Press release from CHDI: [www.highqfoundation.org]

Proceeding to IND work tells us that this therapy (if regulators approve) is approaching first safety studies for HD. Safety will be critically important and we can be sure they are working hard to overcome some of those issues. Advancing to safety studies doesn't mean it will be here tomorrow -- but this is evidence for a very big step towards a very exciting way (potentially) to treat HD.

Thanks to CHDI for being an "enabler" to help push this along.

Sounds very exciting - the link wasn't working for me... would love to read more about it...

great, thank you

I'm trying to find out if they are preparing for an allele-specific trial or not.

I've applied for a log-in; waiting to hear back. If I get it, and nobody else has done this yet, I'll try to copy-clip the article here.

That link just took me to a title - SIRNA Targets Huntingtin. I poked around looking for the article and couldn't find it. I'll volunteer!!

Will

Alnylam, Medtronic, and CHDI Foundation Form Collaboration to Advance RNAi Therapeutics for the Treatment of Huntington's Disease
Commitment from CHDI to Fund up to 50% of Development Efforts toward IND Filing to Advance ALN-HTT, a Novel Drug-Device Combination


Cambridge, Mass., Minneapolis, and New York City, November 3, 2010 - Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), Medtronic Inc. (NYSE:MDT), and CHDI Foundation, Inc., announced today that they have formed a collaboration to advance ALN-HTT, a novel drug-device combination for the treatment of Huntington's disease. ALN-HTT consists of an RNAi therapeutic targeting huntingtin, the gene responsible for Huntington's disease, that is being developed for delivery to the central nervous system (CNS) using an implantable infusion system developed by Medtronic. CHDI is a not-for-profit virtual biotech company that is exclusively dedicated to rapidly discovering and developing therapies that slow the progression of Huntington's disease.


"Alnylam and Medtronic have shown leadership and encouraging progress in developing a novel drug-device combination for the treatment of Huntington's disease," said Robi Blumenstein, President of CHDI Management. "Their collaborative approach demonstrates a combined commitment to tackle this devastating disease and this program is closely aligned with CHDI's mission. We welcome the opportunity to accelerate this program and look forward to continued advancement toward clinical testing in patients."


Alnylam and Medtronic have worked collaboratively to advance ALN-HTT for the treatment of Huntington's disease. Under this new collaboration, CHDI has agreed to initially fund up to 50% of the investigational new drug (IND) application-enabling activities. The agreement between Alnylam and Medtronic will remain as a 50-50 partnership in the United States. Medtronic will commercialize the therapy consisting of the RNAi compound and delivery device. In the United States, Alnylam has the opportunity to invest in clinical development through product launch in return for a proportional share of the profits. In Europe, Medtronic is solely responsible for development and commercialization, and Alnylam is eligible to receive milestones and royalties.


"We are very pleased to add CHDI as a partner in our Huntington's disease program; they bring a tremendous amount of disease area expertise that will contribute to advancing ALN-HTT towards the clinic with Medtronic," said Dinah Sah, Ph.D., Vice President, Research, at Alnylam. "Our pre-clinical data provide a strong rationale for this program, and we remain encouraged by the potential that ALN-HTT may offer to patients."


Over the course of the existing collaboration, pre-clinical data have been generated supporting the continued development of ALN-HTT for the treatment of Huntington's disease, including:
- demonstration that an siRNA targeting the huntingtin gene achieves

sufficient distribution for coverage of brain regions affected in

Huntington's disease;
- data showing that direct delivery to the CNS results in robust silencing of

the huntingtin gene mRNA which was achieved at substantial distances

from the infusion site, an important step towards translating this delivery

approach from pre-clinical models to the larger human brain; and,
- results showing that ALN-HTT is well tolerated following continuous

direct CNS administration over a period of approximately one month.*


"The ALN-HTT program represents an exciting opportunity to combine innovative medicines with our drug delivery technology in an area of extreme unmet medical need," said Gregory Stewart, Ph.D., Director of CNS Drug Therapy R&D in the Neuromodulation Business at Medtronic. "With no effective disease-modifying therapies available currently for patients afflicted with Huntington's disease, the collaboration between Alnylam and Medtronic, and now support from CHDI, will work to develop a novel treatment strategy for this devastating neurodegenerative disease."


About Huntington's Disease
Huntington's disease is an autosomal dominant neurodegenerative genetic disorder that causes motor, cognitive, and behavioral dysfunction. It is estimated that 120,000 people in the U.S. have the genetic mutation that causes Huntington's disease and will experience symptoms during a normal lifetime. The average lifespan for patients after onset of motor dysfunction is approximately 10 to 20 years. There are currently no disease-modifying therapies available to slow the progression of Huntington's disease.


About RNA Interference (RNAi)
RNAi (RNA interference) is a revolution in biology, representing a breakthrough in understanding how genes are turned on and off in cells, and a completely new approach to drug discovery and development. Its discovery has been heralded as "a major scientific breakthrough that happens once every decade or so," and represents one of the most promising and rapidly advancing frontiers in biology and drug discovery today which was awarded the 2006 Nobel Prize for Physiology or Medicine. RNAi is a natural process of gene silencing that occurs in organisms ranging from plants to mammals. By harnessing the natural biological process of RNAi occurring in our cells, the creation of a major new class of medicines, known as RNAi therapeutics, is on the horizon. Small interfering RNAs (siRNAs), the molecules that mediate RNAi and comprise Alnylam's RNAi therapeutic platform, target the cause of diseases by potently silencing specific mRNAs, thereby preventing disease-causing proteins from being made. RNAi therapeutics have the potential to treat disease and help patients in a fundamentally new way.


About Alnylam Pharmaceuticals
Alnylam is a biopharmaceutical company developing novel therapeutics based on RNA interference, or RNAi. The company is applying its therapeutic expertise in RNAi to address significant medical needs, many of which cannot effectively be addressed with small molecules or antibodies, the current major classes of drugs. Alnylam is leading the translation of RNAi as a new class of innovative medicines with peer-reviewed research efforts published in the world's top scientific journals including Nature, Nature Medicine, and Cell. The company is leveraging these capabilities to build a broad pipeline of RNAi therapeutics for the treatment of a wide range of disease areas, including respiratory syncytial virus (RSV), liver cancers, TTR-mediated amyloidosis (ATTR), hypercholesterolemia, and Huntington's disease. In addition, Alnylam formed Alnylam Biotherapeutics, a division of the company focused on the development of RNAi technologies for application in manufacturing processes for biotherapeutic products, including recombinant proteins and monoclonal antibodies. The company's leadership position in fundamental patents, technology, and know-how relating to RNAi has enabled it to form major alliances with leading companies including Medtronic, Novartis, Biogen Idec, Roche, Takeda, Kyowa Hakko Kirin, and Cubist. Alnylam and Isis are majority owners of Regulus Therapeutics Inc., a company focused on the discovery, development, and commercialization of microRNA therapeutics. Founded in 2002, Alnylam maintains headquarters in Cambridge, Massachusetts. For more information, please visit www.alnylam.com.


About Medtronic
Medtronic, Inc. (www.medtronic.com), headquartered in Minneapolis, is the global leader in medical technology - alleviating pain, restoring health and extending life for millions of people around the world.
Any forward-looking statements are subject to risks and uncertainties such as those described in Medtronic's periodic reports on file with the Securities and Exchange Commission. Actual results may differ materially from anticipated results.


About CHDI Foundation, Inc.
CHDI Foundation, Inc. is a privately funded, not-for-profit, virtual biotech company that is exclusively dedicated to rapidly discovering and developing therapies that slow the progression of Huntington's disease. CHDI's scientists work closely with a network of more than 600 researchers in academic and industrial laboratories around the world in the pursuit of these novel therapies, providing project management to ensure that their common goals remain in focus. This helps bridge the translational gap that often exists between academic and industrial research pursuits that adds costly delays to therapy development. In its role as a collaborative enabler, CHDI seeks to bring the right partners together to identify and address critical scientific issues and move drug candidates to clinical evaluation as rapidly as possible. CHDI's activities extend from exploratory biology to the identification and validation of therapeutic targets, and from drug discovery and development to clinical studies and trials. More information about CHDI can be found at www.chdifoundation.org.


* 2009 World Congress on Huntington's Disease; September 12-15, 2009; Vancouver, British Columbia

oh my gosh- this is so great!! I will keep praying.

OK, that sounds very promising.

But curious what is the delivery device? Injection, surgery, ???

If it will substantially help HD, they can be as invasive as needed; but I'm just curious.

The last I heard it was a pump imbedded at the base of the spine.

Any info on how near or far we are from trials in humans? will they be trying this in mice first?

So Sorry my link didn't work. Thanks Marsha for getting up the whole document.

The delivery system is a catheter tube that is placed directly into brain. This is done by a surgical procedure (using x-ray to guide) where a needle (with the catheter inside) is placed up against the caudate area of brain. The medication is then delivered via the catheter from a pouch placed under the skin. At least at the last update I attended, they would need to place catheters on both sides.


They have tested the drug in rodents, and monkeys, If my memory is correct they will also test in the larger sheep brain. The problem isn't whether the drug can lower huntingtin protein -- but delivery -- whether they can get it to all areas in the brain. And though there is work on allele specific therapy at ISIS and others -- I don't think it's ready yet.

Certainly more risky than a pill -- but this type of therapy would be a real "game changer" stopping the disease at it's source.

This is so nice to read about. Thanks so much for sharing this with us...we still have to hang on to that hope!

If it's not allele specific... it will shut down both genes and no huntingtin will be available at all?

Amazing news!

Eric, I don't think they can shut down the whole production of huntingtin. The protein, even thought we don't know a lot about what role it plays, is nevertheless very necessary.
Somewhere I read they were trying to determine what percentage of the huntingtin protein could be shut down and that it is probable that as much as an 80% reduction would be well tolerated.

Wow, this definitely sounds so promising, but I have to say it also sounds very intense and scary. Would this mean testing would take place as early as possible and this procedure done well before symptoms appear, possibly in children?

I have an update on interfering RNA therapies on the HDDW site based on the CHDI meeting in spring 2010 that contain some of this information [hddrugworks.org]: If this link doesn't go through (my computer has been misbehaving), it's on the lower left side of the front page.

Non-allele specific RNAi will not need to lower huntingtin protein more than 40 or 50%, This level has been shown safe in animal models (if the gene is turned off in adulthood). Knocking both out completely is toxic, so the goal is NOT to lower it completely. CHDI helped with this by developing a mouse who's HD gene could be turned on and off. This way they could measure how much lowering appeared safe (at least in the mouse), and how much was toxic. Will it be safe for people used long-term? Won't know until it is tested. But one thing I've learned from CHDI's clinical director Dan van Kammmen is that they pay high attention to safety even when it means going slower. They won't recommend using any treatment in people before they can measure -- in people -- whether it is hitting the target, and can evaluate dose/toxicity in people. Just a guess, but I bet they have a way of measuring huntingtin protein levels in brain -- or something just as good. I don't think they would take this to the FDA otherwise.

Another awesome thing was reported by Dr. Cleveland from San Diego at the recent HSG conference on a slightly different kind of RNAi (ISIS oligonucleotides) -- it takes a few weeks for the drug to lower huntingtin protein -- but after stopping the drug the beneficial effect lasts much longer than two weeks when mutant protein levels returned. Which could mean that the drug could potentially be effective if given at long intervals (every 2 or so months) instead of continuously -- which would give the chance for the normal huntingtin to regain its positive function. This is sort of what happens with many cancer drugs, and immune type of drugs used in MS and rheumatoid arthritis etc.

It would not be used in children first (the FDA would not allow that), Neither will the FDA allow its use in presymptomatic individuals before it been shown to work in those who have symptoms.

Yes this type of therapy will be hard. But we won't be the first to use it. Its used to deliver chemotherapy to brain tumors and a similar process was used in the Parkinson's (GDNF) trial -- which failed because the delivery catheter device had problems. Medtronic reports that it has corrected that problem with its new system.

Will says he will sign up -- and I'd recommend it for my family and my patients when van Kammen and group shows us they have a way of measuring the biochemical response adequately.

This is very positive news, any idea what kind of time line we are looking at (if things go to plan) before this is trialled in humans? I'm behind Will in line, you can go first buddy... I'm sticking to a safe and solid second

[www.hdyo.org]

What will happen if it's not safe?

I am trying to wrap my head around the mixed messages I am getting since we are essentially messing with my kids.

We are saying that creatine and memantine are bad.. and don't mess with them. There might be some minor downside to them. So those are too dangerous to bother with. But something that on the one hand is fatal (the mutant gene) and on the other hand has a tandum gene which is toxic if brought too to low a level and we have no idea what that level would be ... this is something one should enter a trial for? So we risk all the marbles... if we can win all the marbles back.. but gaining a few marbles and possibly ( with thin evidence) trading one marble for it is no good? LaVonne, if your kids are symptomatic or gene positive... you wouldn't go with creatine for them, or memantine later. But this you would with all the very big ramifications?

I don't know what kind of population we are trying to encourage . One who is encouraged to try, or one who is kept on hold for the one big risky hit. Everything else with the slightest risk we aren't recommended to try at all. Even discouraged from trying.

I am not saying this isn't important... it feels a little too hyped already and I am feeling that possible false hope aura that makes me really skiddish. I am a long way from sticking needles in my kids brains.. or even thinking about it. I would say it's way too soon for anyone say they would do this with their kids. Even with all the "if's" attached. Early, mid-stage with a run at memantine for a month or two.. I have no problems exploring. And a don't know why one would chose one of these attempts and not the other.. and tell everyone else not to do the other as well.

For children.. if the latest findings are correct and huntingtin is essential in neurogenisis (cell division), we would probably need allele specific treatment.. leaving the normal gene alone. There would probably be a risk of leaving children disabled to various degrees this way as cell division is essentially child development, happening at a rapid rate. At least some heavy ethics would have to be sorted if medical certainty can't be established. Just my guess about that.

I think some ethics need to be looked at or some general philosophies adopted at the very least. We are getting some confusing messages without outside input. We are also starting to go places where a lot of people don't go if their need isn't dire. I will be interested in what a whole lot of other people have to say before I dive on one of many the many bandwagons. For me, this is in the "interesting development" category. Very far away from "we are all saved" category. It's a good time to get some p's and q's in order.

Hi All,


I'm biased - I'm working on allele-specific silencing.

But I just wanted to address something Eric said. He compared concerns about memantine and creatine to safety concerns with huntingtin silencing. I don't think they're the same at all. Silencing mutant huntingtin is in a class by itself in terms of potential therapies.

No one disagrees with the idea that mutant huntingtin causes HD - this link is indisputable. So turning of mutant (or all) huntingtin is cause for excitement. Cautious excitement, as Lavonne describes, but I think it's the most exciting thing happening in HD science right now. It's the only thing that, if it worked, would truly be a "cure".

Where we're at now is a bunch of pieces of the puzzle are there - we can regularly and easily silence huntingtin in cells in a dish, we've shown we can do it in various mouse models. Different kinds of chemistry work (siRNA vs. antisense, for example). What's been missing is this "enabling" work of putting all these things together and pushing towards human trials. This really seems to be happening now, and I for one am really excited about it.




jeff