Friday, November 13, 2015

parkinson's: GM1 Ganglioside a cure?

Again and again, I accidentally come across some compound that seems to have profound effects for PD, and yet there is no one getting paid to tell us about it, so we never hear about unless it is through each other.  
For example, here's a phase 2 trial completed 4 YEARS AGO for a compound shown in the 1980's to help PD and it shows patients having a REVERSAL of symptoms for as long as they got the 2/day injections.   The patients were forced to stop taking it and began showing normal progression of PD in the 2 years since.   It seems to be very expensive as it needs to be derived from animals, but it might be much cheaper if there was a larger need for it.
JS Schneider has been publishing on GM1 for decades
http://www.ncbi.nlm.nih.gov/pubmed/26099170  (2015, 40 patients)
the clinical trial:
https://clinicaltrials.gov/ct2/show/NCT00037830  (subcutaneous injection, 100 mg, 2 doses per day)
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3532888/  (2012, 77 patients)
http://www.ncbi.nlm.nih.gov/pubmed/20206941 (2010, 16 patients, end of 5 year study)
http://www.ncbi.nlm.nih.gov/pubmed/9633704  (1998, 45 patients)
http://www.ncbi.nlm.nih.gov/pubmed/7783880  (1995 worked in 10 patients)
http://www.ncbi.nlm.nih.gov/pubmed/1613817  (1992 in cats)
http://www.ncbi.nlm.nih.gov/pubmed/1350379  (1992, primates)
http://www.ncbi.nlm.nih.gov/pubmed/2568945 (1989 mice)

http://www.ncbi.nlm.nih.gov/pubmed/6141701  (1983, different researcher, rats)

making body generate GM1, worked a little, using sialidase from bacteria
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4668049/


The link below is the first of 5 research papers in the 1980's showing its benefit for PD in animals.  There are literally 100 natural compounds that have shown the same results in animals, although many of them will probably not reach the human brain, including the most powerful. 
http://www.ncbi.nlm.nih.gov/pubmed/6141701
Three years ago GM1 was discussed on this web site:
https://healthunlocked.com/parkinsonsmovement/posts/631068/another-promising-find-again
And an interesting comment from one poster (3 years ago)
"In the last five years I have seen dozens of these studies. I never see where they actually go into treatment. I am receiving the same treatment I would have gotten twenty years ago. Seems odd."
Moreover, this natural compound may be the underlying reason nilotinib works.  The tyrosine kinase inhibitors like nilotinib induce GM1  (see 2006 article http://www.jimmunol.org/content/176/2/864.long ).   So it begs the question: exactly why are the researchers interested in leukemia's tyrosine kinase inhibitors in the first place?  Did they or Novartis see the work on GM1 and say, hmmm, is there a pharmaceutical that can do this?
There are 61 papers with GM1 Ganglioside and Parkinson's in the abstract.  Here's one of them:
"The nigral neurons of PD subjects that were severely deficient in GM1 showed subnormal levels of tyrosine phosphorylated RET. Also in PD brain, GM1 levels in the occipital cortex, a region of limited PD pathology, were significantly below age-matched controls, suggesting the possibility of systemic GM1 deficiency as a risk factor in PD. This would accord with our finding that mice with partial GM1 deficiency represent a faithful recapitulation of the human disease. Together with the previously demonstrated age-related decline of GM1 in human brain, this points to gradual development of subthreshold levels of GM1 in the brain of PD subjects below that required for effective GDNF signaling. This hypothesis offers a dramatically different explanation for the etiology of sporadic PD as a manifestation of acquired resistance to GDNF. "
http://www.ncbi.nlm.nih.gov/pubmed/25448159

There is a company trying to make this compounds available to people with PD and it seems like it already has FDA approval as an orphan drug, so it could be used off-label for Parkinson's.
http://www.glycoscienceresearch.com/2015/01/24/fda-pind-pre-investigatve-new-drug-application/
"The actual approval status is that the US FDA on December 3, 2012, designated GM-1 as an orphan drug in acute SCI treatment, and GM-1 is now in the US FDA IDE NDA (New Drug Application) and approval process."
"The authors of the letter go on to mention the renewed activity around GM-1 at the Federal Drug Administration (FDA). We were particularly encouraged and interested to hear about this, but upon searching the FDA site, we found only that the orphan drug designation had been given, but that, unfortunately, it was not approved for use in acute spinal cord injury (Figure 1).
"We then noted that the Sponsor for the application at the FDA was TRB Chemedica International S.A. and we wondered whether, if we wanted to use the drug “off-label” for acute spinal cord injury (as Geisler and Coleman are apparently suggesting), it would be available to us. In searching the site of this company that manufactures and sells drugs related to ophthalmology and joint diseases for any mention of GM-1, we found that it was listed in a history of the company back in the 1990s as a potential treatment for Parkinson’s Disease (Figure 2). Direct inquiries to the company on its availability yielded no response.
"It then appears that this renewed activity around the “actual approval status” does not afford the practitioner access to the drug, even if he/she wanted to use it off-label."

 Currently only 2 grams per brain and 1 gram per day is needed:
 Ovine GM1 ganglioside is currently produced from brain tissue supplied by GRI to Avanti Polar Lipids in Alabaster, Alabama.  Ovine GM1 ganglioside is currently produced for research use only.  Levels of GM1 ganglioside from brain are approximately 1.5 – 2.0 grams per brain.  Levels in spinal cord and other tissues such as salivary gland, adrenal gland, liver, kidney spleen, intestinal mucosa and many others are significantly elevated and maximum yield per lambs is expected to approach 4 to 5 grams based on preliminary data.
http://www.glycoscienceresearch.com/exec-summary/

As a reminder, a "cure" for Parkinson's was discovered 20 years ago, with a safety study almost the same as this one:
http://www.ncbi.nlm.nih.gov/pubmed/7783880
It was known even in the 1980's but mad cow disease eliminated the cow-brain source of GM1.
This researcher JS Schneider keeps doing clinical trials (he has 235 papers, most on PD, about 27 on GM1), and the results are always the same: patients were better than at the start of the study for as long as they took it:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3532888/
He first looked into it in 1989 in mice
http://www.jimmunol.org/content/176/2/864.long
The first research on this for PD was in rats in 1983....32 years ago!
http://www.ncbi.nlm.nih.gov/pubmed/6141701
The only reason GM1 is not available to us now is because it requires investment in flocks of sheep, so the pharmaceuticals were not interested.  It will remain a problem because with genetically modified sheep, then can still only get 1 or 2 g per brain, and 0.2 gram is the daily dose used in the trials, 1 sheep brain per 10 days. There is a PhD vetenarian and his M.S. degreed wife who are licensing the raising of the genetically modified sheep, now over 4000 ewes:
http://www.glycoscienceresearch.com/about/
And here's the punch line:  nilotinib may be working the same as GM1.  Nilotinib's cousin imatinib "upregulates" GM1, so if GM1 is not available in enough quantity from the sheep, it can be combined with nilotinib to amplify it:  "Inhibition of Bcr/Abl tyrosine kinase activity by imatinib induces a high surface expression of GM1"
http://www.jimmunol.org/content/176/2/864.long

No comments:

Post a Comment