I take this to be good news, offering some encouragement that RNAi is finally advancing...


Alnylam Announces Publication of Pre-clinical Results with ALN-HTT, an RNAi Therapeutic for the Treatment of Huntington’s Disease, in Experimental Neurology

December 28, 2011

CAMBRIDGE, Mass.--(BUSINESS WIRE)-- Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY - ??), a leading RNAi therapeutics company, announced today the publication of promising pre-clinical results in Experimental Neurology (doi:10.1016/j.expneurol.2011.11.020) related to its ALN-HTT program, an RNAi therapeutic drug-device combination for the treatment of Huntington’s disease.

The findings - the result of a research partnership between Alnylam and Medtronic, Inc., and supported by CHDI - demonstrate that a small interfering RNA (siRNA) targeting the huntingtin gene, when administered by intrastriatal infusion with convection-enhanced delivery (CED), results in widespread distribution of the siRNA and significant silencing of the huntingtin mRNA throughout the striatum. Furthermore, administration of the RNAi therapeutic was well tolerated in these studies. The authors of the paper include researchers from Alnylam, Medtronic, and the University of Kentucky where the work was conducted.

“These published data represent important advancements in our Huntington’s disease program across multiple dimensions. Indeed, these pre-clinical results extend our earlier reported data on siRNA biodistribution in the central nervous system and the degree and scope of therapeutic huntingtin gene silencing. We are also encouraged by the safety results following continuous intrastriatal infusion over approximately one month in this pre-clinical model,” said Dinah Sah, Ph.D., Vice President, Research, at Alnylam. “In aggregate, these studies, which were performed in collaboration with the University of Kentucky, support our continued and combined efforts with Medtronic and CHDI to advance this important research effort.”

The new pre-clinical studies employed direct delivery of the huntingtin-specific siRNA to the striatum using an implantable infusion system and CED. Direct delivery to the central nervous system (CNS) by intrastriatal CED for seven days resulted in broad distribution of the siRNA across the striatum and surrounding brain regions. This level of distribution of the siRNA resulted in the silencing of the huntingtin gene throughout the putamen by an average of approximately 45 percent, as well as reductions in the levels of huntingtin protein when evaluated by immunohistochemistry. This silencing of huntingtin occurred in a manner dependent on infusion rate and siRNA concentration.

A new pre-clinical model developed from these findings suggests that continuous CED of an siRNA targeting huntingtin has the potential to achieve physiologically significant coverage of the striatum of Huntington’s disease patients with therapeutically relevant drug levels.

“We are very pleased with these early results in our research collaboration, which continues to represent an exciting opportunity to combine an innovative therapeutic strategy with state-of-the-art drug device delivery technology for Huntington’s disease. A highlight of this study is that the pre-clinical results suggest scalability of RNAi therapeutic delivery to the striatum of Huntington’s patients,” said Gregory Stewart Ph.D., Distinguished Scientist, CNS Drug Therapy R&D at Medtronic. “The collaboration between Alnylam, Medtronic and CHDI marks an important effort to develop a novel treatment strategy for this devastating neurodegenerative disease.”

This research was done in collaboration with the laboratory of Professor Don M. Gash, Ph.D. at the University of Kentucky College of Medicine in Lexington, Kentucky. Some of these findings have been previously presented at the 2009 World Congress on Huntington’s Disease.

“These findings demonstrate the potential of RNAi therapeutics for the treatment of neurodegenerative diseases, and in particular, intraparenchymal CNS delivery of therapeutics as an important approach to drug delivery,” said Professor Don M. Gash, Ph.D. at the University of Kentucky College of Medicine. “We look forward to the continued efforts in advancing this therapeutic approach to patients with Huntington’s disease.”

Does sound encouraging!

Does "resulted in the silencing of the huntingtin gene throughout the putamen by an average of approximately 45 percent" mean that, if someone had a CAG of, say 42, it could be "silenced" down to something more like a 25? Or am I WAY oversimplifying/misunderstanding?

Bluegrasslady Wrote:
-------------------------------------------------------
> Does sound encouraging!
>
> Does "resulted in the silencing of the huntingtin
> gene throughout the putamen by an average of
> approximately 45 percent" mean that, if someone
> had a CAG of, say 42, it could be "silenced" down
> to something more like a 25? Or am I WAY
> oversimplifying/misunderstanding?

No - it means both the normal huntingtin (say, 17 CAG) and the mutant huntingtin (expanded allele, say CAG 42 ) were both reduced by 45%.

There have been studies that show animals seem to function fine with reduced normal huntintin (however it is essential during fetal development) and that reducing the mutant huntingtin protein by a certain amount (I'm not sure what percent) reduces HD symptoms and extends the lifespan of HD mice.

This study is particularly exciting because of the partnership between the medical doctors and Medtronic, the company that builds the delivery pump. Because the human brain is so much bigger than a mouse brain (which is what most drugs get tested on) there was concern that the siRNA drug wouldn't reach the necessary deep areas of the brain. But it works - so we now have a promising drug delivery system for the human brain.

Also - other researchers have found ways to potentially silence only the mutant huntingtin, in most people, using siRNA again. That would be the best case scenario but this is also very good news.

If you don't already know about it [hdbuzz.net] is a great resource to catch up on the research presented in a very accessible format. I subscribe to the site to get updates.



Edited 2 time(s). Last edit at 12/29/2011 10:39PM by dawnbuie.

So is this something that could actually be brought to the general HD population in 10 years or so? Or is it 10 more years of testing? I know no one can predict the future but just looking for more information. Thanks.

Patty

My best guess would be that gene silencing will be available in five years. This can be done either through RNAi or through an antisense drug. It's not clear yet which method will be available first. It's also possible now to silence the disease gene while leaving the normal one to function.

You can also keep up to date by reading my research updates on the HDSA site. I hope to get the Lighthouse back up to date in 2012 (I have gotten behind for personal reasons) but in the meantime, I do cover all the major findings at www.hdsa.org . (I have been consulting for them since 2007). The entire research section is mine. Links to the latest articles can be found on the left side of the home page.



Edited 1 time(s). Last edit at 12/30/2011 09:47AM by Marsha.

Marsha.

I know its and educated guess, but truly seeing that "five years" was the best gift you could have given me today.

I have followed the research on this for quite some time and have always thought it would be the best chance to achieve a real treatment for HD. I am happy that it is moving along, it seemed the major stumbling block was the delivery method since crossing the blood brain barrier is so difficult. This is exciting news!

Carla

That's so awesome!!

Yes!

That's great news.Will come too late for my daughter though,I doubt she has 5 years left : (

Marsha,

You and I were both certain and said to each other back 13 years ago that it would be the gene silencing that would eventually cure this illness. And it looks like that is finally coming to pass. I like everyone else who comes here have waited alot of years to be able to kick this HD dragon to the curb...This is great news.
I would like to say I won our bet but we both bet for gene silencing...lol



Edited 2 time(s). Last edit at 12/31/2011 11:29AM by Kelly B.

Thank you Marsha! This is very exciting.

Patty

dawnbuie Wrote:

> No - it means both the normal huntingtin (say, 17
> CAG) and the mutant huntingtin (expanded allele,
> say CAG 42 ) were both reduced by 45%.
>

So if someone has a CAG 42 and has been symptomatic for five years and that CAG is reduced by 45%, does that mean the person would stay at the level they are at, or go back to how they were before symptoms? My thinking is that they would stay where they are because of the damage to the brain that has already occurred. But I really don't know. Does anyone?

Patty

Yes Patty, when i heard dr hayden speak about this a couple of years ago, he said the idea would be to treat people that test positive, before they become symptomatic. He said those with symptoms that have had brain cells die, what would be ideal for them would be to silence the gene, and then to also add stem cell therapy to replace brain cells that have died, so both these areas of research are very good right now

Also, remember that some of the HD symptoms are caused by cell dysfunction rather than cell death. Once gene silencing takes place, something of a reversal of symptoms is expected to occur. There has been substantial improvement in mice after gene silencing even at fairly late stages of the disease. Barb is also right in that stem cell technologies are in the works which should also lead to improvement.

Thanks Barb and Marsha. That makes it clearer for me. Happy New Year to everybody!

Patty

I hope if this will get on market someday, it will be approved by health insurence in my country. Don`t know about the costs, but we had discussion about limit for very expensive treatments, but now they pay everything, Rare disease treamtents are often expensive treaments , is this true?



Edited 1 time(s). Last edit at 01/01/2012 08:45PM by sarmiento.

To be sure I'm understanding correctly: pre-clinical results means that the therapy has not been attempted with human patients yet, correct? But, within about 5 years (if Marsha's educated prediction is correct) trials with humans will start?

Does that mean that the only way a person could avail him or herself of the treatment in five years would be through inolvement in a trial? That the therapy will not be available to the general public that soon?

I'm very much hoping that my assumption is incorrect, and that, perhaps, the therapy will be available to all patients in five years. If so, then it would make sense, at that point, to test our son, right? (Assuming the therapy is available and works, and our son is at-risk, that is . . . )

I'm so excited about this, but am trying to remain realistic, too. I don't want to get my hopes up TOO much. Still, it feels good to be hopeful. And I definitely am!

We have our first appointment at the COE on Wednesday (had to postpone it because of some obstacles we hit in getting our LTC insurance in place). We're pretty sure that my husband won't be getting blood drawn this week, though. It'll probably be mid-February, when all is said and done, before we get his results.

He had another two choking episodes over the weekend. :-( Hoping it's non-HD related, since it really would be odd, it seems, for him to be having HD-related choking now, since that is usually (as I understand it) a late-stage symptom. Still, it scares us. :-(

We had a nice weekend, though, other than that. I made an effort to push the HD anxiety from my mind, and had some success in that.

Happy New Year to everyone! It's nice to start the new year with some encouraging research/therapy news, isn't it?

I'm predicting availability in five years. I think trials will start in the next couple of years.

I'm working on my New Year 'where are we with gene silencing' article(s) for HDSA. I'm covering the Alnylam study and two other articles.



Edited 1 time(s). Last edit at 01/03/2012 09:54AM by Marsha.

Sarmiento,

There's no doubt that gene silencing is going to be expensive and I expect insurance companies will want to call it experimental as long as possible. (I will be happy to start an Occupy Insurance Companies movement on this issue, chain myself to pillars like the AIDS activists or whatever it takes!) In countries with public financing of health care, I can think we can successfully make the argument that treating HD, however, costly, is much, much less cheaper than nursing home and years of end of life care.