I am interested in participating in the best clinical trial I can get in to and specifically those targeting Alpha synuclein. So I want to understand ASN and related trials and here is how I interpret the info I've read:
Alpha synuclein (ASN) is one of the most common proteins in your brain – it makes up about 1% of the protein in each neuron. It is very plentiful. What does alpha synuclein do? One thing we know is alpha synuclein is involved with normal synaptic functioning. More recently, we have learned that alpha synuclein is playing an important role in the handling of vesicles at the synapse. It acts as a protein buffer, helping to cluster vesicles at the synapse without affecting the release of the chemical messengers.
That is my basic understanding and I find it super helpful to follow this blog:
I reached out to Simon, the research scientist who runs the blog, and asked about the PASADENA study and expressed my concerns about indiscriminate removal of ASN. Here is what he shared:
"It is important to understand that the approach the researchers are using in the PASADENA study is not ‘indiscriminate’ in its removal of alpha synuclein. PRX002 (the drug being tested in the PASADENA study) is an antibody-based treatment that targets a specific aggregated (or clustered) form of the alpha synuclein protein which is believed to be toxic. It does not affect normal (un-aggregated) alpha synuclein. Exactly what PRX002 is targeting (the precise epitope) is a trade secret for company running the trial: Prothena.
As to the long term consequences of this approach, it all depends on where you stand in the great ‘alpha synuclein’ debate. If you think that aggregated alpha synuclein is the bad guy in PD, then removing it is probably a good idea. If, however, you think that aggregated alpha synuclein is simply an innocent man getting caught in the wrong place at the wrong time, then maybe it’s not such a great idea to remove it. There is some evidence to suggest that the aggregated form of alpha synuclein may be a defensive mechanism inside the cell – playing a role in protecting cells from viruses
(scienceofparkinsons.com/201.... Only time will tell if the PASADENA approach will work. One concern I do have with the study is that the clearance of alpha synuclein alone may not be enough. Perhaps they also need a anti-inflammatory or neuroprotective approach to real slow/stop PD. Follow up studies will be required to address this. Interesting times for Parkinson’s research."
IF ANYONE IS IN THE PASADENA OR ANY ASN RELATED TRIAL PLEASE SHARE YOUR FIRST HAND EXPERIENCE OF COURSE I WELCOME ANY RELATED INSIGHTS.
Simon said, "... it may not be such a good idea." (if a/syn is a consequence and not a cause.) I wish he would've elaborated on what the downside might be. Can it be both protective and toxic at the same time? Also, isn't that in conflict with the goal of Nilotinib being to up regulate autophagy? Seems like everything we've read, for years, says that when a/syn aggregates into the Lewy bodies, it becomes toxic. As you know, I'm a DIY Nilotinib user for the purpose of clearing the gunk out. It's a tough decision, p-oui. I also wish the authors of the theory that it's protective would've explained what it's protecting against, or did they?
I can't tell because I take a lot of other stuff, do fasting, exercise, etc. I take about a dozen supplements and didn't want to waste the time taking 2 or 3 months for each one individually. I believe I'm progressing slowly, though. Could be genetic, a robust regimen, plain, dumb luck or a combination thereof. I suspect if I was eligible for this trial, I'd get in. Seems like there would be more upside then downside from clearing out Lewy bodies. But, who knows?
"DIY" = do-it-yourself, i.e., I don't have the benefit of medical supervision. "Clearing out the gunk" refers to stimulating autophagy which is the process by which cells excrete or expel dead material, in our case a/syn.
Just in case you're considering this - don't. Nilotinib is a dangerous drug and if I haven't dissuaded you, I'll explain why.
I haven't read Marty Hinz's book or much of what he has published, so cannot comment.
This exchange took place over a very well written blog called The Science of Parkinson's. I posted my question at the end of this blog as Pamela and you can find it here: scienceofparkinsons.com/201...
I am also very interested in a calcium trial and hope to get into one. My question to Simon focused on trials generally and specifically those aimed at removing ASN clumps.
Simon, the researcher / blogger seems very receptive to questions and responded quickly.
As for the PASADENA trial, I struggled with the decision on this direct approach to removing ASN clumps via Prothena's experimental new drug for these reasons but also because Phase I of the drug showed no improvements though, to be fair, these were safety studies. Still...
Whew. Brain chemistry is more complex than astrophysics or even my relationship with my EX. I lucked out on this one though - I've been taking 5 mg, 2/day of Isradapine for couple years, now. I didn't see any reference to it being dose-dependent though. I guess this goes to show, if we take enough stuff, a few of them are bound to do some good.
Tell me about it! I am hoping that some combination of blind luck and a good guess will get me somewhere. I am starting with two 2.5 MG 2x Daily and will titrate up to 10MG daily on the Israpidine to mirror the trial out of Rochester but I am on the look out for other trials testing more highly targeted channel blockers.
Because I get my health care at the VA, they don't prescribe off label, so from shopping around I found that Isradapine is cheapest if you get a 90 day prescription and use a GoodRx coupon at Walmart - though I hate giving Walmart my business.
I haven't looked into ASN all that much, could it be similar to plaque in arteries? Ie the body lays down plaque where there's micro-tears, cholesterol doing a patch job?
The body does amazing things in the face of disease, but it's can be difficult to tell between what the body's response is and what the actual underlying problem is. Hope this trial reveals more.
All this makes me think of the contradictory attitudes towards amyloid plaques in Alzheimer's. It used to be seen as the villain in this condition (and still is in some circles) but a number of scientists are beginning to regard it as protective.
another thought provoking article, as offered in another article "it might make sense to treat it more like cholesterol—which is needed by all cells but dangerous in high levels—than something that needs to be completely eliminated"
I don't know a lot about Alzheimer's, but I think that the cholesterol analogy applies quite well to alpha-syn and PD.
It fits in with a key finding from familial PD, that too much alpha-syn (resulting from duplication, or triplication, of the SNCA gene), in and of itself, can cause PD.
Riveting. Thank you for posting. After reading through the articles I keep wondering how the challenge to our thinking around lewy bodies might be related to newly discovered Pa-Syn? I asked Simon and will share what I hear back if he hasn't kicked me off the blog LOL
Thanks for sharing this! It is so difficult to find any info on data from the trials and it takes too long for these reports to get generated. RE this:
"Brys said that as in healthy volunteers, BIIB054 formed complexes with α-synuclein in plasma. That both doses formed similar amounts of complex suggested near-complete saturation of blood synuclein with antibody. Attendees wondered why the antibody bound so much plasma synuclein if its affinity for monomers is so low. Brys explained that, although BIIB054 is more selective for aggregated than soluble α-synuclein, at high doses, it is expected to bind the soluble form. Brys said there were no serious adverse events, and no obvious worsening of PD symptoms in either placebo or treatment arms during this short trial. The SPARK Phase 2 study of BIIB054 is enrolling now.—Marina Chicurel."
It looks okay to me. They seem to be collecting the right kind of data. This should enable them to continue to move forward.
I would guess that the final dose selected will be closer to the low dose (15 mg/kg) rather than the high dose (45 mg/kg), since "both doses formed similar amounts of complex".
Thank you - If I were eligible (I am not due to Azilect) I would be very interested in this trial. Those who are not yet on PD RX might seriously consider it.
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OF COURSE I WELCOME ANY RELATED INSIGHTS.
More Reason for Cautious Optimism
LL-37, a natural antimicrobial molecule present in the brain and gut, Suppresses Alpha-synuclein Clumping in Parkinson’s
A fresh look at an old supp: Curcumin.
