kicks off with a session on systems biology

9:09 – Systems biology tries to understand networks of connected chemicals and processes, rather than focusing narrowly on one thing

9:10 – The hope is that this systems approach will help us better understand Huntington’s disease and develop and test treatments

9:12 – Robert Pacifici of CHDI: one tiny change, the HD mutation, causes lots of changes in the biology of people who carry it

10:35 – Jim Rosinski of CHDI: new technologies are being used to get better understanding of HD, like RNA sequencing – what genes are on/off

10:38 – Rosinski: “Amazing things are possible now” and the HD gene gives us a head start for understanding the disease

10:38 – HD drug development company CHDI is integrating techniques from engineering and computer science to better understand HD

12:10 – Lesley Jones is studying HD mice to understand how much they look like HD patients. In many important ways they’re similar.

12:16 – William Yang is using mouse brains to map out which proteins the HD protein interacts with. More targets for drug developers

12:29 – Collecting all this data from HD patients and animals poses computational challenges, that Steve Horvath is working hard to fix

12:43 – With nearly 300 researchers attending, this is the biggest ever HD therapeutics conference

14:33 – Why do we have an HD gene at all? Elena Cattaneo is studying diverse animals, including sea urchins, to try to understand

14:53 – According to Dr Cattaneo, the normal HD gene seems to have important roles during the development of the brain

15:10 – If the HD gene is important for brain development, what happens in brains of people born with the HD mutation? Peg Nopoulos studies this

15:11 – Nopoulos’ HD-KIDS study follows school-age kids at risk for HD. Gene testing is done without anyone involved finding their result

15:14 – Nopoulos: major brain changes occur throughout childhood

15:19 – Nopoulos: KIDS-HD allows us to study not just HD but also the role of huntingtin in normal brain development

15:20 – Even in HD-negative people, there is variation in the number of CAG repeats in the huntingtin gene.

15:25 – In kids who don’t have the HD mutation, some aspects of thinking and behavior are subtly influenced by CAG repeat length.

15:28 – Some brain areas are also affected by the number of CAG repeats in the HD gene – in kids who are NEGATIVE for the HD mutation.

15:29 – Fascinating insights into the core mystery of Huntington’s disease from Nopoulos: what does the normal huntingtin protein do?

15:33 – In kids who DO carry the HD mutation, Nopoulos finds subtle changes that are compensated for, but are their brains more vulnerable?

15:50 – Audience question from statistician raises concerns that statistical methods used to test Nopoulos’ data may not be rigorous enough for small sample

16:25 – Jeff Macklis of Harvard studies the neurons connecting brain’s cortex (crinkly surface) to the basal ganglia (movement control bit)

16:44 – Macklis: understanding of how different cell types become neurons and how they function has improved dramatically in past 5 years

17:16 – Ali Brivanlou of Rockefeller University is an expert on human development. Huntingtin protein is found in the very earliest embryo cells

17:17 – Using RNA sequencing, Brivanlou has identified 4 new RNA message molecules for huntingtin in embryo cells. These could produce new proteins

17:18 – Brivanlou’s ‘new’ huntingtin molecules are created by reading the huntingtin gene in different ways to create ‘spliced’ RNA messages

17:20 – The function of these new huntingtin forms in embryonic cells is not known. Remember we’re talking about normal, not mutant huntingtin here.

17:31 – Brivanlou: Embryos without huntingtin die after a week of development, but why? It changes the response to growth molecules

17:34 – Brivanlou: huntingtin has an influence on the metabolism of embryos – that’s how they use energy & do chemical reactions.

17:38 – Brivanlou: in embryos with the HD mutation, sugar metabolism is unexpectedly altered. It’s unclear whether this affects development

17:43 – Today’s biggest news: Roche & Isis sign $30million deal to take gene silencing drugs for HD to trials

Sunset conclusions

On the opening day of the biggest ever Huntington’s disease therapeutics conference, we heard a lot about studying the complexities of the brain, and the role of the huntingtin protein, still mysterious twenty years after its discovery – but not very much about drugs. But understanding how the brain develops and works, and ‘knowing the enemy’ – the mutant huntingtin protein and its damaging effects – are both crucial if we are going to safely and rapidly develop the treatments we’re all working towards. You never know where the next big idea will come from, and it’s from fundamental, imaginative research of the kind we’ve hear about today that bright new ideas for possible treatments may well spring up.



HD Therapeutics Conference 2013 Updates: Day 2 10 aprile 2013 16:00

Our second daily report from the annual Huntington’s Disease Therapeutics Conference in Venice, Italy. You can tweet @HDBuzzFeed, comment on Facebook or use HDBuzz.net to send us questions, comments and queries.

9:09 – Good morning! Jeff and Ed will be posting updates from day two of the Huntington’s disease therapeutics conference.

9:14 – Reminder for anyone who missed it: there’s $30million in HD drug research that wasn’t there last week – see our article on the Isis and Roche deal from yesterday.

9:17 – The first session is about the huntingtin protein: what is is, what does it do and how does it cause harm?

9:26 – Dr Hilal Leshuel of EPFL, France has cool ways of making proteins in the lab so they can be played with and studied. He has used these techniques to study a crucial Parkinson’s disease protein, alpha-synuclein. He can artificially ‘tag’ his artificial proteins and see how cells handle them differently with different tags. Adding a tag called ubiquitin to the alpha synuclein prevents it sticking together into clumps (huntingtin does this too). Using techniques developed in Parkinson’s disease, his lab can now study chemical modifications of the HD protein directly. Lashuel says that simple chemical modifications of normal HD protein can make it act like mutant protein – clumping together in ‘aggregates’.

10:06 – Gerardo Morfini: HD patients have loss of ‘white matter’ in the brain, which is made of axons, suggesting it’s important to understand. Morfini is studying axons from squid! They’re huge, so much easier to work with than human or mouse axons. He has found that the mutant HD protein causes traffic jams in axons, slowing down traffic in neurons. He is looking for drugs that increase the speed of traffic in axons, combatting the effects of the mutant HD protein. Morfini wants to understand how ‘axons’ – the long part of neurons that transmit messages to other neurons – die in HD.

10:39 – James Surmeier is trying to understand which specific brain cells are the first to die in HD – what makes them so vulnerable? He is using cutting edge microscopes and techniques to study individual connections – synapses – between neurons in HD mice. He sees that communications between brain cells are improved with a drug which that is soon going to be tested in HD patients.

11:41 – Philip Gregory works with Sangamo, a company developing tools to actually edit the DNA of HD patients to remove the mutation. Gregory says that Sangamo is trying to refine their tools so that they can edit the mutant HD gene, while leaving the normal HD gene alone. Gregory says that editing mutant HD genes works in the brains of living mice, not just cells – good news for moving towards people.

12:10 – David Corey is working on new ways to “silence” the mutant HD gene. He wants to find tools for reducing levels of the mutant HD gene, while preserving the normal gene that has important functions. His team has three different chemical classes of drug that all do the same thing – help cells reduce levels of the mutant HD gene.

14:56 – We’re now in the poster session, where over a hundred cool HD projects are being presented and discussed

16:18 – Dr Steve Goldman of the University of Rochester is giving the keynote address on new cell models for understanding Huntington’s Disease. He tells us that until recently it was thought that the brain can’t generate new neurons, but to a limited extent it can (at least in mice). We are beginning to understand how to direct the production of new neurons by the brain, even in HD mice. In HD mice, new neurons produced by the brain’s own stem cells may appear able to replace lost cells to some extent. Goldman treated HD mice with virus-delivered instructions to make new neurons live longer than untreated mice (Goldman’s work will be published soon in the journal “Cell Stem Cell” and we’ll definitely be writing an HDBuzz article on it!). Replacing brain cells using stem cells from embryos was tried before but didn’t work well, probably because we didn’t understand how to look after the cells, nurture them to become neurons and get them to make the right connections when transplanted into HD brain. Goldman says we are now developing a better understanding of how cell transplants might work (but we’re not ready for new trials yet). The brain contains many types of cells – neurons, which do the thinking, are the most famous, but there’s loads of other ‘support cells’. One type of ‘support’ cell is called astrocytes. Cells from human embryo injected into mouse brain can replace the mouse’s own cells. In HD it might be good to transplant embryonic stem cells and hope they will replace the patient’s HD astrocytes. Astrocytes help the electrical activity of neurons, so having healthy astrocytes could be good for an HD brain. Note that these human/mouse experiments haven’t been tried in HD mice yet – just healthy mice so far. But innovative stuff. Goldman & others have better recipes for generating ‘medium spiny neurons’ from stem cells. Those are the ones that die early in HD.

18:12 – George Yohrling of the HDSA announces Human Biology Research Fellowship program. Funding for patient-centred HD research.

Sunset conclusions

It’s the end of day two, and we’re getting increasingly into the territory of ideas and approaches that are directly aimed at treating HD, now or in the future. We know from talking to family members how frustrating it is to constantly hear that treatments are getting closer, because all HD family members want to hear is that we have a treatment that works now. All we can do is echo the words of Robert Pacifici, CHDI’s Chief Scientific Officer: “The drugs are coming”.

Today we heard about many treatments, some very close to clinical trials, others more exploratory and experimental. Drug-hunters call this a “full pipeline” and it’s a sign of a healthy, thriving research program with the potential to deliver drugs designed for HD that might actually work, and ought to keep getting better with each passing year. Tomorrow, in the final day of the meeting, CHDI’s scientists will give eagerly-awaited updates on their internal programs pursuing some of the hottest targets for Huntington’s disease therapeutics.



HD Therapeutics Conference 2013 Updates: Day 3 11 aprile 2013 04:34

Our third daily report from the annual Huntington’s Disease Therapeutics Conference in Venice, Italy on the final day of the conference.

9:07 – Day 3 of the HD therapeutics conference starts with a session on the most exciting programs at CHDI, getting close to the clinic.

9:10 – Marg Sutherland of the National Institute of Health is describing the programs there directed at funding and supporting HD research. The National Institute of Health is supporting HD research to the tune of 54 million dollars every year!

9:27 – Margaret Zaleska from Pfizer is describing the pharma giant’s work to develop an exciting new drug for HD. Pfizer’s new drug (“MP-10”) targets something called “phosphodiesterase-10A”. In HD mice, MP-10 has a number of beneficial effects, supporting the idea that it might be useful for patients. Encouragingly, MP-10’s beneficial effects in HD mice last longer than the drug, suggesting it might work on more than symptoms. Pfizer’s completed its imaging trial in HD patients that was intended to help decide whether to go ahead with a drug trial. The answer: YES. Pfizer’s trial will assess safety and tolerability in HD patients and will last 28 days with functional MRI imaging. Pfizer expects its drug trial in HD patients to start in 2014.

10:18 – Ladislav Mrzljak gives update on CHDI’s KMO inhibitor research program. Inhibiting KMO should improve the balance of helpful and harmful brain chemicals in HD. CHDI’s drug is called CHDI246. CHDI246 has been chosen as the lead candidate for its KMO-inhibiting properties but doesn’t get into the brain very well – however, it does good things in the blood that then produce benefits for the brain. CHDI246 produces the kind of chemical changes we want to see in the spinal fluid of HD animal models. CHDI246 doesn’t improve the HD mice. A bit of a surprise but may be because of fundamental differences between mice and people. CHDI’s research questions whether JM6, a previously reported KMO inhibitor, works as the publication claims. Despite negative results in mouse trials, favourable chemical changes in primate tests mean CHDI wants to push ahead with CHDI246.

11:07 – Vahri Beaumont of CHDI is describing their work on “HDAC Inhibitors”. Years of work from Gill Bates at King’s College London suggests that blocking a specific HDAC – HDAC4 – helps HD mice. HDAC4 sticks to the mutant HD protein, but not the regular one. That’s a hint that HDAC4 might be up to no good in HD. Getting rid of half of HDAC4 in HD mice make their neurons work much better, and helps them live longer. CHDI is working to develop a drug to block HDAC4 that could be taken as a pill. CHDI have identified several specific drugs that are potent inhibitors of HDAC4 and are testing them in mice. Beaumont tells us that early data shows blocking HDAC4 with a drug in mice doesn’t show big improvements in HD symptoms in mice treated with it. So there’s a lot of work to do to understand HDAC4 in HD.

11:56 – CHDI’s Jonathan Bard gives an update on TrkB activating drugs (pronounced track-bee!). TrkB activators aim to mimic the ‘nourishing’ effects of the brain chemical BDNF. It keeps neurons alive and is reduced in HD. CHDI is also looking into delivering BDNF directly into the brain using a virus called AAV as a delivery truck. CHDI is testing two antibody-based TrkB activating molecules. Early results from the viral-delivered BDNF in mouse brain look good- it increases TrkB activity, as expected. Very early days for CHDI’s TrkB and BDNF programs but looking good so far. These guys really know their stuff.

14:15 – Next up is the biomarker session, figuring out the best ways to measure and predict progression in HD to help tell if drugs work

14:20 – Beth Borowsky of CHDI presents work relating to a substance called 8OHdG, which has previously been reported as a biomarker for HD. 8OHdG is produced when DNA is damaged and a 2006 paper reported that it was increased in the blood of HD patients. Borowsky has led an incredibly careful multi-lab re-evaluation of 8OHdG in hundreds of blood samples. Borowsky reports that there were actually no differences in 8OHdG at any disease stage, or with progression within patients and 8OHdG is not a biomarker of HD state or progression. Rigorous ‘replication’ like this- carefully repeating others’ findings – is an incredibly important part of science but seldom done. Borowsky says that the Track-HD study ran for 4 years and has identified the best imaging, clinical and cognitive (thinking) biomarkers. The latest data from Track-HD tell us that brain volume and other measures can predict how the disease may progress in future (It’s important to note that these measures are not yet useful in individual patients, only when measured in groups). The next step is to use these measures to help run drug trials in HD patients

14:46 – Borowsky: CHDI also supports the CAB study developing optimised thinking tests for clinical trials in HD. ‘Composite’ cognitive scores, combining the results from several different tests, are probably the best. It’s time to test our most promising biomarkers in a clinical trial.

14:52 – Borowsky announces CHDI’s first human clinical trial – of aerobic exercise in Huntington’s disease! The trial will primarily aim to validate the biomarkers we’ve developed over the last few years. But also whether exercise is good.

15:00 – Tiago Mestre gives an update on the Enroll-HD study, which is now active. Enroll-HD combines, updates and replaces the European Registry study and American Cohort study. Enroll-HD is an observational study- participants are studied but no drug is given. Enroll-HD aims to understand the disease, improve clinical care and enable clinical research (eg biomarkers and future drug trials). People who’ve tested HD positive or negative, people who haven’t had a genetic test, and not-at-risk people can all take part in Enroll-HD. The aim is to recruit a third of the HD-at-risk population in each region where the study is running (North & South America, Europe, Australia).

16:07 – Carole Ho of Genentech gives an update on the Alzheimer Prevention Initiative. We must learn from other neurodegenerative diseases. Most cases of Alzheimer’s disease are not caused by a specific mutation (like HD is), but some cases are. Recent Alzheimer’s drug trials have disappointed, perhaps because the drug was given too late in the disease. However, focusing on the small number of patients with genetic forms of Alzheimer’s enables treatments to be given much earlier. Now Genentech is starting trials of its new drug crenezumab in people with genetic Alzheimer’s even before symptoms. Everyone with HD has the same basic genetic mutation, so preventative or very early trials would be possible. Good news for HD!. The Genentech drug wouldn’t work for HD by the way, but we can learn from this way of doing trials. The FDA has recently relaxed its criteria for approving new Alzheimer’s drugs, making it a little bit easier. The Alzheimer’s trial will include the patients in Colombia whose genetic information was used to develop it – the HD community needs to remember and serve the Venezuelan families where HD is very common and whose DNA helped find the HD gene.

17:00 – The final speaker is Kenneth Marek of Institute for Neurodegenerative disorders, CT USA, an expert on ‘molecular imaging’ methods. Brain scans with names like PET and SPECT allow us to see the chemical changes in the brains of live human beings. Molecular imaging is already available to help diagnose Parkinson’s and Alzheimer’s by measuring buildup of harmful proteins. We don’t yet have a way of scanning patients to measure levels of Huntingtin protein, but it would be very useful and its being worked on. However, other types of imaging could be useful for HD research, like one that measures PDE10, the target for Pfizer’s HD drug.

Sunset conclusions

Tonight marks the end of this year’s HD Therapeutics Conference, and we’re saying goodbye to one another and to Venice. Leaving these meetings is always bittersweet – on the one hand, it’s been a very stimulating few days of cutting-edge HD science, and we’ll return to our work re-energized and fully informed. But at the same time, the inevitable challenges along the way remind of the difficulty of our task, and just how important it is to HD families that we’re successful as quickly as possible.

Amongst this year’s most exciting news is the rapid advancement of Pfizer’s PDE10A drug, enabled by their collaboration with CHDI, towards human clinical trials. The HD mouse data presented here is among the most exciting that we’ve seen for any proposed drug. As well as looking like a very exciting drug candidate, the trials that Pfizer and CHDI have planned take advantage of everything we’ve learned from trials like TRACK-HD and PREDICT-HD, and will be the most advanced ever run in HD.

Gene silencing, too, received an exciting boost this week in the form of the announced multi-million dollar collaboration between biotech Isis and Pharma giant Roche to bring HD silencing drugs to the clinic. Like many scientists, we think that gene silencing is the most promising approach to developing meaningful therapies for HD families, and it’s gratifying that large companies are willing to make a large financial investment in the therapy.

Developing treatments for HD is such a huge challenge that it’s certain that some attempts will fail along the way. For example, some drugs that looked hopeful at early stages of development, including the ‘HDAC4 inhibitors’ from CHDI, now seem perhaps a bit less exciting than we’d hoped. Also, the failure of 8OH-dG as a ‘biomarker’ for HD means we have one less tool in our box for clinical trials. We’d encourage families to join us in thinking of these “failures” as positive developments – helping us focus on the most promising approaches.

The road to effective therapies for HD is long. While we are not at the end of this road yet, it’s clear that we’ve made major progress along the path. The developments presented at this meeting leave us energized, excited and hopeful for the future of HD therapies.

Source: HDbuzz.net


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