GDNF AND PARKINSON'S DISEASE -
SAFETY, EFFECTS AND RISKS
SAFETY, EFFECTS AND RISKS
A human therapeutic trial using intraputaminal infusion of glial
cell-derived neurotrophic factor (GDNF) in Parkinson's disease was
abruptly terminated, partly due to safety concerns raised by the
finding of cerebellar lesions in monkeys given high-dose GDNF. [P1]
Potential future treatments for Parkinson's disease should include
those that not only provide symptomatic relief to patients but also
neuroprotective and/or neurorestorative. Low dopaminergic cell
survival and suboptimal fiber reinnervation are likely major
contributing factors for the limited benefits of neural transplantation
in Parkinson's disease (PD) patients. [1]
Glial cell lined-derived neurotrophic factor (GDNF) has been shown
to enhance dopaminergic cell survival and fiber outgrowth of the
graft site as well as promote behavioral recovery in rodent models
of Parkinson's disease. [1,2] Positive results using monkeys have
encouraged the use of GDNF in human trials. [P3]
Shortage of dopamine causes Parkinson's disease leading to
problems in movement, mood and behavior. GDNF seems to be
able to stimulate dopamine production and prevent neuron
degeneration. Three years ago, a group of Parkinson's patients
had been treated with GDNF (glial derived neurotrophic growth
factor) at Bristol's Frenchay Hospital and they were suddenly able
to walk, talk and smile again. [3]
Unfortunately studies have shown mixed results, illustrating the
influence that various parameters of administration can have on
clinical outcome. [P3]
Bolus intraventricular injections of GDNF in primates have shown
some behavioural efficacy, there was no clinical benefit in the first
human trial using this method, which was most likely a result of
inefficient GDNF distribution in the striatal parenchyma. In primates,
however, continuous (rather than bolus) delivery of GDNF into the
ventricles results in significant distribution in the striatum. While
chronic delivery of GDNF into the ventricles has not been assessed
in humans. [P3]
Intraputamenal protein delivery in two Phase I trials have
demonstrated that GDNF considerably reduces Parkinson's
disease symptoms, suggesting that the putamen is the optimal
location for delivery.
However, researchers from Michael J. Fox Foundation for
Parkinson's Research, New York, pointed out that results from a
recent controlled clinical study delivering the neurotrophic factor,
glial-derived neurotrophic factor (GDNF), directly into brain did not
demonstrate efficacy and safety of such a treatment. [P2]
However, the possibility of high levels of GDNF resulting in
widespread distribution of GDNF to non-targeted areas is a cause
of concern. [P3] Consequently, Amgen, the innovator company,
stopped the manufacturing GDNF and claimed that the drug could
cause a serious side effect - brain damage. In a U.S study,
researchers found antibodies in the brain of one or two patients.
While in an animal study, high doses of GDNF caused irreversible
brain damage, and subsequently death. [3, P1]
Is there any evidence about the side effects of GDNF in human?
Researchers at University of Kentucky studied the magnetic
resonance images of the cerebellum or elsewhere from nine
Parkinson's disease patients participating in a trial. They compared
these images with image from 25 normal adults, images taken
between pre and post-GDNF infusion scans using a repeated
measures. They found no significant cerebellar differences in any
of the nine individual Parkinson's disease patients, no significant
morphometric differences between pre- and post-GDNF scans and
no signal abnormalities in the cerebellum detected on the FLAIR
images in Parkinson's disease patients. Basically, they found no
imaging evidence of cerebellar injury in human subjects undergoing
chronic intracerebral GDNF infusion. [P1]
Though the results of findings are exciting, we still do not know the
long-term effects.
Researchers suggest the need of vectors. Vector mediated delivery
of GDNF may provide a suitable means for long-term
intraputamenal delivery. The development of these vectors should
be the way forward for GDNF treatment. [P3]
ALL RIGHTS RESERVED ZHION 2006. THIS ARTICLE IS NOT A MEDICAL ADVICE.
CONSULT WITH YOUR DOCTOR FOR ANY QUESTIONS.
[1] McLeod M, et al, Erythropoietin and GDNF enhance ventral mesencephalic fiber
outgrowth and capillary proliferation following neural transplantation in a rodent model of
Parkinson's disease. Eur J Neurosci. 2006 Jul;24(2):361-70. [2] Dietz GP, et al, Application
of a blood-brain-barrier-penetrating form of GDNF in a mouse model for Parkinson's
disease. Brain Res. 2006 Apr 12;1082(1):61-6. [3] Why won't they let Parkinson's sufferers
take a life-changing drug? NIKKI MURFITT Daily Mail 31st October 2006 [P1] Chebrolu H,
et al, MRI volumetric and intensity analysis of the cerebellum in Parkinson's disease
patients infused with glial-derived neurotrophic factor (GDNF). Exp Neurol. 2006
Apr;198(2):450-6. Epub 2006 Feb 7. [P2] Sherer TB, et al, Crossroads in GDNF therapy for
Parkinson's disease. Mov Disord. 2006 Feb;21(2):136-41. [P3] Eslamboli A. Assessment of
GDNF in primate models of Parkinson's disease: comparison with human studies. Rev
Neurosci. 2005;16(4):303-10.
cell-derived neurotrophic factor (GDNF) in Parkinson's disease was
abruptly terminated, partly due to safety concerns raised by the
finding of cerebellar lesions in monkeys given high-dose GDNF. [P1]
Potential future treatments for Parkinson's disease should include
those that not only provide symptomatic relief to patients but also
neuroprotective and/or neurorestorative. Low dopaminergic cell
survival and suboptimal fiber reinnervation are likely major
contributing factors for the limited benefits of neural transplantation
in Parkinson's disease (PD) patients. [1]
Glial cell lined-derived neurotrophic factor (GDNF) has been shown
to enhance dopaminergic cell survival and fiber outgrowth of the
graft site as well as promote behavioral recovery in rodent models
of Parkinson's disease. [1,2] Positive results using monkeys have
encouraged the use of GDNF in human trials. [P3]
Shortage of dopamine causes Parkinson's disease leading to
problems in movement, mood and behavior. GDNF seems to be
able to stimulate dopamine production and prevent neuron
degeneration. Three years ago, a group of Parkinson's patients
had been treated with GDNF (glial derived neurotrophic growth
factor) at Bristol's Frenchay Hospital and they were suddenly able
to walk, talk and smile again. [3]
Unfortunately studies have shown mixed results, illustrating the
influence that various parameters of administration can have on
clinical outcome. [P3]
Bolus intraventricular injections of GDNF in primates have shown
some behavioural efficacy, there was no clinical benefit in the first
human trial using this method, which was most likely a result of
inefficient GDNF distribution in the striatal parenchyma. In primates,
however, continuous (rather than bolus) delivery of GDNF into the
ventricles results in significant distribution in the striatum. While
chronic delivery of GDNF into the ventricles has not been assessed
in humans. [P3]
Intraputamenal protein delivery in two Phase I trials have
demonstrated that GDNF considerably reduces Parkinson's
disease symptoms, suggesting that the putamen is the optimal
location for delivery.
However, researchers from Michael J. Fox Foundation for
Parkinson's Research, New York, pointed out that results from a
recent controlled clinical study delivering the neurotrophic factor,
glial-derived neurotrophic factor (GDNF), directly into brain did not
demonstrate efficacy and safety of such a treatment. [P2]
However, the possibility of high levels of GDNF resulting in
widespread distribution of GDNF to non-targeted areas is a cause
of concern. [P3] Consequently, Amgen, the innovator company,
stopped the manufacturing GDNF and claimed that the drug could
cause a serious side effect - brain damage. In a U.S study,
researchers found antibodies in the brain of one or two patients.
While in an animal study, high doses of GDNF caused irreversible
brain damage, and subsequently death. [3, P1]
Is there any evidence about the side effects of GDNF in human?
Researchers at University of Kentucky studied the magnetic
resonance images of the cerebellum or elsewhere from nine
Parkinson's disease patients participating in a trial. They compared
these images with image from 25 normal adults, images taken
between pre and post-GDNF infusion scans using a repeated
measures. They found no significant cerebellar differences in any
of the nine individual Parkinson's disease patients, no significant
morphometric differences between pre- and post-GDNF scans and
no signal abnormalities in the cerebellum detected on the FLAIR
images in Parkinson's disease patients. Basically, they found no
imaging evidence of cerebellar injury in human subjects undergoing
chronic intracerebral GDNF infusion. [P1]
Though the results of findings are exciting, we still do not know the
long-term effects.
Researchers suggest the need of vectors. Vector mediated delivery
of GDNF may provide a suitable means for long-term
intraputamenal delivery. The development of these vectors should
be the way forward for GDNF treatment. [P3]
ALL RIGHTS RESERVED ZHION 2006. THIS ARTICLE IS NOT A MEDICAL ADVICE.
CONSULT WITH YOUR DOCTOR FOR ANY QUESTIONS.
[1] McLeod M, et al, Erythropoietin and GDNF enhance ventral mesencephalic fiber
outgrowth and capillary proliferation following neural transplantation in a rodent model of
Parkinson's disease. Eur J Neurosci. 2006 Jul;24(2):361-70. [2] Dietz GP, et al, Application
of a blood-brain-barrier-penetrating form of GDNF in a mouse model for Parkinson's
disease. Brain Res. 2006 Apr 12;1082(1):61-6. [3] Why won't they let Parkinson's sufferers
take a life-changing drug? NIKKI MURFITT Daily Mail 31st October 2006 [P1] Chebrolu H,
et al, MRI volumetric and intensity analysis of the cerebellum in Parkinson's disease
patients infused with glial-derived neurotrophic factor (GDNF). Exp Neurol. 2006
Apr;198(2):450-6. Epub 2006 Feb 7. [P2] Sherer TB, et al, Crossroads in GDNF therapy for
Parkinson's disease. Mov Disord. 2006 Feb;21(2):136-41. [P3] Eslamboli A. Assessment of
GDNF in primate models of Parkinson's disease: comparison with human studies. Rev
Neurosci. 2005;16(4):303-10.
PHARMCEUTICAL
INDUSTRY
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Development
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Colorant
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Orphan Drug
Protein Drug
Niche Market
Novo Norkdisk R&D
Equipment
Blenders
CONTRACT MANUFACT.
Nutrition Supplements
NEW DRUGS
Arranon
Actoplus Met
Alfuzosin
Ambien CR
Avastin
Asmanex(R)
Duodote
Erbitux (cetuximab)
Gardasil
GNDF
GRN163
Herceptin
Increlex (rhIGF-1)
Lidoerm (Lidocaine)
Liraglutide
Lucentis
Lyrica (pregabalin)
Prezista
Rozerem
Sorafenib
Sutent
Tamsulosin
Torcetrapib
Tykerb
Tysabri
Vectibix
Zometa
OLD DRUGS
Lithium Carbonate
DRUG NOTES
[CONSTRUCT]
Clinical Research
Terminologies
FDA ALERTS
Protein Drug Market
Niche Market
Orphan Drug
levothyroxine
Protein Drug 1
Protein Drug2
Double-blind Study
INDUSTRY
Foundamental Science
Colloidal Stabilization
Drug Product
Development
Patent Application
Product Development
Product Ingredients
Colorant
Scale up a batch 1
Drug Delivery Industry
Drug Delivery - Smart
Bomb
Lotion, Cream, Preps
Enteric Coating-Eudragit
Enteric
Coating-Nutrateric
SR Coating-Aquacoat
Drug Industry
Drug Competitions
Drug in Development
Cholesterol-lowering
Drug-Terminologies
Packaging Materials
Market
Drug Dev- 2004
Drug Dev - 2005Q1
Drug Dev- 2005Q2
Drug Dev-2005Summer
Drug Dev-2005Q3
Orphan Drug
Protein Drug
Niche Market
Novo Norkdisk R&D
Equipment
Blenders
CONTRACT MANUFACT.
Nutrition Supplements
NEW DRUGS
Arranon
Actoplus Met
Alfuzosin
Ambien CR
Avastin
Asmanex(R)
Duodote
Erbitux (cetuximab)
Gardasil
GNDF
GRN163
Herceptin
Increlex (rhIGF-1)
Lidoerm (Lidocaine)
Liraglutide
Lucentis
Lyrica (pregabalin)
Prezista
Rozerem
Sorafenib
Sutent
Tamsulosin
Torcetrapib
Tykerb
Tysabri
Vectibix
Zometa
OLD DRUGS
Lithium Carbonate
DRUG NOTES
[CONSTRUCT]
Clinical Research
Terminologies
FDA ALERTS
Protein Drug Market
Niche Market
Orphan Drug
levothyroxine
Protein Drug 1
Protein Drug2
Double-blind Study
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