Here's some good news from our friend, Gene Veritas, just in case you haven't seen it, about upcoming gene silencing trials.

Judy

That does sound promising. Thanks for the post.

Mike

Very exciting!! I wonder what will be considered as early symptoms? Do you know Marsha?

This is very encouraging. I remember talking with Jerry the Lighthouse founder back in the days when HDAC and the Lighthouse were separate sites and agreeing with him antisense gene silencing would probably be the cure.

Let's hope that Isis can pull this off, but if they can't there are other pharmaceutical companies frantically trying to get their RNAi technologies to trial too. And Dr. Jan Nolta and Dr. Vickie Wheeler are starting their own clinical trial using mesenchymal stem cells as a vector. They are starting with BDNF and then moving to RNAi.

There are other techniques not so far in development which may be even better in the long run- allele specific antisense and allele specific RNAi and crispr to cut out the extra CAG repeats. We also have proof of principle in animals that induced pluripotent stem cells (from adult skin cells) can be induced into the brain for restoration. That is much longer down the road but it is coming too.

In short, this just might be the beginning of the end but we are not there yet and clinical trials take years. We need to make sure that we in the HD community stay as healthy as possible, eating well, exercising our bodies and brains, and avoiding stress so that we can be ready for the treatments in the works. This applies to those at risk and HD patients but also to caregivers because we are going to need to be at our best to advocate.

And for those who at risk and who have tested positive, don't let HD rob you of your hope and joy in life. If you allow the prospect of getting the disease in the future to stop you from achieving your dreams and being happy now, think of how sorry you will be if the future brings the cure instead.

Yes Marsha! We need to hold on to hope!

I'm holding on too !! Thanks Marsha!!!

I'm holding on too !! Thanks Marsha!!!

Marsha, I am curious.

What is the potential method of delivery and what could the possible dangers be to those who first start the trials. I'm not trying to be a downer here. Just curious.

Also, why does stress exasperate everything so quickly?

Thanks,

Mike

Mike, since it will be the longest answer, I am going to tackle your second question first. The answer is that we don't know.

Sometimes in research, we know what we don't know, ie we have a series of question in mind that need to be answered. For example, at first we didn't know if stem cells introduced into the brain could survive. We now have proof of principle in animals that they can. Then we didn't whether those cells just sat there doing nothing useful or whether they integrated into the brain, forming networks and interacting with other cells to do the work needed. We now have proof of principle in animals that they do.

Other times in research, we don't know what we don't know. We don't ask the right question because no one even thinks of the possibility. In the case of gene silencing, there are known pitfalls to avoid such as off target responses. For example, we want the HD gene to be silenced, not any other gene. So we look to make sure that that isn't happening in animal models. And in fact it DID happen in some of the formulas which were then discarded in favor of the ones that didn't cause off target problems.

But there can be problems that no one tries to avoid because no one even thinks of them. Here is a good example. In 2002 and 2003, it was reported that three of nine children in France who had been cured of severe combined immunodeficiency disease (SCID) with gene therapy had developed cancer two to three years later. Children born with this disorder will die in the first year of life unless they can find a matching blood marrow donor, which is hard to do because it really has to match in a lot of factors unlike a regular blood donation that you might need because of surgery for example.

Because this is a recessive disorder, adding a normal gene should cure the disease and give the children a functioning immune system. And in fact, it does just that. The unanticipated problem was that the gene doesn't insert itself into the normal place it should appear. It inserts itself in front of another gene and activates it. When that gene is turned on when it isn't supposed to, it will cause leukemia. And that is what happened. This problem was overcome once it was known to occur but no one anticipated it and frankly I don't see how they could have.

So researchers try to look at every possibility. They do primate studies. They continue their studies for months. But something could still go wrong that hadn't shown up before, either because we are different in some way than mice and primates or because the studies don't go on long enough to show problems that occur a few years down the road.

When we do a trial of creatine or CoQ10 the risks are lower because a lot is known about how humans react to these supplements. But there are still risks. When we manipulate genes and gene expression, we are still taking a leap into the dark. Personally I think it has to be taken because it is our best shot at a cure. The HD protein causes so many problems, it is hard to imagine how to treat them all. But we don't know which of several competing gene silencing techniques would be best and we don't know, not for sure, what kind of side effects may occur in any or all of them.

When something important like the SCID trial or the HD ASO trial comes along, we get excited and hopeful. And we should because the payoff is so great if proves to be safe and effective. However, when we sign up or a loved one signs up for the trial, we read over the consent form and we see warnings about possible known side effects and possible unanticipated side effects and we don't really see them, we see CURE in our minds. But we have to be aware that any trial may result in a finding that a potential treatment is actually not effective or not safe or both.

What I want to do here is to educate people about the disease and about potential treatments so that we can really make informed decisions. There have been trials I would sign a loved one up for, trials that I thought were low risk but not likely to pay off (CoQ10) that I wouldn't have, and at least one trial I felt was too risky, the fetal cell transplants back in the late 90s for which patients were charged $50,000 (yes, really). Now, I am not a doctor and I am not a medical researcher. I am a sociologist. But we don't get to trials without a lot of background research and I can read a research report and tell others about it and if there's something I don't understand I write to the researchers. I have loved ones with the disease and I want to have an informed opinion. I want you to have an informed opinion -- and it may very well differ from mine which is fine. The important thing is not to go into these trials without understanding why they are being done and what the evidence for them is to date. We also need to understand our own personalities. If you cannot bear to make a mistake, then perhaps clinical trials are not for you and you need to wait until a treatment is approved. If you want to be fighting on the cutting edge, then it may be. Some people are risk averse and some are risk takers. But my thoughts are that we should know what the research shows to date and know ourselves (or our loved ones). Then, whatever happens, we have made the best decision we could at the time, which is all we can ask of ourselves and others.

I have not been writing now about research for about a year and a half because others are and I need a break, but I have written about the background research associated with all the clinical trials going on now. I will update the site with more information about ASOs and the trial before next spring.

NICE..............

Hi Marsha....

very concise..... you are brilliant as always.... i actually understood that well.......
thanks for dumbing it down for me...........

Looking forward to some good news.............. I believe it will happen.... In the mean time,
look forward to your next discussion on the subject of 'what's coming up'.......

but mostly.... thank you....
say hi to Steve for me........... hope the family is well.... I should drop by more often.....

NICE! Thank you for the breakdown. It is much easier to put into perspective and as skmf12 says it is very concise as usual. Knowing there are good works in process is very encouraging not only for us now but future generations who also have to bear the burden.

Thanks for all you and Steve do.

Mike

Thanks for the great write-up, Marsha. And thanks for inspiring us to stay healthy and positive!

Judy Galasek