[paula_w]

Linda H. said there is an upcoming phase I gene therapy trial being conducted by the.....are you ready.... NIH. 24 participants. I haven't looked it up yet so I don't have any sources. If anyone does, just add it and i will have more later.

This is encouraging because it's the NIH....but I'd like to know where the GDNF came from.....it's a gene not a pump infused protein. Well there are lots of things I'd like to know....the timing is right but don't know what the specs are.

let's hear what you know,
thanks, paula

[indigogo]

I had the same question when this came up at the PAN Forum and kept forgetting to ask!

I'll try to find out.

[LindaH]

This is what I remember from the presentation at the PAN Forum:

At the Emerging Therapies session at the PAN Forum, Dr. Howard Federoff spoke about research on AAV2 virus delivery of GDNF. This was the viral delivery method used in the phase II Ceregene trial. He said it would involve "Convection Enhanced Delivery" (method used in the phase I infused GDNF Un. of Kentucky trials, but not in Amgen's) It gets the GDNF into the brain more efficiently. Also said additional areas of the brain would be targeted. A NINDS consortium has been researchiing viral vector delivery of GDNF in animal models and will be conducting a phase I clinical trial, possibly in Fall 2009. Hopefully more details will be coming....

[paula_w]

Anymore about this? It sounds like something Steve Gill from UK was working on, doesn't it? He stayed a lot out the fray, still wanted to use Amgen in some capacity - heard that quite awhile back tho.

How interesting it is going to be to learn. i'm glad to see it, but suffer from cognitive dissonance - not from PD, just from mankind's failure to launch or similarly, launch with failure to tell --Will the NIH be quick about it? Do we allow ourselves to think that this is real and sometime soon?

I'm including this article received from Carolyn in pipeline email that reveals more unenforced and ignored regulations. It is not connected to the GDNF trial. Just more watchdog info.

20 Mar 2009 http://www.medicalnewstoday.com/articles/142956.php

Although paying finder's fees to researchers and clinicians to identify study participants could compromise the recruitment process and harm human lives, many medical schools fail to address this conflict of interest in their Institutional Review Board (IRB) policies.

Leslie Wolf, an associate professor of law at Georgia State University, studied the IRB policies posted on the Web sites of 117 medical schools that received National Institutes of Health funding. Among the study's findings, Wolf revealed that less than half of the IRB policies discuss finder's fees or bonus payments as conflicts of interest, where research sponsors pay members of the research team or clinicians to identify potential participants or for meeting predetermined enrollment targets.

paula

Originally Posted by LindaH

This is what I remember from the presentation at the PAN Forum:

Originally Posted by LindaH

At the Emerging Therapies session at the PAN Forum, Dr. Howard Federoff spoke about research on AAV2 virus delivery of GDNF. This was the viral delivery method used in the phase II Ceregene trial. He said it would involve "Convection Enhanced Delivery" (method used in the phase I infused GDNF Un. of Kentucky trials, but not in Amgen's) It gets the GDNF into the brain more efficiently. Also said additional areas of the brain would be targeted. A NINDS consortium has been researchiing viral vector delivery of GDNF in animal models and will be conducting a phase I clinical trial, possibly in Fall 2009. Hopefully more details will be coming....

[aftermathman]

knowing how you hang on to my every word, you may have forgotten but back in June 2008 I posted:

"I have heard at a meeting of the Royal Medical Society that Neurosurgeon Stephen Gill at Frenchay (Bristol UK), one of the pioneers of the original GDNF trials, has developed his own delivery mechanism and is close to an agreement with Amgen to trial".

Perhaps this is it.

Take care, you are still my hero

Neil.

[paula_w]

Neil,

Bless you for thinking I'm capable of remembering that far back...I remember that there was a gdnf gene released from Amgen but didn't remember that it was Gill. It's all making sense. Thank you and I do read and enjoy all of your posts because, along with whatever it is you are contributing, you do it with a good sense of humor.

paula

[paula_w]

Bumping this up and recommending that you stay tuned. Linda H. has been doing some checking around and is putting it together. Steven Gill is involved, and one of the researchers goes back to GDNF pre-amgen ownership. Linda is writing up what she has learned and I'm writing this teaser because I am feeling genuine excitement and hope about this one right now...always with the question will it be available in time. Now how to get rid of the placebo surgery....one answer is to get into phase I.

paula

[LindaH]

More on GDNF gene therapy

Connecting the dots…

Parkinson's Disease Gene Therapy Study Group

From University of Rochester newsletter (March 2003) announcing gene therapy consortium
Five-year initiative targets Parkinson's
“Working with scientists from across the nation, the Medical Center is coordinating a national effort to pioneer a new treatment for Parkinson's disease.
The five-year program, funded with $8.8 million from the National Institute of Neurological Diseases and Stroke and additional support from the National Institutes of Health, was conceived by Howard Federoff, professor of neurology and director of the Center for Aging and Developmental Biology.
The program is the first to focus on gene therapy as a treatment for diseases such as Parkinson's, Alzheimer's, Huntington's, or Lou Gehrig's in which neurons die…”
"Our goal is to bring forward, in the most rigorous possible fashion, a gene therapy for patients with Parkinson's disease," says Federoff. "We're proceeding deliberately and cautiously to develop and test new treatments, in a coordinated progression from basic research to preclinical evaluation to clinical testing. Our intention is to lay the groundwork for a future study where new approaches can actually be tested in people."
To accomplish the program's goals, Federoff has brought together many of the world's foremost Parkinson's experts. The new group, known as the Parkinson's Disease Gene Therapy Study Group, is made up of researchers from the University, Northwestern, Rush-Presbyterian Medical Center in Chicago, Yale, and University of California campuses in Irvine, Los Angeles, and San Francisco. ..
Full article at: http://www.rochester.edu/currents/V3...5/story01.html

After attending the 2003 PAN Forum, I posted the following to the Parkinsn list about Dr. Federoff’s presentation:
“Dr. Howard Federoff, of the University of Rochester discussed collaborative (there's that word again) gene therapy research for PD which involves developing preventive tactics, halting and reversing existing damage to neurons, and restoring dopamine production. He is leading the Parkinson's Disease Gene Therapy Study group - a consortium of 7 research institutions throughout the U.S.- all cooperating on an interdisciplinary approach to the research. Each institution is focusing on a certain aspect of the research - such as delivery vectors,
identifying target genes, turning on and off gene switches in the brain, immune reactions and other adverse effects, use of neuroimaging techniques to evaluate treatments, developing new biomarkers for the disease (e.g. identify possible proteins in the blood), bioethical
aspects, and minimizing intellectual property barriers) -- and then will pool all data and results - which will hopefully lead to effective and safe gene therapy treatments.”
https://listserv.utoronto.ca/cgi-bin...=0&F=P&P=19418

At the recent 2009 PAN Forum, Dr. Federoff again talked about the gene therapy consortium and a possible clinical trial this fall on gene therapy delivery of GDNF for Parkinson’s disease. He mentioned it would utilize Convection Enhanced Delivery.

Which led to :Medgenesis

Medgenesis – biotech company that is commercially developing Convection Enhanced Delivery of biopharmaceuticals.
From their website: “Primary target indications for MedGenesis Therapeutix are Parkinson's disease, intractable epilepsy, and GBM. These indications are natural targets for CED-based treatment regimens because of the high unmet medical need, specific blood-brain-barrier challenges, and the invasiveness of the diagnostic and therapeutic armentarium that is currently available to patients.”
“MedGenesis focuses on the development of two product groups:
1. Marketed Compounds which have demonstrated effectiveness but cannot cross the blood brain barrier or do so only in insufficient quantities and/or require anatomically targeted delivery to the CNS. These compounds typically have systemically applied indications and their scope of use is dramatically increased by CED, leading also to increased patent life.
2. Compounds with promising CNS therapeutic profiles which advanced to clinical development but were derailed by systemic toxicity also form pipeline products. Such compounds are "restricted" in the CNS with CED and require significantly smaller quantities than by systemic administration. This approach reduces systemic exposure to such a degree as to render it insignificant. “
For more on the development of their Parkinson’s treatment -see
http://www.med-genesis.com/development.htm

MedGenesis’ Scientific Advisors include Dr. Federoff, and Krystof Bankiewicz, Martha Bohn, and Steven Gill – all have been researching GDNF for many years. See:
http://www.med-genesis.com/scientific_advisors.htm
Searching by the researchers’ names led to the Michael J Fox Foundation, that awarded a 2005 LEAPS grant to Drs. Bankiewicz, ,Martha Bohn and others for their research on:
Development and Optimization of a Regulatable Gene Switch for Gene Therapies of Parkinson's Disease
http://michaeljfox.net/research_MJFF...s_3.cfm?ID=246
Also this year two papers on successful GDNF gene therapy in monkey models have been published – Co-authors include Drs. Federoff and Bankiewicz,. They address some of the targeting and the safety issues cited about the Amgen phase II trial of infused delivery (by pump/ catheter) of GDNF. The trial and all other GDNF treatment were terminated by amgen in Sept. in 2004, and they refused to release their patent to other researchers or companies. Abstracts from PubMed below:

Hum Gene Ther. 2009 Feb 9. [Epub ahead of print]
Clinically relevant effects of AAV2-GDNF on the dopaminergic nigrostriatal pathway in aged Rhesus monkeys.

Johnston LC, Eberling J, Pivirotto P, Hadaczek P, Federoff HJ, Forsayeth J.
San Francisco, California, United States; lou_cj@hotmail.com.
Growth factor therapy for Parkinson's disease offers the prospect of restoration of dopaminergic innervation and/or prevention of neurodegeneration. Safety and efficacy of an adeno-associated virus (AAV2) encoding human GDNF was investigated in aged non-human primates. Positron emission tomography with [18F]-fluoro-meta-tyrosine (FMT-PET) uptake in putamen was assessed 3 months before and after AAV2 infusion. In the right putamen, monkeys received either PBS, low-dose (LD) or high-dose (HD) AAV2-GDNF. Monkeys that had received putaminal PBS infusions additionally received either PBS or HD AAV2-GDNF in the right substantia nigra (SN). AAV2-GDNF increased FMT-PET uptake in the ipsilateral putamen as well as enhancing locomotor activity. Within the putamen and caudate, the HD gene transfer mediated intense GDNF fiber and extracellular immunoreactivity (IR). Retrograde and anterograde transport of GDNF to other brain regions was observed. AAV2-GDNF did not significantly affect dopamine in the ipsilateral putamen or caudate, but increased dopamine turnover in HD groups. HD putamen treatment increased the density of dopaminergic terminals in these regions. HD treatments, irrespective of the site of infusion, increased the number of non-pigmented TH IR neurons in the SN. AAV2-GDNF gene transfer does not appear to elicit adverse effects, delivers therapeutic levels of GDNF within target brain areas and enhances utilization of striatal dopamine and dopaminergic nigrostriatal innervation.
PMID: 19203243
Hum Gene Ther. 2009 Mar 2. [Epub ahead of print]
Functional Effects of AAV2-GDNF on the Dopaminergic Nigrostriatal Pathway in Parkinsonian Rhesus Monkeys.
Eberling J, Kells AP, Pivirotto P, Beyer J, Bringas J, Federoff HJ, Forsayeth J, Bankiewicz K.
Lawrence Berkeley National Laboratory, Functional Imaging, Berkeley, California, United States; jleberling@lbl.gov.
We investigated the safety and regenerative potential of an adeno-associated virus (AAV2) encoding human GDNF in an MPTP primate model of PD. Dopaminergic function was evaluated by positron emission tomography (PET) with 6-[18F]fluoro-L-m-tyrosine (FMT) before and after AAV2-GDNF or PBS was infused bilaterally into the putamen. FMT uptake was significantly increased bilaterally in the putamen of AAV2-GDNF but not PBS-treated animals six months after infusion, indicating increased dopaminergic activity in the nigrostriatal pathways. AAV2-GDNF-treated animals also showed clinical improvement without adverse effects. These findings are consistent with our previous report in aged non-human primates that showed evidence of enhanced utilization of striatal dopamine and dopaminergic nigrostriatal innervation. Clinical improvement and evidence of functional recovery in the nigrostriatal pathway, together with other findings, support the safety of this approach for the delivery of GDNF over a six-month period.
PMID: 19254173

At the risk of encouraging “false hope” -- Could it finally all be coming together with GDNF?

[indigogo]

At the PAN Forum this year, and in the above information provided by Linda, researchers and device manufacturers were still talking about targeting the putamen for gene therapy, this despite the news from Dr. Bartus as relayed in his interview with MJFF that the ceregene trial showed that the neurturin did not transfer to the nigra as it had done in animal models:

"Based on all the pre-clinical and autopsy data we have accumulated in this program, the problem is clear. Delivering CERE-120 to the terminal field (putamen), only, is sufficient in pre-clinical models, but not in the brains of people with Parkinson’s. This suggests a serious problem with axonal transporter mechanisms in Parkinson’s disease. This is a concept that’s growing in popularity and understanding. It is much more clearly established in other diseases involving neurodegeneration, such as ALS and, to some extent, Alzheimer’s disease, but it is gaining acceptance in the movement disorders and Parkinson’s fields. The concept is that, long before the cells die, there’s a loss of processes involving the axonal terminals; and that even before the loss of axonal terminals, there is a deficiency in transport ability within those terminals. While it is our best hypothesis that transport mechanisms in Parkinson’s disease are severely impaired, it is a fact that in the two patients we examined, we saw no evidence for neuturin in the nigra (where we needed it to get), despite adequate levels expressed in the terminal field (where we delivered CERE-120).

Additional support for this interpretation comes from further analysis of the human tissue and its comparison to our pre-clinical experiments. As I stated earlier, only when neurturin gets to the cell body can you expect it to begin repairing the neuron and making dopamine synthesis and other important activities more effective. One way you measure that is by looking at tyrosine hydroxylase (TH), the major synthesizing enzyme for dopamine. In all the pre-clinical studies, when you get CERE-120 in the terminal field, you not only see neurturin expressed in the terminal field and in the nigral cell body, but you also see enhanced TH in both the terminal field and in the cell body. That shows us that when you put neurturin in the terminal field and it gets carried back to the cell body, the neurons become more healthy and functional, including as a better dopamine machine. We saw no evidence for any of that in the Parkinson’s brain. Despite a good neurturin signal in the terminal field, we saw none of the secondary consequences of the neurturin expression that are required for improved function and neuronal repair that were consistently seen in the animal studies. So my point is, simply adding more protein to the terminal field likely won’t do anything because that will not ensure it also gets back to the nigral cell bodies, as is required for efficacy."

(entire interview here)

Is this being taken into consideration for these new trials?

[LindaH]

I think you raise some very important issues. As we learned after the GDNF trial was halted, most scientists hesitate to discuss study results until they are published in a peer reviewed journal.Traditionally this can take up to a year or even more. There was a wealth of information in Dr. Bartus' interview. Hopefully, the Ceregene researchers and the gene therapy consortium will be able to collaborate to possibly improve the protocol and outcome of the GDNF gene therapy study, even if not yet published in the traditional manner. Maybe they already are. If they can learn from the Ceregene trial and advance the science and bring us closer to a cure, it has not been a failure. Perhaps the Fox Foundation can play a role in facilitating communication and collaboration.