Blog: GDNF, CDNF, MANF

[Conductor71]

Hi Linda!

Thanks for confirming.

My other question is that according too what NIH says about Phase I trials is that the treatment doses were likely not to be therapeutic, but Ceregene Phase I did show clinical improvement with GFDNF delivery.

Did Amgen Phase I people show similar response? Does successful completion of the first trial secure you a spot in the next trial? I hate to sound selfish but have to weight trials in terms of my window of benefit from DBS.

Laura

[LindaH]

Hi Laura,
I’ll try to answer your questions.

My other question is that according too what NIH says about Phase I trials is that the treatment doses were likely not to be therapeutic, but Ceregene Phase I did show clinical improvement with GFDNF delivery
.
--The NIH phase 1 trial will test 4 different doses of GDNF. The first group of patients will receive the lowest dose. If this proves safe, the 2nd group will receive a higher dose, and so on for groups 3 and 4
“Phase 1 single-center, open-label, dose escalation, safety and tolerability study of adeno-associated virus, serotype 2 vector (AAV2) containing human GDNF complementary DNA bilaterally delivered by convection-enhanced delivery (CED) to the putamen (450 (alpha) l per hemisphere) of 24 patients with advanced PD. An additional 4 subjects will be allowed for screening failures. Four escalating dose levels will be evaluated in the following dose cohorts (6 patients per cohort): Cohort 1 = 9 x 10(10)vg, Cohort 2 = 3 x 10(11)vg, Cohort 3 = 9 x 10(11)vg and Cohort 4 = 3 x 10(12)vg”

http://www.clinicaltrials.gov/ct2/sh...rm=gdnf&rank=1

---In the Ceregene trials, another growth factor (neurterin) was used.

Did Amgen Phase I people show similar response?
--- Amgen sponsored the phase II trial which delivered the gdnf protein into the brain with an implanted infusion pump and catheter.
The phase I trials were conducted by the University of Kentucky and Frenchay Hospital, Bristol, United Kingdom. Both reported good results.They were both open label – all phase I participants received gdnf and knew it.
Amgen claimed the reason the phase I trials were successful was due to the placebo effect, anfd that the phase II did not meet its endpoints. Many of the trial participants challenged this. You can read about them in the book Monkeys in the middle.
For more on these studies see
http://www.pdpipeline.org/2011/GDNF/...ch_history.htm

At the first World Parkinson’s Congress , I met one of the phase II participants. I could not tell that he had PD. After talking to him, I became a true believer in the potential of gdnf.
The current NIH trial will use gene therapy to deliver the gdnf gene, instead of a pump, although a new pump delivery method is being tested in the UK
Does successful completion of the first trial secure you a spot in the next trial? I hate to sound selfish but have to weight trials in terms of my window of benefit from DBS.
You can only be in one trial. The phase I – all participants will receive GDNF. If it goes on to a phase II, based on curre nt practice , it is likely some will receive the treatment, and the others will receive sham surgery.

[Bob Dawson]

Fascinating to read all the many elements of AMGEN GDNF fiasco. This was where PWP advocacy started
http://www.pdpipeline.org/2011/GDNF/gdnf_table.htm

[crimsoncrew]

Is anyone else feeling optimistic that one or more of GDNF, CDNF, MANF and GM1 Ganglioside may be the "cure" (neuroprotective and/or neurorestorative treatments) we are all so desperately seeking, if only scientists and the biopharma companies can set aside their money, control and political issues and focus on solving the cumbersome and dangerous drug delivery (druggability) aspects of these treatments?

[VICTORIALOU]

Yes, crimson crew, I am feeling optimistic about MANF
new funding

Originally Posted by crimsoncrew

Is anyone else feeling optimistic that one or more of GDNF, CDNF, MANF and GM1 Ganglioside may be the "cure" (neuroprotective and/or neurorestorative treatments) we are all so desperately seeking, if only scientists and the biopharma companies can set aside their money, control and political issues and focus on solving the cumbersome and dangerous drug delivery (druggability) aspects of these treatments?

[VICTORIALOU]

Positive statistical significance results for MANF

"...upon further analysis of the data reported on January 9th, 2013, the striatal reinnervation (densitometry) data produced in the 6 hydroxydopamine (6-OHDA) neurorestoration rat model of Parkinson's disease for MANF at 36ug achieved a statistically significant improvement over the data produced for GDNF, with a P value of 0.047.

In addition to this news there is also a new molecular delivery system to cross the BBB reported in the news today
Experimental Therapy Crosses Blood-Brain Barrier to Treat Neurological Disease

Now all that remains to be done is to merge these 2 therapies and VOILA!!!!

[ol'cs]

It will be a combination of stem cells along with neurotrophic agents which will replace DBS as standard treatment, hopefully soon. There are stem cell treatments available right now, however their claims are still not accepted as "real". Google up " stem cells" and you can see that these have been offered in many countries, using different cells and approaches. The claims are quite surprising, also, that such procedures are not offered in the US, means that they are either "sketchy", or we are being deprived of a significant therapy, all because some of these procedures are derived from human fetal cells (the unholy grail of PD research).

[VICTORIALOU]

From OneMedPlace research

RESEARCH
The disease-modifying capacity of Amarantus BioScience’s lead therapeutic candidate, MANF,
has been significantly validated by recent pre-clinical studies demonstrating that MANF inhibits
neurological deterioration in Parkinson’s disease (PD). These findings corroborate the potential of
MANF as first-in-class curative therapy for PD, which is critically needed. Currently used
medications only alleviate patient symptoms and do not function to reverse or stop disease
progression.
Additionally, Amarantus has recently announced the acquisition of Neurodegenerative
Diagnostic’s intellectual property portfolio, which includes diagnostics for PD and ALS – further
positioning the company as an emerging player in the field of neurological disorders.
Identified by Amarantus’ proprietary bioengineering and drug discovery platform, MANF is a
biological protein that stabilizes the nervous system in the body and has been found to have a
striking ability to save neurons from cell death when disease conditions were presented. The
present studies described show that key clinical hallmarks in an animal model of PD are
significantly improved by MANF, but not by GDNF, a therapeutic protein currently in Phase II
clinical trials, once developed by Amgen and now in trials through MedGenesis Therapeutix.
Specifically, research performed at UCLA’s School of Medicine shows that MANF improves
behavioral deficits by approximately 50% four weeks post-treatment, with a 35% improvement
seen as early as two weeks post-treatment. In contrast, GDNF did not provide any improvement in
behavioral deficits at any time point assayed. In a separate study performed at Neuroscience
Associates, MANF was shown to actually increase the density of neurons in the brain by
approximately 14%, whereas GDNF treatment showed no benefits in maintaining neuron density.
Finally, a third study performed at PharmaNet shows that MANF treatment produces a 100%
increase in dopamine concentration within the brain. Dopamine is a neurotransmitter produced in
the brain that is required for neurological health, and decreased dopamine is a major etiological
factor underlying PD and a primary target for therapeutic stabilization. GDNF was found to have
no effect on dopamine concentration in the brain.
Collectively, these data show that MANF: has potent curative properties that stops/or reverses the
progression of PD; improves behavior, the fundamental treatment goal of PD therapeutics;
increases the density of neurons in the brain, which are significantly decreased in PD; and
increases the concentration of dopamine in the brain, which decreases in PD and serves a major
etiological factor underlying the disease.


NOTE: This summary was
produced by OneMedPlace
(OMP). Research based on
information provided by the
company and other sources.