Anti-Rejection Organ Transplant Drugs
 

This is new for me. It appears that, in a survey, anti-rejection drugs taken for organ transplants have a very good protective effect against Alzheimers compared to the general population, see bar graph first http below. This should apply to PD as well. The bad news is we have to wait forever for it.

http://content.iospress.com/download...se%2Fjad150065

Could Toning Down Calcineurin Neutralize α-Synuclein? | ALZFORUM

http://www.psychiatryadvisor.com/alz...rticle/419660/

Overall, no matter what the age group examined, the patients who were taking one of the two drugs had far less prevalence of Alzheimer's and dementia than the general public, the researchers reported in the Journal of Alzheimer's Disease. For example, while 15.3% of the general population over the age of 75 had dementia, just over 0.6% of the study group did.

ashleyk said: "This should apply to PD as well."

I think this is a leap too far.

From the 1st link: " ... these results strongly indicate that inhibition of [calcineurin] ... may protect neurons from the damaging effects of amyloid-beta
oligomers."

This, for me, is the essence of the paper. No mention is made of alpha-synuclein, and no mention is made of PD.

From the 2nd link: "When a cell becomes overloaded with alpha-synuclein, calcium surges into the cytoplasm and binds the protein calmodulin, which then activates calcineurin. The phosphatase plucks phosphates from dozens of different proteins."

I can understand that inhibiting calcineurin could very well limit the damaging effects of toxic forms of alpha-synuclein. However, a more direct approach would be to target alpha-synuclein itself, an approach which has been adopted by many other research efforts.

I think that you have made a good point jeffreyn.

There are a few papers out there which suggest similar findings for calcineurin and α-synuclein-mediated neurotoxicity.

This is the most recent free-access one that I can find PNAS Plus: Calcineurin determines toxic versus beneficial responses to α-synuclein.

It is interesting but is mainly based on tissue culture and yeast models.

PD α-synuclein Cyclosporine / FK506 Calcineurin
 

I believe the current thinking on Alzheimers and PD is that they both are considered a form of prion disease in that plaques are observed in the brain. In the article below, a case is made that anti-rejection drugs like FK506 and cyclosporine have a noticeable effect on A-synulclein and could be very useful in treating PD. See Fig. 3 bar graph. These drugs have been used for years in people with organ transplants to prevent rejection. In this article it is suggested that there is an optimal dose of FK506 to suppress A-synulein (not too little not too much) and that the drug could be taken intermittently.
It's too bad that these FDA approved drugs are not fast tracked into some sort of trial to see how effective they could be in PD and AD. Many are years into these diseases and time is running out.

Calcineurin determines toxic versus beneficial responses to α-synuclein
Because inhibition of calcineurin activity is routinely exploited clinically through the use of FK506 (tacrolimus) as an immunosuppressant, we now suggest that the repurposing of FK506, a compound that readily traverses the blood brain barrier merits investigation in the management of PD. Because it persists in the central nervous system long after systemic effects have resolved (49), intermittent dosing with this already FDA-approved drug could avoid systemic immunosuppression, while still providing a readily implemented, disease-modifying treatment strategy that targets a fundamental mechanism in the pathogenesis of α-synucleinopathies.

I do not know of anybody who argues that AD and PD are prion diseases.

The various prion diseases (Creutzfeldt–Jakob disease among others) arise when prion protein (PrP) misfolds. The misfolded form of PrP has pathological effects. The misfolded form of PrP can catalyse conversion of the normally-folded form of PrP into its misfolded (pathological) form. This leads to an exponential increase in the level of misfolded PrP.

AD and PD are both protein misfolding diseases. In AD the main suspect is Aβ (there are probably others). Aβ can misfold, which leads to the formation of amyloid - this is why insoluble amyloid plaques are characteristic of AD. The evidence suggests that insoluble amyloid plaques containing Aβ are relatively inert - what does the damage is soluble Aβ complexes along the amyloidogenic pathway though the mechanism(s) of this are controversial. There is no evidence that I know of that the misfolded form of Aβ can catalyse conversion of other molecules of it into the misfolded form, as happens in prion diseases.

PD is similar - there is good evidence that misfolded α-synuclein is neurotoxic. However, I don't know of any evidence that misfolded α-synuclein can catalyse conversion of its normal form into a misfolded form, as in the prion diseases.

kiwi33 said: "I do not know of anybody who argues that AD and PD are prion diseases."

I think you may have just walked into a minefield kiwi33!

For example, have a look at this comment on PubMed Commons, from just a few days ago (about half way down the webpage):

The prion model for progression and diversity of neurodegenerative diseases. - PubMed - NCBI

Prion, prion-like, transcellular prionoid, ... I just hope they can get the terms sorted out ASAP!

Here is another relevant (and recent) reference:

Targeting α-Synuclein as a therapy for Parkinson's disease: The battle begins - Olanow - 217 - Movement Disorders - Wiley Online Library

(It's behind a paywall, but you can preview the 1st page for free. If you register as a patient or carer (patientACCESS), US$3.50 is the price you pay for the complete article.)

Thanks for those links jeffreyn, very interesting.

I have "walked across minefields" often when thinking about protein (mis)folding with my colleagues and may do so again.

I think that the critical experiment to show whether misfolded proteins other than PrP have prion-like properties is to use a mouse knock-out model. For example, one could make (say) α-synuclein KOs and then challenge them with misfolded α-synuclein. The prediction is that not much will happen to the KOs but wild-type mice will get sick because of the infectious (prion-like) properties of misfolded α-synuclein. I don't know if this or similar has been done.

This experiment has been done with mouse PrP KOs - they did not respond to the challenge of misfolded PrP compared to WT mice, who became sick. I heard about this at a conference - the speaker, somewhat flippantly, summed it up with the last slide; "PrP KO mice are OK.".

This is personal for me. A much-loved uncle of mine in NZ died from PD a couple of years ago. My job, apart from offering family support, was to translate what his care team told him into English.

I think that it would be best if investigators of the various protein misfolding diseases focused on mechanisms without being unduly fussed about "angels on a pinhead" arguments about prions.

ashleyk said: "It's too bad that these FDA approved drugs are not fast tracked into some sort of trial to see how effective they could be in PD and AD. Many are years into these diseases and time is running out."

Okay, now I see where you are coming from.

I don't disagree with you. It seems to me that it would indeed be a good thing if some researcher took the initiative and sought funding for a trial of one or more of these drugs in PD and AD, similar to what is happening in the case of nilotinib.

As you say, time is running out for many PWPs and PWAs.

kiwi33 said: "I don't know if this or similar has been done."

My understanding is that the answer is "yes". From my 2nd link: "... these findings were not seen in a-synuclein-null animals, consistent with the need for host a-synuclein to participate in permissive templating (or the prion conformer reaction) to sustain a prion-like chain reaction."

Yes, that's right, I broke into my piggybank and spent some money!

e-mail this thread to Fox Foundation
 

I began this thread by casually stating that PD is a form of prion disease, something I remember reading about. If one does a search of "PD and prion", a lot of information comes up.
Alzheimer’s and Parkinson’s diseases: The prion concept in relation to assembled Aβ, tau, and α-synuclein | Science
Transcellular propagation of protein pathogens, reminiscent of the spread of viruses, represents an unprecedented concept of disease. It is now known to extend beyond CJD, to include AD and PD, which are the most common neurodegenerative diseases. For all three diseases, there is a long prodromal phase, during which neurodegenerative changes develop and eventually lead to brain dysfunction. The interval between the formation of the first protein inclusions and the appearance of disease symptoms may offer a therapeutic window, provided sufficiently sensitive diagnostic techniques can be developed. Other protein pathogens, such as aggregates of TDP-43 and mutant superoxide dismutase 1, exhibit similar properties (134–136).

The point I was trying to bring to this forum is that, to me, this is new and anti-rejection drugs for the hopeful treatment of PD could be a game changer even if it's not a cure. And along with Nilotinib maybe it could be piggy backed with the forthcoming trials on Nilotnib. They are both FDA approved drugs and should move a lot faster thru the trials.
I am going to forward this thread to the Fox Foundation and others.

ashleyk said: "... [viewing PD and AD as forms of prion disease] is new and anti-rejection drugs for the hopeful treatment of PD could be a game changer even if it's not a cure."

These two things are quite separate. I think you might have more success with your pursuit of the "anti-rejection drugs for PD and AD" proposal without complicating it more by simultaneously entering the current debate about what is and is not a prion disease.

ashleyk said: "I am going to forward this thread to the Fox Foundation and others."

That's certainly one way to proceed with your proposal. Please let the forum know how you get on.

Ashleyk, I agree with jeffreyn about this.

FK-506, as a calcineurin inhibitor, was approved by the FDA as an immunosuppressant for people with organ transplants in 1994.

That means that Phase 1 clinical trials (using healthy volunteers to look at dosages, clearance rates, adverse side-effects, etc) will have been done.

Because of that, proceeding to Phase 2 clinical trials for FK-506 and maybe other immunosuppressants in people with PD should be easy, subject to funding and regulatory approval. In a Phase 2 trial a relatively small number of people with PD would be given FK-506 in open-label format.

If the results of a Phase 2 trial are encouraging then the next step is a Phase 3 trial (double-blind, placebo-controlled, with many more subjects).

I am not sure about forwarding this thread to third parties. This is because, quoting from something at the bottom of all NT pages, "All posts copyright their original authors.". You may be in breach of copyright by forwarding it - a member of the NT admin team should be able to advise you about this.

The Fox Foundation and others should know about these different phases of clinical trials - good luck with your endeavours on this.

Ashleyk,

If you have not yet contacted MJFF, here is a suggestion.

Debi Brooks (MJFF) is a member of this forum (she started a new thread about a week ago).

I suggest you PM (private message) Debi and outline to her your proposal. You could include in the message a link to your thread.

Jeff

I sent emails.
 

It appears that the Fox Foundation is sponsoring research concerning a-synuclein. However reading about what these researchers are working on, I found nothing concerning anti rejection drugs. It seems that what ever they may come up with it will take many years of clinical trials, where as anti rejection drugs are FDA approved.
If you want to email these people doing the sponsored studies, Fox has a website giving their names and programs. Or, email Fox directly.

Parkinson's Disease Grants funded by the Michael J. Fox Foundation | Parkinson's Disease

Small-Molecule Pharmacological Chaperones Reverse Alpha-synuclein-impaired Debris Removal | Parkinson's Disease

Contact The Michael J. Fox Foundation for Parkinson’s Research | Parkinson's Disease

Alpha-synuclein and Parkinson's Disease | Parkinson's Disease

Thoughts from MJFF staff researcher, Kuldip Dave PhD
 

I asked my colleague Kuldip to share some insights and below are his contributions.... Debi



Let me provide you with some more relevant information around the work we are doing regarding the topics being discussed here. First of all, we should be very cautious in calling PD a prion disorder. Infectiousness is a central hallmark for prion disorders. However, it has never been reported or documented in PD patients. Even clinically, a prion disease such as Creutzfeld-Jakob disease (CJD) is very different from PD. CJD, once it manifests, has a rapidly progressing phase over a period of few months whereas PD is a slow progressive disease with a time frame of years and decades to develop. The brain pathology also looks vastly different in that spongiform encephalopathy is observed in CJD (and not in PD) and Lewy bodies are observed in PD (and not in CJD).

A few similarities do exist as to how PrP protein (involved in prion diseases) and alpha synuclein protein (involved in PD) may behave at the molecular level. Both of these proteins have the ability to misfold and aggregate. Pathology resulting from aggregation of these proteins has been shown to spread from cell to cell in animal models. Although these similarities exist in the way the two proteins behave, the mechanism by which the pathology spreads from cell to cell is not fully understood. It is also not fully understood whether the spreading of alpha synuclein pathology seen in a test tube or an animal brain has any direct relevance or link to the human PD pathology (as in what’s happening in “real” life)!

MJFF is currently funding studies to define further how alpha synuclein spreads, understand the mechanism by which it is doing so, trying to see if we can use alpha synuclein’s “spreading” phenomenon as a potential biomarker and finally funding therapeutic approaches that may try to leverage blocking this spread as a way to modify PD disease progression.

With regards to drugs that fall into the “anti-organ rejection” category, MJFF has funded research both validating the targets as well as therapeutic development in this area. For example, we funded to determine if FKBP reduction (one way by which anti organ rejection drugs work) would work as a proof of concept and the study showed that it worked positively in preclinical experiments. The main challenge in repurposing “anti-organ rejection” drugs for PD has been side-effects such as immunosuppression. Use of such drugs for a shorter duration (months) for organ rejection versus giving it chronically to Parkinson’s patients (for years) has to be explored.

We continue to monitor the field to identify gaps in research and fund field-enabling and critical experiments to understand the disease and find a cure.

Kuldip Dave, Ph.D.
Director, Research Programs

More info
 

Dr. Kuldip Dave and Debi,

Thank you for your informative post, I hope you stay in touch. I have always thought that organ transplant recipients had to take anti-rejection drugs for life? In the case of the paper below, it seems the authors have found that there is a therapeutic range where this type of drugs will keep a-synuclein regulated at a healthy level. It may be that a smaller amount of these drugs could be taken lessening side effects?

http://www.pnas.org/content/111/34/E3544.full

Surprisingly, however, both deletion and overexpression of CN increased toxicity in the HiTox strain (Fig. 2 A and B). One explanation for these apparently contradictory results is that an intermediate level of CN activation is protective against α-syn, whereas either too much or too little is detrimental.
Significance

Ca2+ homeostasis is indispensable for the well being of all living organisms. Ca2+ homeostasis is disrupted by α-synuclein (α-syn), whose misfolding plays a major role in neurodegenerative diseases termed synucleinopathies, such as Parkinson disease. We report that α-syn can induce sustained and highly elevated levels of cytoplasmic Ca2+, thereby activating a calcineurin (CN) cascade that results in toxicity. CN is a highly conserved Ca2+–calmodulin (CaM)-dependent phosphatase critical for sensing Ca2+ concentrations and transducing that information into cellular responses. Limiting, but not eliminating, the availability of CaM, CN and/or CN substrates directly with genetic or pharmacological tools shifts the α-syn–induced CN cascade to a protective mode. This has mechanistic implications for CN's activity and provides a therapeutic venue for the treatment of synucleinopathies.