(This is also posted on the "Andy Grove speaks out" thread where the comments by Greg are listed in their entirety from the PAN website, but since it is really a different subject, it deserves a separate listing... Oh and by the way 3 cheers for Andy who would be a wonderful spokesman for any cause, and we are fortunate to have him think and speak so clearly about our cause....pc)

I want to applaud my friend and fellow advocate for PD Greg Wasson for articulating in such eloquent, almost poetic terms, which is one of his special and unique talents, all the reasons why it is so important that patients take on new roles in the management of our own disease and that we be represented at the table at all levels of health care policy. I also want to applaud PAN for their bold stand to publicly sponsor Greg's words.

As a patient advocate who has worked many years on the issues that Greg speaks about, I would like to reinforce and embellish his statement in several areas based on the experience of the Parkinson Pipeline Project, which I founded to do what we as PWP can uniquely do to speed the delivery of more effective treatments to patients. Both Greg and Ann have worked with the Pipeliners to not only get to the table but to implement a comprehensive strategy to enhance the process of developing new therapies after we have taken our seats at the table.

The one man band joins an orchestra

I first became involved with FDA when I was recruited to the FDA Advisory Committee for Deep Brain Stimulation in March 2000, as a Patient Representative. After subsequent training, and interaction with staff, I began to be invited to advocacy meetings. Drawing on my contacts from over 25 years in Washington, I also began to meet key people in the review of PD treatments and in the planning and liaison offices established to buffer the communication responsibilities of reviewers with the public, so the reviewers can do their main tasks. As government officials FDA staff scouted and held public meetings and invited advocacy groups in from all of neurology to get viewpoints from a broad spectrum of the community.

With persistence and patience, after 3 years I was able to convince the FDA staff to add PD to their pilot program in oncology for Patient Consultants to FDA reviewers and 1.5 more years to implement the program and find ways to cope with restrictive Conflict of Interest procedures. The Pipeline Project has been a collaborator with the FDA staff to recruit, train and continually inform these advocates about important developments. This gives us leverage, in what I call a “teachable moment” for study staff and sponsors who want to get their protocols endorsed by review staff. For an appraisal of the entire comprehensive program designed to not only get to the table but also actually do something constructive once you are there see the Pipeline Project web site (www.pdpipeline.org)

The voice of the patient

Living in Washington, I go to many meetings on health policy and advocacy issues, including meetings sponsored by Government Agencies (particularly FDA, NIH, also CDC and AHRQ), Industry Associations (most often BIO, but also PhRMA), Professional Associations (such as the AAN), Coalitions of Patient Advocacy organizations (such as the Working Group on Evidence Based Medicine, the Personalized Medicine Coalition), and health policy forums (such as the Institute of Medicine). Often I am invited to speak from the patient perspective, but if I am not invited to speak, I will take the opportunity to make a statement on behalf of the patient perspective which is often different than the views of research institutions and even more different than the views of non-patient consumer organizations. I ask the simple question, why am I the only patient in the room, the only one who has participated in a clinical trial and the only one who lives with PD 24/7. Invariably several people come up to me afterward to say how important these statements are, because if no patients are in the room, patient interests are often overlooked.

After more than a half dozen years as a lonely messenger for incorporation of patient views into FDA and other healthcare decisions, in the past 1-2 years I have been coming into contact with greater numbers of leaders in the different forums who share this patient perspective. This increase in recognition of the value of patients’ input to decisions at all levels of health care research and decision making is rightly emphasized by Greg in words that echo the motto of the Pipeline Project on our home page (www.pdpipeline.org). I often use this statement when being interviewed, “The missing ingredient in development of new therapies is the voice of the patient.” The article “Deadly Caution” by award winning journalist Clifton Leaf in Fortune (2/2/2006) used this quote from me as the bottom line for a simple solution to the many problems of the FDA and the waning productivity of medical research.

PD Organizations

I cannot overestimate how important it is to have the backing and political support from our Parkinson's Organizations for the views of grass roots patients. Taking a pro-patient stance is not as simple as it would appear from the common sense view of the patient who listens to the rhetoric of industry and science. You would be surprised how often I have gotten my hand slapped for taking a patient oriented position with respect to what a clinical trial sponsor wants to do because of fear of reprisals, and even though I have a Ph.D. from a leading technical university, I have been excluded from meetings of vital interest to patients as well as researchers because I was a patient. As Greg points out in his presentation, medicine is traditionally doctor dominated. Patients are not perceived as competent and are expected to follow orders for treatment, and in experiments we are expected to measure up to animal models. PD organizations like many disease group s represent broad interests of researchers, universities, and funders from industry as well as patients interests so it is a milestone to have an organization as important as PAN to take up this goal.

Quoting from Greg's words provided on the PAN website

"The Parkinson’s Action Network (PAN) applauds this as an example of the FDA’s response to the general criticism that the missing voice at the healthcare policy table is the voice of the patient. I think it is vital that the patient voice be included not only in individual health care decisions, but at every level of decision making, including IRB’s, Advisory Committees to PhARMA and Biotech companies, and relevant government agencies. Patient participation in health care decisions still has a long way to go before it is an accepted fact and not just a platitude, but thankfully we are making a start. ……"

…… “Likewise, we must create tools by which the unique perspective, which only patients can give as to the experience of their illness and its treatment can be captured and used to better inform the policymaking process. Creating these tools will not be simple or easy, but create them we must if we are to make the once passive recipients of health care decisions made by others into effective and meaningful collaborators in developing healthcare policies and practices which will meet the new requirements of a new century.”

I believe we the many have been screaming for cures for almost 8 years -
we started in 2000 with MJFox Team and Joan Samuelson,
and even more to the point as it is very pertinent to our WORLD -
WE have been Protesting this War from the Terrorists in DC...
I believe we are under an insane precedent, as I see greater things must happen first -
The Tyrant of the U.S. and his regime must be taken from power, because we aren't running under our "American Constitution" -we are being run by the
"Patriot Act" -people are making money from War and Death, and until
the WAR is ended - we do not stand a chance being heard.
Have you seen the millions of protestors all over the World, asking for peace,
asking for the President's resignation?
The little girl died - from our documentary -"DIED" -August 12, 2007...
I spoke directly to the President and hugged him and shook hands with him - "President Clinton" couldn't buy us a cure because there is not enough money to buy health back not when we allow ourselves to be used as lab rats for free -and give our patriotic blood of our sons and daughters for free...

-if we do not get our country back first -you can play hell getting a cure...

I have no free speech in the U.S. but they can't kill my spirit, it dosen't belong to the Government ...
the worst thing they have done is dope us all up on the idea we must take drugs - we are one nation under bigpharmas thumb, they believe they have absolute power, and therefore they are corrupt absolute...
we are just wildflowers in a field we bloom yet for a second and then we pass away...
prayer is more powerful.

this is from the Homeland Security Act/ like the Enabling Act WWII nazi germany -
the word is the President needs this done by 2010? wont his term be up in 2010?
http://www.dhs.gov/xoig/assets/mgmtr...8-01_Oct07.pdf

part of the script says -
PIV card is a smart card that contains stored identity credentials (e.g., a photograph, digital certificate and cryptographic keys, or digitized fingerprint representations) that is issued to an individual whose identity of the cardholder can be verified against the stored credentials by another person or through an automated process.
Progress Has Been Made But More Work Remains in Meeting Homeland Security Presidential Directive 12 Requirements
sincerely,
Tena

Oh Tena, it has been many more than 8 yrs!!

Perry, may I post/copy your words above to another forum??

Thanks,

That's where Perry lives and he has taken advantage of his location to work tirelessly to have patients included in the decision making that involves their own lives. Looking at recent events, I think he is being heard.

The goal is to make it all move faster. To state it in far too simple terms, Perry is suggesting the perspective and use of patients. Andy Grove is talking about speed of turn around, failures that aren't really failures at all, and the need for a new funding system for success.

Put these together, along with open mindedness, the FOX Foundation's innovation and the ever improving support, education, services and collaboration of PD organizations and there is truly a chance for change in our lifetime.

paula

12 October 2000

Nature 407, 661 (2000) © Macmillan Publishers Ltd.


Medicine Nobel goes to raiders of the brain's chemical secrets

ALISON ABBOTT



In 1990, the film Awakenings won Robert De Niro an Oscar nomination for his portrayal of a patient with a severe form of Parkinson's disease, who was released from his trance-like state by the drug l-DOPA. This week, the pharmacologist who made the treatment possible is one of three researchers to win the Nobel Prize in Physiology or Medicine for their pioneering discoveries about how signals are transmitted between nerve cells.

EPA

Nervous Nobels: Kandel (left), Greengard (middle) and Carlsson.

Arvid Carlsson, of the University of Gothenburg in Sweden, is honoured for showing that dopamine is a neurotransmitter in the brain, and that lack of this chemical causes the symptoms, such as impaired movement, seen in Parkinson's disease. He also showed that both the chemical deficiency and clinical symptoms can be reversed — at least temporarily — by l-DOPA, a dopamine precursor that is converted into the neurotransmitter in the brain.

Carlsson's discoveries laid the foundations for the work of the US neuroscientists Paul Greengard and Eric Kandel, who share the prize. Studying dopamine-releasing nerve cells, Greengard unravelled the cascade of molecular events needed for a signal to pass across the synapses, the junctions between nerve cells. Kandel showed that changes in synaptic function are essential for learning and memory.

In a series of experiments in the 1950s, Carlsson showed that dopamine was concentrated in parts of the brain involved in movement control. He noted that reserpine, a natural alkaloid used at that time to treat schizophrenia, depleted dopamine stores in the presynaptic neurons. Rabbits treated with reserpine became incapable of voluntary movement, but they recovered when they were given l-DOPA, which compensated for the depleted dopamine.

Carlsson realized that the 'frozen' rabbits were similar to patients with severe Parkinson's, and within a few years l-DOPA was in clinical use. Carlsson also showed that drugs to treat schizophrenia work by blocking dopamine receptors on the surface of postsynaptic nerve cells, stopping the signal from being passed on. Overall, his work has revealed how important dopamine balance is in the brain: too much results in psychosis, too little causes motor disorders.

Greengard, now at Rockefeller University in New York, acknowledges his debt to Carlsson. "One of the reasons I started working on dopamine transmission was because Carlsson had shown the role of dopamine in schizophrenia and shown that antischizophrenic drugs work by disrupting dopamine signalling," he told Nature, shortly after learning of his award.

In the 1960s, Greengard began to focus on what happens after dopamine binds to receptors on the surface of postsynaptic neurons. It was known that when some hormones bind to their receptors there is an increase in the level of the second messenger, cyclic AMP. This activates enzymes known as kinases, which add phosphate groups to various proteins, modifying their functions.

"Greengard had the vision and courage to take these concepts of second-messenger signalling processes to the brain — a very tough playground," says Alfred Gilman of the University of Texas Southwestern Medical Center in Dallas, who shared the 1994 Nobel prize for his work on signal transduction within cells.

Over the years, Greengard showed that dopamine, as well as other neurotransmitters, provokes a complicated cascade of phosphorylation and dephosphorylation events. In particular, he found that a protein called DARPP-32 plays a fundamental role in regulating the phosphorylation states of many of the proteins in dopamine signalling pathways. He also investigated interactions between different pathways. "The more complicated the interaction between different signalling pathways becomes, the more intriguing it all becomes," Greengard says.

Eric Kandel of Columbia University in New York studied the cellular processes involved in learning and memory using the sea slug Aplysia as a model. Aplysia does not have much to remember — but it does have a reflex to protect its gills. Kandel found that some stimuli amplified this reflex for days or weeks. This 'learning', he showed, arises from an increase in neurotransmitter release at synapses connecting the sensory nerve cells to those that activate the muscles involved in the reflex. This rise is mediated by protein phosphorylation mechanisms similar to those studied by Greengard.

Kandel elucidated the cellular basis of short- and long-term memory in Aplysia and has extended the studies to mammals. "He has been a leader in the field and it is appropriate that he is rewarded," says Tim Bliss, head of neurophysiology at the National Institute for Medical Research in London, who in the early 1970s described a molecular mechanism for learning and memory known as long-term potentiation (LTP). "Kandel created the intellectual climate in which LTP could be studied, by showing that changes in synaptic efficiency could lead to changes in behaviour," Bliss adds.

http://www.nobel.se/


Nature © Macmillan Publishers Ltd 2000 Registered No. 785998 England.

Arvid Carlsson
The Nobel Prize in Physiology or Medicine 2000

http://tinyurl.com/38qrg9

Chronic, controlled GDNF infusion promotes
structural and functional recovery in advanced
parkinsonian monkeys
Richard Grondin,1,2 Zhiming Zhang,1,2 Ai Yi,1 Wayne A. Cass,1 Navin Maswood,1
Anders H. Andersen,1,2 Dennis D. Elsberry,3 Michael C. Klein,4 Greg A. Gerhardt1,2 and
Don M. Gash1,2
1Department of Anatomy and Neurobiology and 2Morris K.
Udall Parkinson's Disease Research Center of Excellence,
University of Kentucky Medical Center, Lexington, KY,
3Medtronic Inc., Medtronic Neurological Division,
Minneapolis, MN and 4AMGEN Inc., Thousand Oaks, CA,
USA

Correspondence to: Dr Richard Grondin, Department of
Anatomy and Neurobiology, University of Kentucky
Medical Center, Room 305, Davis Mills Building, 800
Rose Street, Lexington, KY 40536-0098, USA
E-mail: XXXXXXXXXX
Summary
The powerful trophic effects that glial cell line-derived
neurotrophic factor (GDNF) exerts on midbrain dopamine
neurones suggest its use in treating Parkinson's
disease. However, some important questions remain
about the possible therapeutic applications of GDNF.
Here we demonstrate that the chronic infusion of 5 or
15 mg/day GDNF into the lateral ventricle or the striatum,
using programmable pumps, promotes restoration
of the nigrostriatal dopaminergic system and signi®-
cantly improves motor functions in rhesus monkeys
with neural de®cits modelling the terminal stages of
Parkinson's disease. The functional improvements were
associated with pronounced upregulation and regeneration
of nigral dopamine neurones and their processes
innervating the striatum. When compared with vehicle
recipients, these functional improvements were associated
with (i) >30% bilateral increase in nigral dopamine
neurone cell size; (ii) >20% bilateral increase in
the number of nigral cells expressing the dopamine
marker tyrosine hydroxylase; (iii) >70 and >50% bilateral
increase in dopamine metabolite levels in the striatum
and the pallidum, respectively; (iv) 233 and 155%
increase in dopamine levels in the periventricular striatal
region and the globus pallidus, respectively, on the
lesioned side; and (v) a ®ve-fold increase in tyrosine
hydroxylase-positive ®bre density in the periventricular
striatal region on the lesioned side. In addition, chronic
GDNF treatment did not induce the side-effects generally
associated with chronic administration of levodopa,
the most widely used treatment for Parkinson's disease.
Thus, the results suggest that the prolonged and controlled
delivery of GDNF into the brain could be used
to intervene in long-term neurodegenerative disease
processes like Parkinson's disease. Additional studies
are required to determine the potential differences
between chronic, intraventricular and intraputamenal
(or intranigral) delivery of GDNF to maximize the
ef®cacy of infusion treatments.
Keywords: GDNF; Parkinson's disease; dopamine neurones; regeneration; non-human primates
Abbreviations: DOPAC = 3,4-dihydroxyphenylacetic acid; GDNF = glial cell line-derived neurotrophic factor; HVA =
homovanillic acid; MPTP = 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; TH = tyrosine hydroxylase
Introduction
Converging evidence from a number of laboratories suggests
that glial cell line-derived neurotrophic factor (GDNF) is
capable of halting or reversing the progressive degeneration
of the nigrostriatal dopamine system in animal models of
Parkinson's disease (Tomac et al., 1995a; Gash et al., 1996;
Choi-Lundberg et al., 1997; Bjorklund et al., 2000; Kordower
et al., 2000). The most likely mechanism is through the
trophic actions of GDNF on midbrain dopamine neurones in
the substantia nigra. These neurones are the principal target of
the pathophysiological processes underlying Parkinson's
disease, and the consequent neuronal injury and subsequent
degeneration lead to the profound depletion of basal ganglia
ãGuarantors of Brain 2002
Brain (2002), 125, 2191±2201
dopamine levels that characterizes the disease
(Lang and
Lozano, 1998a, b).

While there is good general agreement in results between
laboratories using a variety of animal models of Parkinson's
disease, some important questions remain about the possible
therapeutic applications of GDNF. For instance, GDNF
appears to be both neuroprotective and neurorestorative for
dopamine neurones (Gash et al., 1998; Kordower et al., 2000;
Costa et al., 2001); the protective effects are manifested
within hours, whereas the regenerative actions are not evident
for days to weeks. In many published animal studies, it is
dif®cult to distinguish between the results that arise from
protective (injury prevention) and restorative (recovery after
an injury) effects because GDNF treatment is initiated in the
hours or days following a lesion while the injury sequelae are
still unfolding. However, the distinction is important in
assessing treatment strategies for Parkinson's disease using
GDNF. If the primary effects were protective, then GDNF
treatment would be most bene®cial in the early stages of
Parkinson's disease, before devastating losses of dopamine
neurones have occurred. On the other hand, if the primary
actions of GDNF are on restoration, then treatment at all
stages of Parkinson's disease could be bene®cial.
Another important issue is the titre of biologically available
GDNF necessary to produce bene®cial effects.
Information in this area is especially limited for methods
involving the extended release of GDNF into the nigrostriatal
pathway in animal Parkinson's disease models using viral
vectors or encapsulated cells genetically engineered to
produce GDNF (Lindner et al., 1995; Choi-Lundberg et al.,
1997; Bensadoun et al., 2000; Kordower et al., 2000). While
these procedures show promise, techniques for determining
and controlling dosing and the timing of delivery are in the
developmental stage (Bjorklund and Lindvall, 2000; Olson,
2000). Thus, while signi®cant bene®cial effects can be
quanti®ed on host dopamine neurones and neuronal processes
after viral vector GDNF transfection or implantation of
GDNF-producing cells, the levels of biologically available
GDNF producing these effects are unclear.
The present study had the following aims. (i) To assess
the restorative actions of GDNF under conditions where
neuroprotection would have only a minor role, the late
stages of human Parkinson's disease were modelled in
rhesus monkeys with stable, advanced hemiparkinsonian
features induced by the neurotoxin 1-methyl-4-phenyl-
1,2,3,6-tetrahydropyridine (MPTP) (Bankiewicz et al.,
1983; Smith et al., 1993; Emborg-Knott and Domino,
1998). In this model, MPTP infusion through the right
carotid artery results in ~75% loss of dopamine neurones
expressing the phenotypic marker tyrosine hydroxylase
(TH) in the right substantia nigra and >99% depletion of
dopamine in the right putamen (Gash et al., 1996). These
reductions are comparable with advanced human parkinsonism,
in which cell counts typically show 60±70% loss
of nigral dopamine neurones (Jellinger, 1986) and 99%
dopamine depletion in the putamen (Kish et al., 1988).
(ii) To determine the titre of biologically available GDNF

Perry is responsible for many of us getting so involved in advocacy; he eats and breathes advocacy.

And Greg is responsible for many of us getting involved in legislative issues.

There are many out there with so many talents (in spite of PD) that can help the patient's voice be loud and clear. Do something more than just wait for better treatments - join an advocacy group, start a local support group, back a presidential candidate who will further research, write a lettr to the editor, speak to a civic group, to church groups,

We must jooin forces. One voice has to be "collectively speaking."

thank you, Perry!

We're in this together and
we're behind you all the way!