PD: Search for the Holy Grail

[PDConscience]

🔼 Hint: The ever elusive "Holy Grail" lies among these little blue arrows 🔼

"We believe we can be optimistic that the next 20 years will see major breakthroughs towards the discovery of therapies that may slow, stop, or reverse PD." It's hard to be overly optimistic after 2 centuries without a solution, but here's a summary of the 'main contenders' for PD breakthroughs for the next 2 decades:

"New therapeutic targets following the discovery of genetic risk factors, such as autosomal dominant mutations in the LRRK2 gene; and the enzyme glucocerebrosidase (GCase), which is reduced in patients with mutations in the GBA gene - including treatment with Ambroxol, a drug already licensed for lung surfactant deficiency.

"Targeting "non-motor" features of PD such as cognitive, speech, gait, and balance difficulties and autonomic failure, which may precede the onset of motor symptoms, and could provide an even earlier window to start therapy, with an opportunity to slow or stop the development of even the first motor symptoms of PD.

"Treatment with glucagon-like peptide 1 (GLP-1) receptor agonists that are licensed for the treatment of type 2 diabetes and have neuroprotective properties across the whole range of animal models of PD, including two alpha-synuclein models. There are plans for a phase 3 trial of exenatide, and there is growing interest in exploring other drugs in this class for their potential disease-modifying properties;

"Repurposing drugs used in other therapies such as those used to treat primary biliary cirrhosis and chronic myelocytic leukemia, and agonists of the beta adrenoceptor (Salbutamol, Clenbuterol).

"Use of immunomodulatory therapies to prevent or slow disease progression, including, for example, Azathioprine and Sargramostim.

"And finally, the authors mention the prospects for harnessing nanotechnology. 'The grand vision would be to develop a therapy that would accurately target alpha-synuclein pathology, dissolve the toxic aggregates, and push the equilibrium back towards normal monomeric alpha-synuclein.'

"We now have better understanding of the processes involved in PD degeneration and can therefore have greater confidence that laboratory data and positive results from early clinical trials will ultimately translate to therapies that slow down PD progression."

Article: eurekalert.org/pub_releases...

[WinnieThePoo]

Looks like we sort of crossed in the post. My post was the source report by Dr Foltynie

(0bviously I am particularly interested in the monoclonal antibody bits)

[ddmagee1]

I have taken the genetic testing, offered by the Fox Foundation, within their clinical trial setting. This is an ongoing project. So far, "23 and Me", the Indiana University testing group, has not found anything in my DNA, suggestive of an affiliation pertaining to the Parkinson's Disease mutation (s). We will see what they come up with, as this process of evaluation and research continues. Thank you for sharing this information! Knowledge is power!

[jeffmayer]

I still believe the best way to control your pd is vigorous exercise I hate being negative because it isn't my nature but to be realistic the hope of a cure is way off and most of us wont benefit being as they cant even slow it down the best option to me is to keep fighting back against this shite condition and don't let it rule your life I believe if you say no I cant I have pd your knackered

[ddmagee1 in reply to jeffmayer]

Exercise is an important part of dealing with the travails of dealing with having PD, that's for sure, in my opinion.

[WinnieThePoo]

This article was curiously selective in its chosen sources of optimism. If you look at Dr Foltnyies original article in my post "Exanatide, BIIB054 the microbiome..." it included a reference to strenuous activity

ncbi.nlm.nih.gov/pmc/articl...

and microbiome management, and the further research proceeding and needed (and noting a link to diabetes and the glp1 receptor agonists)

and BIIB054 (well, its twin sister PRX002) "This far, it appears that CNS penetration is indeed adequate with the antibodies currently in trials, and that serum alpha synuclein levels fall following sustained antibody administration [21, 22]"

So I think, rather than seek one sole resource for "fighting back" there is merit in tackling the shite condition on multiple fronts, which is proposed in the article. Vigorous exercise is surely an important part in that mix - but not a "magic bullet" or "one-stop shop"

[PDConscience in reply to WinnieThePoo]

It seems to me that the ideal solution would need to address the problem on TWO fronts: the replenishment of DA neurons lost over the past 10-20 years (with something like Yamanaka's IP stem cells); and the cessation of the ongoing process behind the loss (i.e., misbehaving proteins, oxidation, inflammation via one of the above-mentioned 'holy grails' - antibodies, trophic factors, gut-flora interventions...).

[WinnieThePoo in reply to PDConscience]

Yes , I agree. At least 2 fronts. I think the science of PD guy Simon, thinks 3 fronts

A disease halting mechanism

A neuroprotective agent

Some form of cell replacement therapy

The Foltnyie article I quote also refers to neuroprotective solutions like Exanatide, and a disease halting mechanism like BIIB054, used in combination. But these would not be incompatible with exercise and microbiome management too, and it discusses how much more complicated research criteria will become as there is a need for a tailored approach

"The divergent approaches being brought into clinical trials, if any signal of effect can be robustly confirmed, will likely also ultimately require testing in combination to explore additive/synergistic effects (Fig. 1). It is tempting to speculate that the future patient may be recruited into research reminiscent of the current state of play in HIV/cancer fields, e.g., where following genotyping/ microbiome testing, they are either given the curative enzyme corrective therapy or randomised to receive combination therapies rather than any/each of these alone."

(The fig1 he refers to is the diagram you have at the start of your post)

And the stem cell solution appears to have some limitations too from what I read (particularly of the Japanese trial) in that the new cells are not native embedded cells and may over produce dopamine causing diskinesias and the like which will then have to be managed with drugs. In that regard, the Bristol university trials into GDNF-7, to regrow the original cells in situ, look most interesting to me.

In the mix, would probably also be advances in MRI type, non-surgical DBS.

However, your core point , I believe, that the "cure" is multi-faceted , rather than a simple single pill, is surely true.