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?