thanks marsha

why is my reply to Marsha way up a few posts before her last one , about the occupy camp ?

This whole discussion gets me so emotional! I pray so desperately for this to work!! I'll be right with you, Marsha, fighting the insurance companies, because it would be a form of torture or assisted suicide to withhold this therapy for people with HD if it works!!

Marsha, thanks for your response. I am hearing that the five year target is a good one but that will require that Alnylam move forward aggressively. To answer someone else's questions, monkey trials have been performed with good results for distribution and knockdown and negligible results on tox.

Medtronic is the one is who more motivated to push this forward. They are the delivery device people who are taking on the blood-brain barier with their devices. Here we are talking about a surgically implanted pump in the chest and a surgically implanted stent in the brain, and Medtronic is currently pursuing this same approach with Lilly's GDNF for Parkinson's. Humans are next. If you recall, Amgen tried this GDNF approach back in 2004 with no benefits and some lawsuits in which brain damage occurred, so they are trying to get it right.

Marsha, perhaps you can explain if there is any different approach here with HTT, versus GDNF (Parksinson's), where the Huntington gene is known. I would think that would help us further in silencing the gene, before other neuro-degenerative diseases in which the gene has not been identified. ??

When this is ready for the HD trials with HTT and Medtronic delivery, it will involve early onset patients.

Thanks, Ty



Edited 1 time(s). Last edit at 01/07/2012 01:29PM by TylerFitz.

The delivery of GDNF, a neurotrophic factor thought to protect dopaminergic cells, to the brains of Parkinson's patients is controversial. It is helpful in animal models but the PD animal models are not as good as the animal models for HD. We have a genetic model but the PD animal models are based on acute insults to the brain that mimic PD damage whereas PD is a slowly progressive disorder. There are small studies showing benefits of GDNF for PD patients but as the studies get larger the results don't hold up. That raises several questions. The big one of course is whether the results in animal models are really proof of principle so that one could expect the same results in people assuming all is done is safely and effectively? Assume for argument's sake that that is true (although we don't know), then why haven't the results been good? Is the delivery effective? Is the right area of the brain being target? Are safety problems preventing good results? The whole thing is really puzzling because if GNDF really has potential than problems of safety and delivery should be worked out. But what if it doesn't?

The latest approach to GDNF is described here: [www.technologyreview.com]

A viral vector will be used to deliver the GDNF gene to the putamen. What is being done here is to ADD a gene, not silence one. Potential problems are 1) whether neurotrophic factors might encourage the growth of tumors after a number of years and 2) whether the gene will insert itself in a problematic place. Sometimes the gene will insert itself into the genome in such a place that will cause more problems. There is a genetic defect that causes children to be born without functioning immune systems. Experimental therapy was tried several years ago to insert the correct gene and it worked! However, the gene was inserted in a place where it causes genes to be turned on whose expression causes leukemia. So then the children had functioning immune systems AND leukemia. They were treated for leukemia and I believe one died and the others survived.

A comparable study being planned for HD involves delivering BDNF to HD patient brains although the delivery method will likely be mesenchymal stem cells rather than a viral vector and I believe that the MSCs will be engineered to overexpress BDNF so there won't be a problem with an insertion of the BDNF gene in the wrong place. Another difference that I see in potential GDNF and BDNF is that with HD patients we already know BDNF is reduced so a therapy of some kind that increases BDNF is really aimed at fixing a known problem whereas as far as I know GDNF is not reduced in PD brains (I have asked several neurologists and they have said not as far as they know), so GDNF therapy would be aimed in achieving ADDED protection.

What RNAi and antisense therapies involve is silencing the HD gene. The issues are effective delivery (it doesn't naturally cross the blood brain barrier), safety (the primate study was short term), and whether to pursue an allele specific strategy.

Delivery methods have improved, we have the primate safety study, and an argument can be made for moving ahead with a non-allele specific strategy just as an argument can be made for pursuing an allele specific strategy. But at some point we are going to take a leap in the dark and go forward. I think that gene silencing strategies have the potential to be a virtual cure but really no one knows if unforeseen problems will occur in clinical trials with people. I don't want to discourage people but it's important to understand in entering clinical trials that they might not result in a valid treatment (that's why we are having the trial, to find out) and that safety issues are always a potential problem (again, that's why we're having the trial to find out).

This gives me more stuff to read up on, and I am sure I will get more excited. I am encouraged!

Marsha, thanks for the follow-up, that's good stuff!

It seems to me that everything with HD is pretty slow. Why CO10 Five years times 3, its a supplement, creatine 3 years times 3. I am too very excited about what I have read on gene silencing and seems to be the most viable with the pump already used. I know I can make 5 years, but I hope this at least makes that. I also would be very interested in the clinical trials, as I sure all of us are. Keep us informed.

Hi, I'm new. My husband has just tested positive. He is showing the beginning symptoms of H.D. His number is 45, and he is 42 years old. I hope he can get this "gene silencing " as soon as possible. We have 2 boys 10 and 12, and I have promised them that we would go where ever the treatment is being offered! I have to give them some hope, and I pray to God this is our cure!

Marsha,
I read all of this information on the RNAi, and I'm obviously so excited, but I'm also so scared, should I be? Everything I read about it gives me such hope, but also extreme anxiety, because it sounds so intense, to say the least. (but then I think 'I guess it would need to be, though, to cure such an intense disease like HD') I don't want to come across as negative, because I've never been more hopeful about anything . . . but when I think of my son, who is at-risk, this procedure scares the daylights out of me, too (although, I know if, God forbid, he were positive, he'd probably sign right up for the clinical trials!!).

Also, I'm just wondering, how often would a person need to have this procedure done? Would it be a one-time thing or multiple procedures (brain surgeries, I guess) in order to keep the gene silenced? So much hope, but so much fear, too . . .

By the way, thank you for all that you share and do! I always love reading your posts and all the knowledge and info that you have.

Michelle

What is uptoday on RNAI

Thanks

Here's the latest article I've written about gene silencing. Clinical trials could start within 18 months. [www.hdsa.org]

Michelle, I do think this is somewhat scary because it's new and it's the brain and people are more complex than monkeys. It would be a recurring treatment, at least at this point in time.

Another piece of news is that Dr. Jan Nolta did get the funding she wanted to move forward with mesenchymal stem cell delivery of BDNF to the brain. I believe that clinical trials are projected to take place in two years. While this is not gene silencing, MSCs can also be engineered to delivery RNAi if this is shown to be a good delivery method.

Did you see this article?
[www.scientificamerican.com]

Common Lab Dye Found to Interrupt Formation of Huntington's Disease Proteins
A small molecule agent like methylene blue that has been grandfathered into approved use as a diagnostic tool in humans can be studied further as possible treatment for the neurodegenerative illness

By Kathleen Raven

.From Nature Medicine's "Spoonful of Medicine" blog:

A compound already sitting on the shelves of biomedical laboratories and emergency room supply closets seems to interrupt the formation of neurodegenerative protein clumps found in Huntington’s disease, according to a preliminary animal study published August 7 in the Journal of Neuroscience.

This versatile agent, called methylene blue, gets a mention in medical literature as early as 1897 and was used to treat, at one time or another, ailments ranging from malaria to cyanide poisoning. The U.S. Food and Drug Administration has never formally approved it as a therapy for any illnesses. But that fact hasn’t stopped biomedical researchers from tinkering with the agent’s apparent ability to improve cognitive function. And although the new paper out today relies on a Huntington’s disease model in flies and mice, scientists are hopeful. "Because of existing knowledge of methylene blue and the fact that it’s not harmful to humans, I would hope that progress toward clinical trials could go relatively quickly," says Leslie Thompson, a neurobiologist at University of California–Irvine and lead author on the new study.

Huntington’s disease occurs when the C-A-G sequence of DNA base pairs repeat too often on the HTT gene, resulting in an abnormally long version of the huntingtin protein, that therefore folds incorrectly and forms clumps in the brain. The illness usually begins to affect people in their 30s and 40s, causing movement problems and early death. No drug is currently available to stop the disease from progressing.

For their experiment, researchers fed methylene blue mixed with food for a week to Drosophila flies engineered to carry a mutated copy of the HTT gene. An examination of the flies’ brains showed that protein clumps had been reduced by 87 percent compared with a control group. Meanwhile, mice designed to carry the mutated gene were given methylene blue and underwent several tests to assess mobility. At two months of age, the treated mice showed abnormal clasping of their hind claws only 20 percent of the time in a reflex test, whereas their untreated counterparts clasped at a 60 percent rate. (Less clasping meant healthier mice.) While the number of mice used was not sufficient to provide statistically significant results and the difference in the test quickly dropped off at nine weeks of age, Thompson still views the data as hopeful, because even a delay in Huntington’s symptoms would be very helpful. Thompson quickly points out that more research is needed. "The early steps of aggregation [protein clumping] are getting altered in a test tube, in flies and in mice—and that’s significant," she says, and speculates that methylene blue may possibly prevent the mutant Htt protein from sticking to itself.

What these findings mean for the approximately 25,000 to 30,000 individuals with Huntington’s disease in the U.S. right now is that a small molecule agent like methylene blue that has been grandfathered into approved use as a diagnostic tool in humans can be studied further as possible treatment for the neurodegenerative illness. "This study shows promise pre-clinically and follow-up studies are needed in a more representative mouse model that expresses the full-length Huntingtin protein and allows more study of the disease’s neurogenerative properties," says Albert La Spada, a neurogeneticist at the University of California–San Diego. Thompson underscores this point as well: "Methylene blue would absolutely require further testing in mouse models and would need safety and efficacy trial before it could be used for humans."

This article is reproduced with permission from the magazine Nature Medicine. The article was first published on April 7, 2012.