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

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

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

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.