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GDNF - How to Produce More
GDNF Intranasal Gene Therapy
The Controversy Surrounding GDNF
The existence of GDNF has been known for well over twenty years. Only in 2006, at the World Parkinson’s Congress held in Washington DC, was it first announced that GDNF is produced in the brain, by the glial cells, and that GDNF repairs the damaged brain cells.
If everybody in the Parkinson’s world knew about GDNF in 2006, why do only a few people, outside of the scientific world, know anything about it yet?
If the medical profession does know about GDNF then they should have jumped onto the bandwagon, in 2006, and made every effort to tell their patients about it!
That has not happened, at least not in my neck of the woods. Does this mean that this vital information is not being disseminated amongst all the players in the medical world?
If so, why would that be?
At that World Congress, we were told that fast walking is the best way to go about producing GDNF in the brain. Patients should all be shown that they are capable of walking, at least most of them can. Whatever walking they do manage to do would be better than nothing.
Getting better, even by a little bit is better than continuing to get worse.
As far as I know, scientists knew about the existence of GDNF, long before 1993, when the first clinical test was performed in England. If they knew about it so long ago, why did we all not know about it?
- I assume that it must have been found first inside the brain of a human being.
- The purpose of GDNF must have been known, otherwise, why would Amgen have made an artificial version of it?
- When the 1993 trials were started, they must have known that GDNF repairs the damaged brain cells, and they were conducting these trials to see how effective it is!
- I must therefore assume that because GDNF - a natural cure, which is produced in the brain - does not generate income for anybody; it was more important to do trials using artificial GDNF, rather than getting some pd patients to do some walking and then measure how much they managed to improve over a period of time, as they did before the 2006 World Parkinson’s Congress.
- That would have cost next to nothing, compared to what that first artificial GDNF trial must have cost.
- Are we all so powerless that we are unable to take action against this silence on what fast walking can do for us?Artificial GDNF has been produced in the USA by a company named Amgen. This GDNF was first used in the trial mentioned above in 1993, carried out by Dr Steven Gill, at the Frenchay hospital in Bristol, England. This was the published result of that trial:Results: “After one year, there were no serious clinical side effects, a 39% improvement in the off-medication motor sub-score of the Unified Parkinson's Disease Rating Scale (UPDRS) and a 61% improvement in the activities of daily living sub-score. Medication-induced dyskinesias were reduced by 64% and were not observed off medication during chronic GDNF delivery. PET scans showed a significant 28% increase of dopamine storage after 18 months, suggesting:Methods: A brain autopsy was performed on one of the Bristol, United Kingdom phase I GDNF trial participants, who had died of an unrelated heart attack.Results: The autopsy analysis revealed re-growth of nerve fibers in the putamen area of the brain. Professor Love, who examined the brain stated that ***********************
- “This was the first neuropathological evidence that infusion of GDNF in humans causes sprouting of dopamine fibers, in association with a reduction in the severity of Parkinson’s Disease."
- “A direct effect of GDNF on dopamine function.”
Why won't they let Parkinson's sufferers take a life-changing drug?
By NIKKI MURFITT
When Tom Isaacs was 27 he was diagnosed with Parkinson's disease. The condition gradually destroys the brain's ability to control the muscles - there is no cure.
Determined to give himself the best possible prognosis, Tom embarked on a very personal journey to meet leading scientists in the hope of finding new treatments that would help him.
Three years ago it seemed he'd found the answer: a new drug GDNF (glial derived neurotrophic growth factor). A group of Parkinson's patients had been treated with GDNF at Bristol's Frenchay Hospital in 1993 and their transformation had been remarkable: sufferers who'd been trapped in a living hell were suddenly able to walk, talk and smile again.
Parkinson's is caused by a shortage of dopamine, a chemical messenger involved in movement, mood and behaviour. Why this happens is still not known.
GDNF seems to work by stimulating dopamine production and preventing degeneration of the brain cells. The drug is delivered via a catheter permanently implanted in the brain. The catheter is connected to a Jaffa cake-sized pump sewn into the abdomen.
When GDNF was given to the Bristol patients the results were astonishing. 'Men who had been unable to get up out of a chair unaided were walking normally across a room. Their hand co-ordination was unbelievable, in exercises they could move their hand easily from left to right, something that had previously been impossible under the onslaught of Parkinson's,' says Tom.
So impressive were the results that the study was rolled out to North America and by September 2004, 50 patients were receiving the drug. The Parkinson's Disease Society in the UK planned to hand over** £1.2 million to fund further trials in Bristol.
But suddenly, at the end of 2004, and without warning, this lifeline was snatched away. Amgen, the American drug company which holds the patent for manufacturing GDNF, claimed the drug was dangerous as it could cause brain damage and refused to continue prescribing it.
The below link is to an online book by Anders Bjorkland which discusses some truly interesting aspects of the Bristol study:
Case Inspires Parkinson’s Crusade
Parkinson’s patients in the US, who are suing a drugs company for withdrawing a pioneering treatment, say a man treated in Bristol has given them fresh hope.
Amgen halted medical trials of glial cell line-derived neurotrophic (Repair) factor (GDNF) because of side effects. But an autopsy on the brain of Henry Webb, who volunteered to undergo tests at Frenchay Hospital, showed signs that his nerve fibers were re-growing.
The company said it had no plans to restart the trials.
Mr Webb, from Blackwood in South Wales, died from a heart attack last December. He was one of six patients with advanced Parkinson's Disease involved in the GDNF trials at Frenchay.
He told BBC News in 2003 the drug had given him back his life.
"Mr. Webb's case is important because it shows that GDNF is a safe and effective treatment."
Lower dosage
Kristen Suthers, daughter of one of the US patients fighting to get the medical trials restarted, said: "We believe high doses of GDNF causes lesions. But we've seen the study from Mr. Webb, and that it is not the case, if you give patients a lower dosage of GDNF.
A spokeswoman for Amgen told the BBC: "It is a case of interest, but you have to remember, it was phase one of the study."In the phase two study, those on placebos did well, sometimes better, than those on the drug."
http://news.bbc.co.uk/2/hi/uk_news/england/bristol/somerset/4695567.stm
Question: Why would this second study come up showing a totally different result, when the first study, held ten years previously, showed a highly successful result? This looks so very suspicious to me!
This is an interesting bit from Oxford Journal:
Restorative treatments for brain disorders are rare. In neuroscience research, it is not uncommon to suggest that experimental treatment strategies may have great clinical potential. The rescue or regeneration of a few cultured neurones may be sufficient to entice such optimism. However, the path to a new clinical therapy is typically painstakingly long and difficult to navigate. In our minds, we would like it always to be a straight path starting with tests in cell models in rodents providing us with mechanisms of action and leading to trials in non‐human primates. Then open‐label tests can be performed in small patient groups and eventually large controlled clinical trials are conducted. In reality, however, the path may be tortuous, filled with detours that set the field back, as well as shortcuts and parallel tracks that yield different strategies which develop at their own speed. The development of glial cell line‐derived neurotrophic factor (GDNF) as a treatment for tgciq’s disease over the past nine years provides an example of such an interesting journey. Moreover, it illustrates one role of non‐human primates in preclinical development of a novel therapy.
In this issue, Grondin and co‐workers (Grondin et al., 2002) present evidence for structural and functional benefits of infusions of GDNF in rhesus monkeys previously rendered parkinsonian by unilateral intracarotid injection of 1-methyl-4phenyl-1,2,3,6- tetrahydropyridne (MPTP).
Using mini‐pumps, they infused 5–15 µg/day GDNF either into the lateral ventricle or the dopamine‐depleted dorsal putamen. Starting during the first month, there was a gradual and marked reduction in parkinsonian symptoms, including bradykinesia and rigidity, without any signs of adverse effects. Post‐mortem examination revealed partial restoration of dopamine and its metabolites in the corpus striatum, as well as evidence for an increased number of nigrostriatal dopaminergic fibres and cell bodies in the substantia nigra. Interestingly, there were no significant differences between the intraventricular‐ and intraputamenal‐ infusion groups, so the data for both groups were pooled. This is the first demonstration that GDNF infused directly into the brain parenchyma of non‐human primates is effective in restoring dopaminergic function. The treatment was not initiated until over 3 months after the MPTP lesion, when most of the dopaminergic cells had probably died due to the toxin. Therefore the authors argue that GDNF most likely worked through a neuroregenerative mechanism as opposed to one of acute neuroprotection (Grondin et al., 2002).
Read more on:
http://brain.oxfordjournals.org/content/125/10/2149.full
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This is interesting! It tells why the drug company making GDNF stopped the trial – or the reasons given by them — and the Michael J. Fox Foundation’s role in halting the trial:
Trial of New PD Treatment Halted: Some Patients and Advocates Protest
By Robin Elliott
On Friday, February 12, Amgen Inc. announced that, after much internal hand wringing, it was denying a request by participants in trials of a molecule known as GDNF, an experimental Parkinson's treatment, to continue receiving the treatment following termination of the trials.
California-based Amgen, the world's largest biotechnology company, had abruptly concluded its own double-blind trial almost six months earlier, saying that the treatment had not been shown to be effective and citing safety concerns in two areas. In one of these, several subjects were found to have developed antibodies that could potentially attack the body's own GDNF, a naturally occurring product that is essential for the production of dopamine, the chemical messenger that is deficient in Parkinson's.
The other safety concern came out of a separate trial involving monkeys. It turned out that a few of the animals were found to have evidence of lesions in the area of the brain known as the cerebellum.
Several leading scientists and advocacy groups take issue with Amgen's decision
Several of the scientists who had served as investigators in the Amgen trials, including Drs. Michael Hutchinson of New York University, Don Gash and Greg Gerhardt of the University of Kentucky, Richard Penn of the University of Chicago and Steven Gill at the University of Bristol, England, have challenged Amgen's interpretation of both the efficacy and the safety data. As to efficacy, some have argued that the wrong statistical test was used, and that an alternative test would have showed GDNF to be effective. (Amgen, supported by several investigators including Drs. Jay Nutt of the Parkinson Center of Oregon and Anthony Lang of the University of Toronto, has held to its original opinion that the trials failed to show efficacy.)
As to the safety issues, some of the doctors have argued that Amgen has overreacted on both counts. The antibody issue, they say, is frequently seen in such studies and does not necessarily have any adverse effects on the health of the patient. (Indeed, they note that when the antibody findings first surfaced in the spring of 2004, Amgen seemed unconcerned by the data and would have continued with preparations for a larger-scale Phase III trial of GDNF, had the second wave of monkey data not come along.)
As for the monkey data, some of these doctors point to evidence that suggests that the cerebellar damage was caused, not by the toxicity of the intervention, but by its precipitate withdrawal (six months into the trial). They also point out that the dose used for the monkeys was many times the doses used in the human trials.
Michael J. Fox Foundation stages "Scientific Summit" on GDNF
At a meeting in Chicago in early August 2004, where the efficacy data on GDNF were announced, Debi Brooks, President and CEO of the Michael J. Fox Foundation for Parkinson's Research, offered to host a scientific summit on the subject. The summit, which was held in November, drew some 30 scientists from North American and European centres for Parkinson's research and concluded with a broad consensus that while GDNF remained a promising potential treatment, more animal studies should be done to assess the health concerns before any new human trials should be undertaken.
What this discussion did not address was what should be done about the 48 people in the U.S. and the United Kingdom who have participated in one of the Amgen-sponsored trials, several of whom have indicated that they wish to continue receiving the treatment. Most observers believe that the "risk-benefit" calculus for these people is different from what it would be for a new patient because all of them have already undergone the surgery necessary to participate in the trial, and several of them have been on GDNF for as long as three years. Representatives of this group have set up a website - www.GDNF4Parkinsons.org - which has be-come a rallying-point for the Parkinson's community.
Not surprisingly, Amgen's February announcement was especially galling to this group - many of whom had written personal letters to Amgen pleading for reinstatement of GDNF. They were backed by several of the community's advocacy groups, including the Parkinson's Disease Foundation, the Parkinson's Action Network and the Parkinson Pipeline Project.
To understand how GDNF got to this point, we need to look at the scientific history of the molecule.
GDNF - The trials and tribulations of a promising Parkinson's treatment
Glial-cell line-derived neurotrophic factor, or GDNF, is one of the most powerful naturally-occurring human factors known to nourish and foster the growth of dopamine-generating neurons. Soon after GDNF was identified in 1993, Dr. Gash and colleagues at the University of Rochester and later at the University of Kentucky showed that the injection of GDNF protein into both rat and monkey models of parkinsonism showed therapeutic promise.
Dr. Gash's work was soon followed by the first gene therapy trial of GDNF, conducted in a rat model by Dr. Martha C. Bohn and her colleagues at the University of Rochester. This seminal study, which was published in the journal Science in 1997, showed that continuous delivery of GDNF at low levels using a so-called "viral vector" was able to protect dopaminergic neurons from neurotoxin-induced cell death.
Drs. Jeffrey H. Kordower and Marina E. Emborg, along with their colleagues at Rush University Medical Center in Chicago and the University of Lausanne in Switzerland, picked up the ball by conducting the first study of GDNF gene therapy in a monkey model. Their studies showed improved motor performance in the animals which received the GDNF gene (compared with animals that received no treatment). In the treated animals, parkinsonian symptoms were reduced, and, after the animals were sacrificed, the numbers of healthy dopamine neurons were found to be significantly enhanced. A summary of the findings was published in Science in 2000.
The investigation in humans
While the animal studies were continuing, scientists began to examine how GDNF might work in humans. Based on the preliminary results of Dr. Gash's studies in rat and monkey models, Amgen initiated a human, randomized, double-blind trial of GDNF, led by Dr. Nutt. The results, published in a 2003 edition of the journal Neurology, were disappointing; the treatment showed little benefit and several side-effects, confirming that benefit in animals does not necessarily translate to benefit in humans.
Some two years later, a British team conducted a follow-up study that greatly raised world interest in the promise of GDNF. In this study, led by Dr. Gill and his colleagues at Frenchay Hospital in Bristol, scientists implanted catheters in the brains and pumps in the abdominal walls of five people with moderate Parkinson's. The pumps continuously fed GDNF into specific areas of the brain via the catheters at a precise rate of infusion. All five patients showed improvements in "off" states comparable to their "on" states within two months of the onset of the trial. Their motor skills continued to show improvement and even gait difficulties were eased. Brain scans documented the patients' progress while the dosage of anti-Parkinson's medications was steadily reduced. The results showed significant improvement in the functioning of the dopaminergic system.
The Amgen "double-blind" trial
Impressive as the new data appeared to be, the Bristol trial did not provide an answer as to whether GDNF works. The reason is that it was of the so-called "open-label" variety, in which every participant received the treatment and some of them - human nature being what it is - may have imagined that they felt better than they really were. To correct for this factor, known as the "placebo effect," scientists try to confirm early data by conducting what is known as a "double-blind" trial, in which some patients are randomly placed on the treatment and the others are given a sugar pill. To test the validity of the British data, Amgen initiated such a trial for GDNF in 2003 with 34 patients.
As reported by Dr. Lang at a meeting of the American Neurological Association in October, 2004, the study did not prove the efficacy of GDNF. The investigators judged the patients' "off" periods to be somewhat improved, but saw no improvement in "on" periods.
The Uncertain Future of GDNF
Dr. Clive N. Svendsen of the University of Wisconsin (co-investigator in the Bristol study), as well as other investigators involved in GDNF research, has suggested that the studies' dissimilar results may have been a consequence of the different dosages used, as well as by the different sizes of the catheters used to infuse the treatment.
Dr. Bohn says she is encouraged by the Bristol results but believes that a delivery system utilizing gene therapy rather than infusion via catheter may ultimately be safer (since it does not require the administration of live virus to the brain) and may offer a better long-term outcome for patients. Dr. Svendsen agrees, and suggests that another potential delivery technique might be the implantation of genetically-engineered stem cells that could in turn release GDNF.
Dr. Svendsen also reports that he and other study participants are meeting with Amgen to analyze the differing results of the studies to date and to seek consensus on whether and when there will be further studies of GDNF. Meanwhile, additional animal studies are being pursued.
The reinstatement issue continues
While discussions continue concerning the long-term future of GDNF, the short-term issue of the patients who were in the trials to date remains unresolved. Some have indicated that they would like to go back on GDNF if the opportunity were to be offered, but several have now had their pumps and catheters removed. Voluntary organizations such as PAN and PDF are continuing to explore options of persuading Amgen to reconsider its position. In the words of a recent open letter from leaders of the Parkinson Pipeline Project, a group of patient advocates: "[Reinstatement] is important not only to today's patients but to our prospects of being able to recruit sufficient numbers of people for future trials…[without people to participate] all of us - companies as well as patients - will be the losers."
Robin Elliott is the Executive Director of the Parkinson's Disease Foundation.
If you are keen on reading medical evidence, both for and against GDNF infusion into the brain, then read more:
http://www.pdf.org/en/winter04_05_Trial_of_New_PD_Treatment_Halted
This article discusses the mixed results of the trial, concerns over GDNF, and is a good, brief read:
Is all this argument about how to get GDNF into the brain and what dose we should take really worth all the money t is costing?
Are we not forgetting that the brain produces GDNF as a natural product, which has no side effects?
Surely the medical profession should be leading the charge and telling their patients to start doing some FAST WALKING and to slowly reduce their Pd medication until they get to the point - at which I have been for the past 13 years - Pd medication-free and able to live a normal life
I am not cured, but hey, I am healthier than most people of my age!
Perhaps this is just a pipe-dream on my part. I hope not!
GDNF as a Treatment for Parkinson’s Disease
Translational Research as of June 2011
Prepared by: Linda Herman, Therapies Coordinator, Parkinson Pipeline Project (Last updated 6/2/11)
Delivery Methods:
Pump infusion
“The infusion system, also known as 'direct protein therapy,' involves placing a long thin tube (called a catheter) into the part of the brain affected by Parkinson’s disease. This tube is hooked up to a pump implanted under the skin that contains a reservoir of the GDNF protein. The protein slowly flows into the damaged area of the brain and can provide support to injured or dying cells” (M. J. Fox Foundation, April 26, 2011).
This delivery method was used in the early phase I trials at the University of Kentucky, at Bristol Hospital in the UK, and for the Amgen-sponsored phase II trials. In 2004, Amgen terminated all further human research and clinical trials with their recombinant GDNF, claiming it didn’t work and citing possible safety issues based on their monkey studies, It wasn’t until 2010 that Amgen licensed another company (Med Genesis) to resume GDNF research in humans.
However in the ensuing years, many scientists and patients continued to believe in the promise of GDNF, and animal research continued on ways of improving the delivery system – making it more targeted and effective. By 2011, a few early clinical trials were starting and others were on the cusp of translating laboratory research into clinical treatments.
Examples of Pump Infusion Delivery:
Dr. Steven Gill, designed the new infusion pump and catheter system. Funded in part by Cure Parkinson’s Trust (UK). Expected to enter clinical trials in 2011.
“Professor Gill plans to conduct a two year double blind, randomized, placebo-controlled phase 2 study of intermittent intraputamenal GDNF infusions for the treatment of Parkinson’s in 36 patients. CPT’s Research Committee has asked that brain imaging be included in the study to provide further evidence of the efficacy of GDNF in the brain, which in turn supports the development of other GDNF-related therapies using a range of delivery methods." (Cure Parkinson’s Trust)
MedGenesis Therapeutix, partnered with Biovail until Nov 2010.
“On January 12, 2010, MedGenesis "announced that it has successfully entered into an agreement with Amgen Inc., granting MedGenesis an exclusive, worldwide license for glial cell line-derived neurotrophic factor (GDNF) protein in CNS and non-CNS indications"
“The MedGenesis approach is to "deliver a known therapeutic utilizing the MedGenesis cutting-edge CED (Convection Enhanced Delivery) platform to a well-defined local target inside the blood-brain-barrier
This is the first time, Amgen has allowed another company to research it's GDNF molecule in treating humans since the halt of Amgen's phase II clinical trial in Sept. 2004.
"... As part of the license agreement, Amgen now holds a small equity stake in MedGenesis." (MedGenesis web site)
(Dr. Gill, Dr. Howard Federoff and Dr. Bankiewicz (NINDS consortium) are scientific advisors to MedGenesis.)
Eli Lilly/ Medtronic: Preclinical.
Lilly announced in April 2011 a new formulation of GDNF, delivering it to the brain through a catheter connected to a new implanted pump and drug reservoir supplied by Medtronic.
Gene Therapy
In gene therapy, the brain is genetically modified in order to produce the therapy itself within the brain tissue. This is achieved through the injection of a genetic vector in order to allow the brain to produce the trophic factor.” (MJFF website)
Examples of Gene Therapy:
Parkinson's Disease Gene Therapy Study Group, a consortium of seven research institutions throughout the U.S., funded by NINDS.
Phase I trial planned to begin in fall 2011, uses Convection Enhanced Delivery to distribute the genes efficiently to the targeted areas of the brain. An adeno-associated virus (AAV2) encoding human GDNF is the vehicle for gene transfer to the central nervous system. This is the same viral vector used by Ceregene in its research on neurturin – a neural growth factor and a close relative of GDNF (currently in phase II clinical trial.)
Amsterdam Molecular Therapies (Netherlands)
Preclinical: “Amsterdam Molecular Therapeutics (AMT), announced in 2010 that it obtained a license from Amgen to use their GDNF gene together with AMT's proprietary adeno-associated virus (AAV) gene therapy platform for the development of a gene therapy treatment for Parkinson's disease. (AMT website)
Encapsulated GDNF Producing Cells, lead researcher: Olle Lindvall, Lund University, Sweden. Funded in part by MJFF
Pre-clinical research to develop a neuroprotective therapy based on the implantation of encapsulated cells that produce GDNF directly into the brain.
Final outcome report in 2010, “Cell clones were developed that produced GDNF in vitro. Additionally, the encapsulated device was generated. However, cell clones did not produce sufficient GDNF when implanted into the brains of pre-clinical models. Though significant efforts were made, the team was unable to overcome the limitation of insufficient in vivo production of GDNF.” (MJFF website)
Intravenous GDNF Gene Therapy of Experimental PD (AGT 190)
Preclinical: Lead researcher, William Pardridge. Sponsors: UCLA and Armagen Technologies; also funded by MJFF. Applied for FDA approval of Phase I trial.
Therapeutic gene encodes GDNF, and is engineered to restrict expression of the GDNF gene in only parts of the brain related to PD…This research provides a new approach to the selective targeting of a GDNF gene therapy in PD without the use of viruses or neurosurgery.” (MJFF Web site)
If phase I has no safety problems, new funding source needed to continue development, estimated at $15 million. (Vastag)
Oral delivery of GDNF
Cogane - Sponsor: Phytopharm.
“Cogane (PYM50028) arose from research into the activity of an Asian medicinal plant…. In pre-clinical models, Cogane™ reverses the changes in the area of the brain involved in Parkinson’s disease by inducing the body’s own production of proteins known as neurotrophic factors. In particular, one of these factors known as 'GDNF' has been shown to be particularly effective in re-growing damaged nerves. Since GDNF is a protein it cannot be given orally (in pill or liquid form) because it is degraded in the stomach and intestine, and also does not readily cross the blood-brain barrier. ... Cogane™, which can be taken orally, readily crosses the blood-brain barrier and stimulates the release of GDNF in the brain…” (Pipeline Project Database)
Phase II clinical trial began in 2011: “Randomised, Double-blind, Placebo-controlled Study to Investigate the Efficacy, Safety and Tolerability of PYM50028 in Subjects With Early-stage Parkinson's Disease Administered Once Daily for 28 Weeks.” (clinicaltrials.gov)
Completion expected Dec. 2012
References
Amsterdam Molecular Therapeutics. Company website. Accessed online on 6/3/11 at: http://www.amtbiopharma.com/about/company
Cure Parkinson’s Trust. GDNF appeal. 2011. Accessed online on 6/1/11 at: http://www.cureparkinsons.org.uk/document_1.aspx?id=0:60951&id=0:36727
Humphries, Courtney. Keeping Neurons Alive in Parkinson’s Patients. Technology Review, June 6, 2011. Accessed online on 6/6/11 at: http://www.technologyreview.com/biomedicine/37708/?mod=chfeatured&a=f
Investigation of Cogane (PYM50028) in Early-stage Parkinson's Disease (CONFIDENT-PD). Clinicaltrials.gov. Accessed online 6/1/11 at: http://clinicaltrials.gov/ct2/show/NCT01060878?term=cogane&rank=22
MedGenesis Therapeutix. Company web site. Accessed online on June 3, 2011 at: http://www.medgenesis.com/
Michael j Fox Foundation. Website and database. Accessed online on June 2, 2011 at: http://www.michaeljfox.org/research.cfm
Michael J Fox Foundation. Trophic Factors: Specialized Proteins that Nurture and Protect Neurons. 2007. Accessed online June 3, 2011 at: http://www.michaeljfox.org/living_viewpoints_researcherAreaPositionPapers_trophic.cfm
Parkinson Pipeline Project. Therapy Development Database. Accessed online 6/1/11 at: http://apexutf.shellprompt.net/pls/apex/f?p=162:12:5997922620574622
Vastag, Brian. Biotechnology: Crossing the barrier. Published online 18 August 2010
To Order my Book - Reverse Parkinson's Disease, Go to My Website
The Body's Built-in Healing Kit (GDNF)
GDNF Trials
Informaation supplied by My very good Friend, Mr Greg Maier of Concord, California
Dear John: While not comprehensive, this is a general timeline of the GDNF trials at Bristol’s Frenchay Hospital. It is comprised of study abstracts, articles, and the like. The information is chronological. You can click on the links to read the information in its entirety; in some cases I have excerpted the most relevant language.
http://www.pdpipeline.org/2011/GDNF/gdnf_research_history.htm
The above link will direct you to a page that gives the abstracts of numerous journal articles detailing the GDNF studies; some detail the outright failure of studies began in 1996, but other mention evidence of improvement, e.g.:
Methods: Phase 1, open-label safety trial of GDNF pumped into an implanted catheter and delivered into the putamen of five Parkinson patients. Outcomes measured by UPDRS scores and PET scans that track dopamine production and use.
Results: “After one year, there were no serious clinical side effects, a 39% improvement in the off-medication motor sub-score of the Unified Parkinson's Disease Rating Scale (UPDRS) and a 61% improvement in the activities of daily living sub-score.Medication-induced dyskinesias were reduced by 64% and were not observed off medication during chronic GDNF delivery. PET scans showed a significant 28% increase of dopamine storage after 18 months, suggesting a direct effect of GDNF on dopamine function.”
Title: Intraputamenal infusion of glial cell line-derived neurotrophic factor in PD: a two-year outcome study.
Location: Frenchay Hospital, Institute of Neurosciences, Bristol, United Kingdom .
Authors: Patel NK; Bunnage M; Plaha P; Svendsen CN; Heywood P; Gill SS. Published in: Annals of Neurology. 2005 Feb; Vol. 57 (2), pp.298-302.
Method: The authors reported on a 2 year outcome study of intraputamenal infusion of GDNF in five Parkinson’s patients, conducted at Frenchay Hospital in Bristol, United Kingdom. The authors had previously reported good results after 6 months of GDNF treatment.
Results: After 2 years of continual GDNF infusion there were “no serious clinical side effects and no significant detrimental effects on cognition. Patients showed a 57% and 63% improvement in their off-medication motor and activities of daily living subscores of the Unified Parkinson's Disease Rating Scale, respectively, and health-related quality-of-life measures (Parkinson's Disease Questionnaire-39 and Short Form-36) showed general improvement over time.”
This one is particularly interesting:
è Title : Glial cell line−derived neurotrophic factor induces neuronal sprouting in human brain
Location of Study: Bristol, U.K.
Authors : Seth Love, Puneet Plaha, Nikunj K Patel, Gary R Hotton, David J Brooks & Steven S Gill
Published in: Nature Medicine (2005) 11, 703 – 704.
Methods: A brain autopsy was performed on one of the Bristol, United Kingdom phase I GDNF trial participants, who had died of an unrelated heart attack.
Results: The autopsy analysis revealed re-growth of nerve fibers in the putamen area of the brain. Professor Love, who examined the brain stated that “This is the first neuropathological evidence that infusion of GDNF in humans causes sprouting of dopamine fibres, in association with a reduction in the severity of Parkinson’s Disease."
University of Bristol press release: Click here to read the full article. [12/09; item no longer online]
At this link (below), you will find the rest of the following article:
Why won't they let Parkinson's sufferers take a life-changing drug?
By NIKKI MURFITT
Last updated at 11:01 31 October 2006
When Tom Isaacs was 27 he was diagnosed with Parkinson's disease. The condition gradually destroys the brain's ability to control the muscles - there is no cure.
Determined to give himself the best possible prognosis, Tom embarked on a very personal journey to meet leading scientists in the hope of finding new treatments that would help him.
Three years ago it seemed he'd found the answer: a new drug GDNF (glial derived neurotrophic growth factor). A group of Parkinson's patients had been treated with GDNF at Bristol's Frenchay Hospital and their transformation had been remarkable: sufferers who'd been trapped in a living hell were suddenly able to walk, talk and smile again.
Parkinson's is caused by a shortage of dopamine, a chemical messenger involved in movement, mood and behaviour. Why this happens is still not known.
GDNF seems to work by stimulating dopamine production and preventing degeneration of the brain cells. The drug is delivered via a catheter permanently implanted in the brain. The catheter is connected to a Jaffa cake-sized pump sewn into the abdomen.
When GDNF was given to the Bristol patients the results were astonishing. 'Men who had been unable to get up out of a chair unaided were walking normally across a room. Their hand co-ordination was unbelievable, in exercises they could move their hand easily from left to right, something that had previously been impossible under the onslaught of Parkinson's,' says Tom.
So impressive were the results that the study was rolled out to North America and by September 2004, 50 patients were receiving the drug. The Parkinson's Disease Society in the UK planned to hand over £1.2 million to fund further trials in Bristol.
But suddenly, at the end of 2004, and without warning, this lifeline was snatched away. Amgen, the American drug company which holds the patent for manufacturing GDNF, claimed the drug was dangerous as it could cause brain damage and refused to continue prescribing it.
The below link is to an online book by Anders Bjorkland which discusses some truly interesting aspects of the Bristol study:
A link to an interesting 2005 article:
Case inspires Parkinson's crusade
Parkinson's patients in the US, who are suing a drugs company for withdrawing a pioneering treatment, say a man treated in Bristol has given them fresh hope.
Amgen halted medical trials of glial cell line-derived neurotrophic factor (GDNF) because of side effects.
But an autopsy on the brain of Henry Webb, who volunteered to undergo tests at Frenchay Hospital, showed signs that his nerve fibres were regrowing.
The company said it had no plans to restart the trials.
Mr Webb, from Blackwood in South Wales, died from a heart attack last December.
He was one of four patients with advanced Parkinson's Disease involved in GDNF trials at Frenchay.
Lower dosage
He told BBC News in 2003 the drug had given him back his life.
Kristen Suthers, daughter of one of the US patients fighting to get the medical trials restarted, said: "We believe high doses of GDNF causes lesions. But we've seen the study from Mr Webb that it is not the case if you give patients a lower dosage of GDNF.
"Mr Webb's case is important because it shows that GDNF is a safe and effective treatment."
A spokeswoman for Amgen told the BBC: "It is a case of interest, but you have to remember, it was phase one of the study.
"In the phase two study, those on placebos did well, sometimes better, than those on the drug."
http://news.bbc.co.uk/2/hi/uk_news/england/bristol/somerset/4695567.stm
This is an interesting bit from Oxford Journal:
Restorative treatments for brain disorders are rare. In neuroscience research, it is not uncommon to suggest that experimental treatment strategies may have great clinical potential. The rescue or regeneration of a few cultured neurones may be sufficient to entice such optimism. However, the path to a new clinical therapy is typically painstakingly long and difficult to navigate. In our minds, we would like it always to be a straight path starting with tests in cell models and rodents providing us with mechanisms of action and leading to trials in non‐human primates. Then open‐label tests can be performed in small patient groups and eventually large controlled clinical trials are conducted. In reality, however, the path may be tortuous, filled with detours that set the field back, as well as shortcuts and parallel tracks that yield different strategies which develop at their own speed. The development of glial cell line‐derived neurotrophic factor (GDNF) as a treatment for tgciq’s disease over the past nine years provides an example of such an interesting journey. Moreover, it illustrates one role of non‐human primates in preclinical development of a novel therapy.
In this issue, Grondin and co‐workers (Grondin et al., 2002) present evidence for structural and functional benefits of infusions of GDNF in rhesus monkeys previously rendered parkinsonian by unilateral intracarotid injection of 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP). Using mini‐pumps, they infused 5–15 µg/day GDNF either into the lateral ventricle or the dopamine‐depleted dorsal putamen. Starting during the first month, there was a gradual and marked reduction in parkinsonian symptoms, including bradykinesia and rigidity, without any signs of adverse effects. Post‐mortem examination revealed partial restoration of dopamine and its metabolites in the corpus striatum, as well as evidence for an increased number of nigrostriatal dopaminergic fibres and cell bodies in the substantia nigra. Interestingly, there were no significant differences between the intraventricular‐ and intraputamenal‐infusion groups, so the data for both groups were pooled. This is the first demonstration that GDNF infused directly into the brain parenchyma of non‐human primates is effective in restoring dopaminergic function. The treatment was not initiated until over 3 months after the MPTP lesion, when most of the dopaminergic cells had probably died due to the toxin. Therefore the authors argue that GDNF most likely worked through a neuroregenerative mechanism as opposed to one of acute neuroprotection (Grondin et al., 2002).
Read more: http://brain.oxfordjournals.org/content/125/10/2149.full
This piece is interesting, tells why the drug company making GDNF stopped the trial –or the reasons given by them—and the Michael J. Fox Foundation’s role in halting the trial:
Trial of New PD Treatment Halted: Some Patients and Advocates Protest
By Robin Elliott
On Friday, February 12, Amgen Inc. announced that, after much internal hand wringing, it was denying a request by participants in trials of a molecule known as GDNF, an experimental Parkinson's treatment, to continue receiving the treatment following termination of the trials.
California-based Amgen, the world's largest biotechnology company, had abruptly concluded its own double-blind trial almost six months earlier, saying that the treatment had not been shown to be effective and citing safety concerns in two areas. In one of these, several subjects were found to have developed antibodies that could potentially attack the body's own GDNF, a naturally occurring product that is essential for the production of dopamine, the chemical messenger that is deficient in Parkinson's.
The other safety concern came out of a separate trial involving monkeys. It turned out that a few of the animals were found to have evidence of lesions in the area of the brain known as the cerebellum.
Several leading scientists and advocacy groups take issue with Amgen's decision
Several of the scientists who had served as investigators in the Amgen trials, including Drs. Michael Hutchinson of New York University, Don Gash and Greg Gerhardt of the University of Kentucky, Richard Penn of the University of Chicago and Steven Gill at the University of Bristol, England, have challenged Amgen's interpretation of both the efficacy and the safety data. As to efficacy, some have argued that the wrong statistical test was used, and that an alternative test would have showed GDNF to be effective. (Amgen, supported by several investigators including Drs. Jay Nutt of the Parkinson Center of Oregon and Anthony Lang of the University of Toronto, has held to its original opinion that the trials failed to show efficacy.)
Read more: http://www.pdf.org/en/winter04_05_Trial_of_New_PD_Treatment_Halted
This article discusses the mixed results of the trial, concerns over GDNF, and is a good, brief read:
http://www.zhion.com/drug/GDNF.html
2011