Prepared by:
Linda Herman, Therapies
Coordinator, Parkinson Pipeline
Project (Last updated 6/2/11)
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
References
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
Parkinson Pipeline Project. Therapy Development Database.
Accessed online 6/1/11 at:
http://apexutf.shellprompt.net/pls/apex/f?p=162:12:5997922620574622
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
