So, thanks to RUCDR and BioStorage for the invitation to speak today and tell you a little bit about the Michael J. Fox Foundation.  What I thought I would do is divide this presentation up into two main parts.  One is just to give you an introduction to what the Fox Foundation does and our philosophy.  And then tell you a bit about a project, one of our largest, actually our largest study that we funded to date that has given me particular insight into the intricacies and importance of sample management, sample collection, quality assurance et cetera.

So, just to tell you a little bit about the Fox Foundation.  I think you all know that it was started by the actor Michael J. Fox in 2000.  And we have a singular mission.  And that is to fund research with the objective of accelerating therapies and drugs for Parkinson's, and the ultimate goal of closing our doors and finding a cure. 

So, we rely on over 60,000 individual donors every year to support this research.  And we're pleased to say that we've supported close to $350 million of Parkinson's research all over the world since inception.  So, we have somewhat of a unique model in the non-profit world.  And that is that we have no endowment.  Every January 1 we essentially start from scratch in terms of our dollars raised.  And as we raise the money we spend the money.  And so, we--every year we have to re-raise the money.  We average about--this last year we raised about $55 million of research and we expect that to spend that money on research. 

And we're--this creates a sense of accountability to our donors, a sense of urgency internally on staff, but also to our investigators and our awardees, to really make sure that the projects that they--that we are supporting them for are actually being executed.  And so, we do take a pretty active role in managing every research project that we support.

And this is just to remind me to tell you that the patient needs are at every decision, at the center of every decision we make when evaluating a project.  We really--obviously, was started by a patient, the organization was started by a patient.  We rely on many, many 1,000's of patients to provide us input on what are the unmet needs, what are the important areas of research that they would like to see move forward.  And when making a decision on a grant or an award to fund, we keep that patient perspective in mind.

So, we don't fund research just for research sake.  Even though we are proud that we funded over--close to $350 million of research, we still think that is a relative drop in a bucket compared to some other constituents and stakeholders that are supporting research in Parkinson's disease.  So, we really try to be strategic in where we place our bets and where we place our support. 

And so, when we look at the landscape of who's supporting research, obviously there's a lot of money that comes from the government, NIH.  In our view most of that is early discovery type of work.  And then on the other spectrum of the drug development pipeline, venture capitalists and biotech and pharma are really supporting larger scale phase three clinical trials.  And it seems to be getting pushed back later and later in terms of what pharma is supporting.  And so, that creates a real need that we see our role in filling in this translational gap from early discovery to early clinical testing.  And so, that’s where we put most of our efforts and most of our resources in everything from target validation, of validating targets for Parkinson's, to early or late stage I&D enabling studies to early phase one, phase two clinical trials.

And our support falls into two general categories.  The first being drug development and we support a lot of very narrowly focused specific projects from academic labs, biotech or pharma on drug programs.  And we support different--at different levels, depending on the need.  And these are drugs focused on potentially disease modifying targets that really would hopefully slow or stop the progression of Parkinson's disease and the brain cell lose in Parkinson's. 

And then on top of drug development, we support what we call field wide challenges and we think are enabling or actually prohibiting drug development.  And so these things are like things like pre-clinical research tools, animal models, reagents, developing biomarkers that will assist in clinical trials, focusing on some of the regulatory hurdles that all of pharma is facing in developing neuro protective strategies for CNS disorders.  And so, it's kind of a mix of this very specific drug development projects, coupled with some of these pre-competitive challenges that are plaguing the field.  And those are the two general categories where we support research.  But it's not just check writing that we do.  We see over 1,000 different applications a year focused on all different areas of Parkinson's research.  So that enables us to have what we call intellectual capital and really knowing where the needs are and addressing some of these needs.  And so, we do a lot of convening, focusing on developing workshops, one day workshops, that have a really specific area in mind and convene key opinion leaders in the field to really focus on this problem solving.

So, I mentioned we support industry.  We support universities, government industry all over the world.  But, just this is a slide to highlight that close to $100 million of that 350 that I mentioned has gone to industry support, everything from small virtual biotechs to large companies like Pfizer and BMS. 

So, these are a couple of examples of the field wide challenges or some solutions that we think are addressing field wide challenges that we've developed.  The first is called the Parkinson's progression marker initiative and this is the study I mentioned in the beginning that I'll tell you a lot about.  This is really a flagship observational study to develop biomarkers of disease progression for Parkinson's. 

The second is a consortium that we've developed focused on pre-competitive tools.  It's composed of industry and academic researchers that nominate different tools that are really needed for the field.  So, we've developed many, many genetic animal models.  We have developed some useful antibodies that are available to the public as well as viral rectors [sp], cell lines, et cetera. 

The third example I wanted to share with you is a somewhat new initiative that we've developed.  It's called Fox Trial Finder.  And one of the things we've learned in the last--in the 13 years since we've started the organization was that we can support all of the basic and translational research we want and get these drugs in the--to the point of clinical testing.  But there's a real paucity of patients that are available or have nowhere to go to volunteer for clinical trials and the observational trials.  But, yet, if you ask most patients 80 to 90 percent of them would like to participate and just don't know how, don't know where to go.  And so, we created what we call a match.com for clinical research matching the clinical trials with the volunteers that are interested in participating.  And the patient can enter some general information about their symptoms, their duration of disease, their geographic area and then they can see all of the clinical trials that are ongoing and the observational studies that are ongoing in their area and reach out to the coordinators and the clinicians that are running these studies.

Conversely, the clinical researchers can enter their trials and look up to see who in their area qualifies for their studies and then reach out to them directly.  So, we obviously source a lot of the information from websites like clinical trials.gov, but this is a unique focus on Parkinson's clinical research.  And we've seen over 20,000 registered volunteers just in the last year and half that it's been in its existence.  And so, we anticipate this growing and really being a resource for sponsors of clinical trials, CRO's and academic centers that are looking for volunteers.

So, just switching gears a little bit, and I wanted to tell you a little bit about this Parkinson's progression market initiative.  We call it PPMI.  And one of the things we realized as we were supporting more clinical trials was that there is a real lack of biomarkers that are available, objective biomarkers that are available to assist in clinical trials and specifically clinical trials of disease modifying therapies.  Developing symptomatic therapies is relatively more straightforward than trying to demonstrate that a new drug actually slows the course of progression of Parkinson's disease.  And so, it was with this that we developed PPMI to verify biomarkers of disease progression.  And this is just a schematic of--I borrowed from Dr. Ken Marick [sp] who's in New Haven and he's the principal investigator of this study.  It's really just demonstrating where PPMI fits in.  So, this is a schematic of neuronal function and in the pre-diagnostic phase before you--one is diagnosed with Parkinson's disease, what symptoms developed at this stage and then the diagnosis may not occur for months or years until after the symptoms develop.

So, we are trying to find people and have enrolled Parkinson's patients, as well as age matched controls in this area where the degeneration has already occurred but is still early in the disease duration.  And so, this just shows you the clinical presentation of Parkinson's increases and the symptoms get worse as the neuronal function declines.

And so, in this population of newly diagnosed Parkinson's patients and controls is where we're collecting a comprehensive set of information in PPMI.  There's three general tenants to PPMI.  One is having a specific data set.  We wanted to enable research to occur by collecting a complete comprehensive data set of clinical information on disease subjects and controls, biologic information collecting bio samples from these individuals and imaging data.  So, we have specked and MRI that’s being collected on these individuals.

We just completed in April the baseline recruitment of this study.  So, this is in 600 newly diagnosed Parkinson's patients, 200 age and gender matched controls.  And we tried to keep this to relatively a small number of sites.  And that speaks to the second point, which is standardization.  As most of you know, the more sites you have the more variability that could be introduced into the study in terms of how samples are collected, how data is collected.  And so, the second key tenant of this study is standardization of data acquisition, uniform storage of the samples and a strict QC on all of the data and the samples.

And then the third tenant is another unique thing in biomedical research.  And I think we're seeing this shift a little bit.  And I think PPMI is on the cusp of that.  And that is to provide access to these data in real-time.  So, all of these data, as they are collected, are available through a web portal.  It's PPMI-info.org.  They're available to any researcher throughout the world.  And the samples are stored in a central repository and are available to request access to for biomarker verification work.  We are following these individuals over a minimum of three years, a maximum of five years.  And in the first year they come in every three months and contribute information.  So, it's a very intensive, rigorous study.  And it's a unique population that has committed themselves and their fluids and their bodies to this project.

So, this is just a general synopsis of what is being collected.  I mentioned it's about 600 individuals, 200 controls, 400 Parkinson's patients, collecting both motor and non-motor clinical information on these individuals.  In terms of the bio samples that we're collecting we're collecting and storing DNA, serum, whole blood, plasma that’s collected at each visit.  Urine is collected every year.  Something also unique and unprecedented in the Parkinson's world is that we are collecting spinal fluid from these individuals and not just once, but a potential seven times over the course of the five years of study.  Many people didn't think we could do this.  And it actually took some more convincing of the neurologist than it did to the subjects.  But, there is scientific rational, we see a lot of potential useful biomarkers emerging in spinal fluid.  And there was a first publication from the PPMI study released in August that reported on some of these results. 

So, we think it's important and so far we've seen about a 90 percent adherence to providing lumbar punctures in accordance with the protocol, so the samples aliquotted and stored in central biorepository.  There's a repository in Milan, Italy in Europe for the European sites and we're using Curial [sp] in Campton, New Jersey.  And there are some initial biomarkers that we are testing right off the bat.  Most of the samples will be stored for request or access to investigators, but we are doing some verification studies initially.  So, we are the major supporter of this study.  But, since we think the biomarkers and developing quality objective markers will benefit pharmaceutical companies and those sponsors that are developing new drugs we thought it was an important point to engage these companies.  And we're proud to say we have 13 industry sponsors that are both contributing financially, but also intellectually.  And they have a seat at the table in developing the analysis for this study. 

So, I just wanted to share a little bit of information on the status of the sample submissions.  As Jay mentioned, I'm a pharmacologist.  I had no experience with this before embarking on this study.  So, this was eye-opening and illuminating to me in terms of all of the details that are required for a quality sample management and storage.  But, to date we have over 15,000 different specimens in the bio repository.  This is a schematic just showing what's collected, serum, plasma, CSF, blood, patching [sp] tubes for RNA, whole blood and EDTA and urine.  They are aliquotted the site and then sent to the repository for storage. 

This is a very busy slide, colorful slide and I just wanted to share it with you for the purposes of showing how obsessive we are about tracking these samples and the handling of these samples.  So, Dr. Les Shaw [sp], who is at University of Pennsylvania, is head of the bio analytics core for this study.  He developed this slide and it's really just to show you how we track how long from sample collection it takes--this is in spinal fluid, it takes to centrifuge to the sample, how long it takes to aliquot the sample and then how long it takes to freeze the sample at the site.  And we track this for each site, site by site.  And so, we can see if there are outliers or sites that are not adhering to the protocol.  We can work with them to course correct and do some retraining.

But, this is just kind of a very small part of the information that we track in real-time to make sure that standardization is adhered to.  One of the other learnings that we've had is to not just store the samples but, to the extent that you can use the samples to measure some quality assurance parameters.  It identifies not just issues with the sample collection, but also handling, storage and any issues that could be ironed out early on in the process. 

So, one example is that we measure total hemoglobin in all serum and plasma samples stored at the--or received at the repositories to understand whether there's any hemolysis that occurs in processing.  So, you can see the results here in serum and plasma.  Another QC metric we use is spinal fluid hemoglobin so there are a number of proteins that seem to be associated with Parkinson's disease in spinal fluid that potentially could be useful biomarkers.  But, unfortunately, these proteins are found at extremely high levels in red blood cells.  And so, it's really important to control for any blood contamination in your spinal fluid.  And so, on every sample we measure the total hemoglobin levels to give us an indication of any blood contamination in the spinal tape.

And then finally, this is just an example of some of the QC that’s done on the RNA.  I don't think I have to go through this slide in great detail.  But, essentially we measure RIN [sp] values.  We measure the average concentration, 260, 280 ratios.  And I should point out that the RNA extractions do occur centrally at the central repository.  So this is not done at the site.  So, we have fewer people doing the extractions.

So, with that I just wanted to thank the Fox Foundation research team.  We've grown a lot in the last several years and there's a tremendous team that’s helped generate this work that I showed you.  We have about 12 PhD's and MD's on staff now, along with business project managers that project manage the awards that we support.  And then I just wanted to plug my boss's new show.  It airs Thursdays on NBC, tonight is the second showing, so please check it out.  And with that I wanted to thank you for your attention and look forward to learning more the rest of the day.