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