No, I didn't compare the safety of creatine etc. to anything else.. at least that wasn't the point. I am talking about discouraging people in one direction, and encouraging in another.. and using safety as the reasoning. I sited the payoff might be big here... but not sure I see anything that seems safe about it yet. I mean we are playing with the good gene here too aren't we? The gains from the others are small in comparison but any of those pesky little comments about their safety are pretty marginal. It's that I don't get promoting one.. and discouraging the other... if safety is the issue. It's about the philosophy of how we are being spoken to. And a touch of either hype or hypocrisy. I bet when this hits in "x" number of years.. no one will be saying don't do it, instead eat a good diet and get a good night's sleep. I am ok about people taking a leap if the day comes ... but for this very moment all we have are little jumps. A midstage person right now may not ever get to leap for this thing. So I don't get this.. "I will tell my kids to this thing".. but not want anyone else to do the other.

Jeff ... are you biased or is your direction, if successful, based on a rationale that points to it being a better way to go? I gather you may be a step or two behind in development. Or maybe not? I do understand that both directions are hypothetical in a certain regard. And it may not be in reality an "either/or" choice in practice. But if dreams were realized for both... wouldn't your path be the least evasive?

I'm very excited about gene silencing too and I can see the value of moving ahead with reducing levels of both the normal and the HD protein but I would prefer to have this done with antisense oligonucleotides while researchers work on allele specific silencing. If there's a problem with the ASO, the drug can be stopped while the effects of RNAi are long lasting.

I understand what Eric is saying. He's confused because Lavonne is very cautious these days about creatine or memantine, both of which my ex's doctor think might work and are low risk but she's not cautious about non-allele-specific gene silencing through RNAi which would seem to him (and me too actually) to be much higher risk. Does the potentially huge payoff justify the higher risk or would it be better to wait for ASOs or allele specific RNAi? This may be a real issue in my family, not an academic one, since my ex is interested in a gene silencing trial and will want my opinion and also since we don't know what other family members might test positive or become symptomatic.



Edited 1 time(s). Last edit at 11/04/2010 05:56PM by Marsha.

Any time horizon when sRNA or antisense maybe will be avaliable for doctors to prescribe for HD patients? 10 years from now?

Eric,

I think we should use caution with any supplement or approved drug as well as experimental therapy. And if there is any evidence for toxicity, I will recommend against such therapies outside of a clinical trial.

There was a time -- before trials for minocycline showed the negative (and clearly toxic for ALS) effects for HD, I suggested that it might be tried. Clearly -- I was very wrong.

I have no trouble recommending trehalose, for which no toxicity questions have been raised. It may help, so I say why not use it.

However, I do have concerns when memantine and HIGH dose antioxidant therapies (low dose okay) are used because of suggested toxicities when we don't have clinical trial evidence of benefit. That's why I don't recommend them outside of a clinical trial.

My message is consistent. We need to have as much safety established as we can with any proposed therapy. First trials -- which will take a while - with RNA interference will be exclusively for safety. If there are safety problems, then it's back to the drawing board.

Work towards an IND is just one more step forward that has been reached in development. CHDI is supporting studies that enable the companies to to go forward with focus on the safety and efficacy balance.

When we have a good safety and efficacy balance -- whether it is a pill or a brain catheter -- that's the time to stand in line.

Let's say that the RNAi therapy has no serious side effects or toxicity. What are the potential benefits? Would the chorea stop? Would speaking, swallowing, behavioral, cognitive symptoms, etc. be reduced or eliminated? Or would this simply stop the disease from progressing any further, keeping the current symptoms from getting any worse? Is there any evidence from the pre-clinical studies that indicate what the ceiling is for this treatment? It seems to me that assessing the risk associated with this would depend on what a "best case" scenario might look like.

There are two mouse studies that you can find on the Lighthouse. In the Yamamoto study (2000), a conditional mouse model of HD was made so that the HD gene could be turned off. Symptoms were reversed. They were pretty early in the disease process however so in 2006 Diaz-Hernandez repeated the study with later stage mice and got recovery of motor symptoms. So the hope is that gene silencing will do more than stop the disease from proceeding but result in some degree of recovery.

[hdlighthouse.org]

I agree with Marsha and Eric.
I am having very good results with trying 5ml of mementine and my docter thought it was safe to try .
But the thought of this RNA seems risky and scary to me.
So I would really need to be convinced!
Laura

I'm the caregiver for someone with HD and my son is at-risk, so when I read this and think about its' use for my son, it sounds so promising, yet so intensly scary. My son and I have had some conversations about this, because of the talk about it on the forum and the first thing he said was, "I'd try anything to not end up how Daddy is." So from the prespective of a person with HD or at-risk, this at the moment definitely seems like it could be the miracle they've been waiting for. I guess, as with anything else, we have to be cautiously optimistic.

Marsha - I agree with you about antisense. I'd rather use a drug we can stop using if there are safety concerns along the way. Oh wait, I'm biased again.

Something we should all be watching closely is the antisense study being done in familial ALS (Lou Gehrig's disease). Isis Pharmaceuticals is running a trial in the US in patients with this genetic form of the disease. More than one patient has already been dosed in the central nervous system with drugs that are chemically very similar to what we'd be using in to silence huntingtin expression for HD:

[clinicaltrials.gov]

If this works, it'll be a huge vote of confidence for the approach. Of course, there are some differences between ALS and HD. Most importantly, the protein that causes ALS seems more dispensable than the one that causes HD - so they may have an "easier" time with that trial than we will. But, if it works, it will prove that the tricky delivery issues that LaVonne and others have mentioned are getting worked out.

I think we all agree that we'd vote for an effective allele-specific RNAi therapy that is easily and safely delivered. But, two points:

First, it's impossible to know the best way to proceed to get to that point most quickly. That's why the CHDI money is supporting the work of both ISIS and Alnylam -- and several basic researchers working on different ways to silence the bad without decreasing the good protein.

And 2nd, No matter what type of therapy or drug gets to people first, each of these companies (and others we hope) will work to improve both efficacy and ease of delivery for the next drug.

This is just a step, and No doubt there is a ways to go . . L.

I think we need to remember that this is a long way away.. there are other trials coming up that may help manage HD more and more comfortably. This is one hypothetical treatment, which may or may not work or work well. Just like any of them. If you are not up to snuff on things in the pipeline... here is a link to what's going on.

[www.hdlighthouse.org]

Eric -

Why do you think this is a "long way away"? What information do you have that lets you comfortably suggest this? It's fine for you to be negative for yourself, but people are reading your posts here, so you might as well back up what you say with some data.

Here are some facts.

Alnylam and Isis both have multi-million dollar projects, supported in part by CHDI, to silence huntingtin for HD therapy.

Alnylam, Isis and a number of academic researchers have formed a "consortium" to rapidly develop this therapy. Like when the gene was found, researchers are working together with minimal competitive spirit, in hopes of moving the best option forward.

Isis, at least, has a track record of moving these molecules into people rapidly. They began a phase I trial in people of their fALS compounds less than 3 years after publishing their basic mouse work. Real people with a fatal genetic neurodegenerative disease are being given drug right now.

The mouse work for both siRNA and ASOs is rapidly being completed. This is not nickle and dime stuff. Major labs like those of Don Cleavland and Michael Hayden are exerting huge effort to get this done. So major studies on the efficacy and safety of ASOs, at least, are nearing completion.


So you can be negative and blase if you like, but I'm excited and hopeful. It's a nicer place to be.

Jeff, I think that there is a different sense of time here between HD families and HD researchers. I understand from your perspective that gene silencing is close - researchers have overcome one challenge after another, a great deal of money is being spent to move forward, and most importantly from my perspective, there's a strategic plan to get it done. I am tremendously excited about this.

But go over what you just said. A phase I study three years after publishing the mouse work. Isis hasn't published the HD mouse work yet, have they? Phase I, Phase II and Phase III studies have to follow with maybe some adjustments along the way (like the ACR16 trials needing to adjust doses) then waiting for the FDA to decide, then marketing. I would bet the farm on gene silencing succeeding, but it won't happen right away. From your perspective it's close and when I look at this as someone who lives, breathes and writes about HD research I see it that way too. But when I see it as a family member or as an advocate for families battling bureaucracies which don't understand HD, I don't see it as close because it's years away, isn't it?

Eric is losing his beloved wife right now. He has an adult son and a young teen. My ex, whom I love dearly, is ten years after clinical diagnosis. Steve's ex whom he also loves is in a nursing home. My daughter is 32 and my stepdaughter (or daughter of the heart as I prefer) is 27. We all have close friends with HD and people we care deeply about on this board who are symptomatic. HD families have decisions to make right now about how to treat symptoms that can ruin the quality of people's lives, decisions about how to manage health so as to benefit from gene silencing treatments of the future.

I am getting a little tired of the professional perspective that trying memantine, getting excited about the potential of ACR16, clinical trials for drugs to manage symptoms, or taking supplements or exercising to fitness are meaningless or silly in the face of the virtual cure to come. My family is not sitting back waiting for CHDI to save us all although heavens knows they'll probably do it.

Jeff, I don't know how long you have read, or what you read... right now as we speak, my wife is literately on her death bed... and I have not only survived 20 years of her HD but other family members as well. The cure, cure, cure people have rattled on about that for the whole time. Just like you .. and Lavonne are doing now. If you are right and when you are right I will gladly take "I told ya so". But not one person really helped me otherwise with the ups and downs of HD that whole time... nor will you if this is a total flop will you? No.

So I have developed my own coping skills and eternal hope and listening to "don't worry, be happy" isn't it. I know what messes have to be cleaned up over over-hype. And what you do and others are, to me, are no more than interesting developments.

How long will it take Jeff? Have a date? What will the FDA do with this? Are you saying my sons will be cured... are you saying have kids based on all this? What if it's a jhd kid? Don't think people don't take the hype to heart?... People say it still... they firmly believe a cure is right around the corner. Their kids will never be sick.

You can be as hopeful as ya want. Within the month my wife will be gone.. and I have lived though all the claims... and still ZERO.

Lastly I spoke to Robi several years ago... the timeline was 15 years... he was hoping... not hyping it.. just realistic in his mind. No guarantees or anything false. 5 years is a long time... 10 is longer. I have generation three, who, in any year from now to then, might be symptomatic. You won't be there for me with them.. or anyone else you speak to. Nor lavaonne nor CHDI. All this is single agenda... not at all sympathetic to anyone else.

I have a who lot of history to learn from. It's not negative. It's guarded from people who will say things way before they should have in a way the shouldn't.

So you want to argue dates of this "cure"? I have all of history to claim it's a long way away. What is long to you? Give me date that makes me any more wrong than you. I should bank on your outlook? Yes? This is positively gonna go smooth as silk... right? It won't have to go back the the drawing board... right?

Don't scold me about my attitude... I have deep concern for a lot of people and understand what you say affects them in many ways. Making them happy today can be a huge let down tomorrow... and the endless cycle of this ruins your and all others credibility each time it happens. We out here have to be ready for any eventuality... cure or no cure. And various treatments which carry many differing pros and cons.

I'm going to stop reading this site - I'm not finding the attitude useful. I'm sorry for the difficulties you all are having, and wish you the best.



If anyone needs any thing from me, I can be reached at: jcarroll@cmmt.ubc.ca. I'll be starting my new position in Boston eventually, but shouldn't be too hard to find.




Best of luck to all.

I appreciate all the information that you have all been giving in regards to this information.
Marsha & Jeff (if you are still here), please tell me what time frame we are looking at since we would need to go thru all the phases of trials for this. My husband is just starting to show signs now. Any hopes of it helping him?



Edited 1 time(s). Last edit at 11/06/2010 08:35PM by Sally.

quote from marsha:

Phase I, Phase II and Phase III studies have to follow with maybe some adjustments along the way (like the ACR16 trials needing to adjust doses) then waiting for the FDA to decide, then marketing. I would bet the farm on gene silencing succeeding, but it won't happen right away

So 8 years from now ? Too long?

Sally, yes, I think you can be hopeful.

Sarmiento, I think it can be less time than that. Right now, clinical trials are organized over multiple sites each with a separate institutional review board that has to give approval, and by staff with multiple responsibilities, not just research, so trials are taking a long time. I would imagine that the trials for RNAi and ASOs will be organized more centrally and efficiently so there aren't long delays while each site has to gear up to come on board or delays while the data is gathered up and sent in. Also, I am hoping that as a result of the observational studies like Predict-HD, COHORT, and Track-HD in Europe, we will soon have validated biomarkers to shorten disease modifying trials so they don't have to go on for 30 months. That's why these studies are so important and why I am so grateful to everyone who is participating. Also, if we can get the word out about future trials of any kind a little better and go beyond the Internet so that people can review the plans and those who feel the trial is right for them can sign up promptly we can shorten a lot of time there as well.

It's not that I am not excited about gene silencing. I've been writing about it for six years now and I think it's going to be a virtual cure. It's just that I am hopeful for treatments in the meantime as well, symptomatic certainly and maybe neuroprotective as well. It's never a good idea to put all of one's eggs in one basket. If there are any delays with gene silencing, unexpected challenges to work through, I want there to be other things in place. To me, that's just good sense.

There really is no need to leave, Jeff. You are very welcome here and you must know that people on the forum do get into some spirited debates here from time to time.

Thank you Jeff, I appreciate all your hard work and dedication. It is disappointing that someone like Jeff, who is contributing a huge amount to this community, is made to feel uncomfortable here.

[www.hdyo.org]

I'll second Mattie's comment. Jeff has a leg in both camps. His dual perspective as a researcher and a HD person is valued. Please stick around, Jeff.

Will