GDNF AND PARKINSON'S DISEASE -
SAFETY, EFFECTS AND RISKS
A few words
When I was searching "which drug can offer the most effect on Parkinson's disease", I found GDNF. There are exciting
data from the clinical studies in Phase 1, however, GDNF may also cause a serious side effect.

About GDNF
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]
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2013

Encapsulated of GDNF in Microspheres
Vascular endothelial growth factor (VEGF) and glial cell line-derived neurotrophic factor (GDNF) were separately
encapsulated into polymeric microspheres to obtain a continuous drug release over time. The treatment of
6-OHDA-lesioned rats with GDNF microspheres and with both VEGF and GDNF microspheres resulted in improved
results in the rotation behaviour test. Both groups also showed higher levels of neuroregeneration/neuroreparation in the
substantia nigra than the control group did. [A1]

Microspheres are tiny particles in micron. By an appropriate route, e.g. injection, the microspheres can stay in certain
tissues (non-circulated, the target area) for a long time, depending the degradation rates of the polymer used in the
manufacturing. This method may minimize side effects of the non-target area.

Convection-enchanced Delivery
Taylor H and co-workers at University of Bristol suggest the use of convection-enhanced delivery CED to facilitate more
widespread and clinically effective drug distribution. In a study of rats, two weeks after single dose CED, recombinant
methionyl human glial cell line-derived neurotrophic factor was below the limit of detection by ELISA but detectable by
immunohistochemistry when infused at low concentrations (0.1 and 0.2 µg/µL). At these concentrations, there was no
associated neuronal loss or synaptic toxicity. CED at an infused concentration of 0.2 µg/µL was associated with a
significant increase in synaptogenesis. The CED: Adult male Wistar rats were anaesthetised, and then placed in a
stereotactic frame. A midline skin incision was made from glabella to occiput to expose bregma. Bilateral burr holes were
drilled using a 2 mm drill. All CED procedures were performed using a custom-made catheter with an outer diameter of
0.22 mm and inner diameter of 0.15 mm, composed of fused silica with a laser cut tip. The cannula was attached to a 1
ml syringe connected to a rate-controlled microinfusion pump and the tip placed at stereotactic co-ordinates derived from
the Paxinos and Watson stereotactic rat brain atlas, in order to target the striatum [A2].

AAV2-neurturin
AAV2-neurturin (CERE-120) is a gene therapy vector. A study of 6 subjects with  Parkinson disease, bilateral stereotactic
injections of CERE-120 into the SN and putamen showed that AAV2-neurturin is safe and well-tolerated. [A3]

There are also a lot of studies about how GDNF improves
Parkinson's disease in animals in 2013, the results are
consistent to the earlier stage. I think, the key is how the scientists deliver GDNF as to minimize its side effects (in
non-target area).

Links
Current Medications for Parkinson's Disease
Herbs for Parkinson's Disease
Symptoms of Parkinson's Disease

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ALL RIGHTS RESERVED ZHION. 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. [A1] Herrán E et al, In vivo administration of VEGF- and GDNF-releasing biodegradable polymeric microspheres in a severe
lesion model of Parkinson's disease. Eur J Pharm Biopharm. 2013 Apr 30. [A2] Taylor H et al, Clearance and toxicity of recombinant methionyl human glial cell
line-derived neurotrophic factor (r-metHu GDNF) following acute convection-enhanced delivery into the striatum. PLoS One. 2013;8(3):e56186 [A3] Bartus RT, et
al, Safety/feasibility of targeting the substantia nigra with AAV2-neurturin in Parkinson patients.Neurology. 2013 Apr 30;80(18):1698-701