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GDNF as a Treatment for Parkinson’s Disease

Translational Research as of June 2011

Prepared by: Linda Herman, Therapies Coordinator, Parkinson Pipeline Project (Last updated 6/2/11)

Delivery Methods:

Pump infusion

“The infusion system, also known as 'direct protein therapy,' involves placing a long thin tube (called a catheter) into the part of the brain affected by Parkinson’s disease. This tube is hooked up to a pump implanted under the skin that contains a reservoir of the GDNF protein. The protein slowly flows into the damaged area of the brain and can provide support to injured or dying cells” (M. J. Fox Foundation, April 26, 2011).

This delivery method was used in the early phase I trials at the University of Kentucky, at Bristol Hospital in the UK, and for the Amgen-sponsored phase II trials. In 2004, Amgen terminated all  further human research and clinical trials with their recombinant GDNF, claiming it didn’t work and citing possible safety issues based on their monkey studies, It wasn’t until 2010 that Amgen licensed another company (Med Genesis) to resume GDNF research in humans.

However in the ensuing years, many scientists and patients continued to believe in the promise of GDNF,  and animal research continued on ways of improving the delivery system – making it more targeted and effective. By 2011, a few early clinical trials were starting and others were on the cusp of translating laboratory research into clinical treatments.

Examples of Pump Infusion Delivery:

Dr. Steven Gill, designed the new infusion pump and catheter system.  Funded in part by Cure Parkinson’s Trust (UK).  Expected to enter clinical trials in 2011.

“Professor Gill plans to conduct a two year double blind, randomized, placebo-controlled phase 2 study of intermittent intraputamenal GDNF infusions for the treatment of Parkinson’s in 36 patients. CPT’s Research Committee has asked that brain imaging be included in the study to provide further evidence of the efficacy of GDNF in the brain, which in turn supports the development of other GDNF-related therapies using a range of delivery methods." (Cure Parkinson’s Trust)

MedGenesis Therapeutix, partnered with Biovail until Nov 2010.

“On January 12, 2010, MedGenesis "announced that it has successfully entered into an agreement with Amgen Inc., granting MedGenesis an exclusive, worldwide license for glial cell line-derived neurotrophic factor (GDNF) protein in CNS and non-CNS indications"

“The MedGenesis approach is to "deliver a known therapeutic utilizing the MedGenesis cutting-edge CED (Convection Enhanced Delivery) platform to a well-defined local target inside the blood-brain-barrier

This is the first time, Amgen has allowed another company to research it's GDNF molecule in treating humans since the halt of Amgen's phase II clinical trial in Sept. 2004.

"... As part of the license agreement, Amgen now holds a small equity stake in MedGenesis." (MedGenesis web site)

(Dr. Gill, Dr. Howard Federoff and Dr. Bankiewicz (NINDS consortium) are scientific advisors to MedGenesis.)

Eli Lilly/ Medtronic: Preclinical.

Lilly  announced in April 2011 a new formulation of GDNF, delivering it to the brain through a catheter connected to a new implanted pump and drug reservoir supplied by Medtronic.

Gene Therapy

In gene therapy, the brain is genetically modified in order to produce the therapy itself within the brain tissue. This is achieved through the injection of a genetic vector in order to allow the brain to produce the trophic factor.” (MJFF website)

Examples of Gene Therapy:

Parkinson's Disease Gene Therapy Study Group, a consortium of seven research institutions throughout the U.S., funded by NINDS.

Phase I trial planned to begin in fall 2011, uses Convection Enhanced Delivery to distribute the genes efficiently to the targeted areas of the brain. An adeno-associated virus (AAV2) encoding human GDNF is the vehicle for gene transfer to the central nervous system. This is the same viral vector used by Ceregene in its research on neurturin – a  neural growth factor  and a close relative of GDNF (currently in phase II clinical trial.)

Amsterdam Molecular Therapies (Netherlands)

Preclinical: “Amsterdam Molecular Therapeutics (AMT), announced in 2010 that it obtained a license from Amgen to use their GDNF gene together with AMT's proprietary adeno-associated virus (AAV) gene therapy platform for the development of a gene therapy treatment for Parkinson's disease. (AMT website)

Encapsulated GDNF Producing Cells, lead researcher: Olle Lindvall, Lund University, Sweden. Funded in part by MJFF

Pre-clinical research to  develop a neuroprotective therapy based on the implantation of encapsulated cells that produce  GDNF directly into the brain.

Final  outcome report in 2010, “Cell clones were developed that produced GDNF in vitro. Additionally, the encapsulated device was generated. However, cell clones did not produce sufficient GDNF when implanted into the brains of pre-clinical models. Though significant efforts were made, the team was unable to overcome the limitation of insufficient in vivo production of GDNF.” (MJFF website)

Intravenous  GDNF Gene Therapy of Experimental PD  (AGT 190)

Preclinical: Lead  researcher, William Pardridge.  Sponsors: UCLA and Armagen  Technologies; also funded by MJFF.  Applied for FDA approval of Phase I trial.

Therapeutic gene encodes GDNF, and is engineered to restrict expression of the GDNF gene in only parts of the brain related to PD…This research provides a new approach to the selective targeting of a GDNF gene therapy in PD without the use of viruses or neurosurgery.” (MJFF Web site)

If phase I has no safety problems, new funding source needed to continue development, estimated at $15 million. (Vastag)

Oral delivery of GDNF

Cogane - Sponsor: Phytopharm.

“Cogane (PYM50028) arose from research into the activity of an Asian medicinal plant…. In pre-clinical models, Cogane™ reverses the changes in the area of the brain involved in Parkinson’s disease by inducing the body’s own production of proteins known as neurotrophic factors. In particular, one of these factors known as 'GDNF' has been shown to be particularly effective in re-growing damaged nerves. Since GDNF is a protein it cannot be given orally (in pill or liquid form) because it is degraded in the stomach and intestine, and also does not readily cross the blood-brain barrier. ... Cogane™, which can be taken orally, readily crosses the blood-brain barrier and stimulates the release of GDNF in the brain…” (Pipeline Project Database)

Phase II clinical trial began in 2011: “Randomised, Double-blind, Placebo-controlled Study to Investigate the Efficacy, Safety and Tolerability of PYM50028 in Subjects With Early-stage Parkinson's Disease Administered Once Daily for 28 Weeks.” (clinicaltrials.gov)

Completion expected Dec. 2012


Amsterdam Molecular Therapeutics. Company website. Accessed online on 6/3/11 at: http://www.amtbiopharma.com/about/company

Cure Parkinson’s Trust. GDNF appeal. 2011. Accessed online on 6/1/11 at: http://www.cureparkinsons.org.uk/document_1.aspx?id=0:60951&id=0:36727

Humphries, Courtney. Keeping Neurons Alive in Parkinson’s Patients. Technology Review, June 6, 2011.  Accessed online on 6/6/11 at:  http://www.technologyreview.com/biomedicine/37708/?mod=chfeatured&a=f

Investigation of Cogane (PYM50028) in Early-stage Parkinson's Disease (CONFIDENT-PD). Clinicaltrials.gov. Accessed online 6/1/11 at: http://clinicaltrials.gov/ct2/show/NCT01060878?term=cogane&rank=22

MedGenesis Therapeutix. Company web site. Accessed online on June 3, 2011 at: http://www.medgenesis.com/

Michael j Fox Foundation. Website and database. Accessed online on June 2, 2011 at: http://www.michaeljfox.org/research.cfm

Michael J Fox Foundation. Trophic Factors: Specialized Proteins that Nurture and Protect Neurons. 2007. Accessed online June 3, 2011 at:  http://www.michaeljfox.org/living_viewpoints_researcherAreaPositionPapers_trophic.cfm

Vastag, Brian. Biotechnology: Crossing the barrier. Published online 18 August 2010 | Nature 466, 916-918 (2010). Accessed June 1, 2011.  http://www.nature.com/news/2010/100818/full/466916a.html


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