April 26, 2011
News in Context: Eli Lilly and Medtronic Announce New Preclinical Partnership to Develop GDNF for Parkinson's Disease
Pharmaceutical giant Eli Lilly and Company and Medtronic, Inc. today announced a new Parkinson’s drug-device collaboration. According to both groups, the goal of the collaboration is to move the needle toward an effective GDNF-based treatment for PD through the combination of Lilly’s modified form of the neurotrophic factor GDNF and Medtronic’s implantable drug infusion system technology.
MJFF’s Chief Program Officer Todd Sherer, PhD, explains what this initiative could mean to ongoing efforts to treat the symptoms and possibly even the progression of Parkinson’s by introducing neurotrophic factors into the right areas of the brain at the appropriate levels. But he warns that there is still much work to do, and many hurdles to overcome, before this treatment approach can realistically be considered a viable one to treating Parkinson’s.
NOTE: The medical information contained in this article is for general information purposes only. The Michael J. Fox Foundation has a policy of refraining from advocating, endorsing or promoting any drug therapy, course of treatment, or specific company or institution. It is crucial that care and treatment decisions related to Parkinson’s disease and any other medical condition be made in consultation with a physician or other qualified medical professional.
MJFF: Let’s begin with the basics. What are trophic factors?
Sherer: Trophic factors are proteins that are naturally found in the brain. The analogy we often use at our Foundation is to think of trophic factors as fertilizer for the brain that keeps brain cells alive and functioning well.
Researchers have demonstrated in pre-clinical models of neuronal injury and neurodegenerative diseases that increasing the levels of trophic factors can serve to protect the cells in these model systems. From a Parkinson’s drug discovery and development standpoint, this is exciting because in theory, trophic factors could protect the dopamine cells that die in Parkinson’s disease.
MJFF: Is this how trophic factors could lead to a breakthrough treatment for Parkinson’s disease?
Sherer: Yes, again, in theory. One of the main goals we are working toward at MJFF is to find a disease-modifying therapy for PD. This means a treatment that would target and affect the underlying processes related to the onset and progression of Parkinson’s, not just treat the symptoms. Treatments available today only treat the symptoms.
Because trophic factors have shown potential to keep brain cells alive and functioning properly, they are potentially very important to R&D experts in Parkinson’s who are looking for the breakthroughs that will lead to disease-modifying therapies.
MJFF: What are some of the challenges, then, in trophic factor therapeutic development?
Sherer: The biggest challenge to the viability of trophic factors as treatment relates to the delivery of the therapy. Trophic factors can’t be given orally — for example, in pill form — because they can’t easily get into the brain, where they need to go. They are large proteins, and because of their size, they cannot penetrate the blood-brain barrier — a membrane that surrounds the brain. The blood-brain barrier is actually a very important mechanism, because it protects molecules of a certain size from entering into the brain including disease-causing pathogens and viruses. However, the blood-brain barrier also represents a challenge for finding new and better ways to treat neurological disease, because in addition to keeping out the bad stuff, it blocks many potential therapies, including trophic factors, from entering the brain.
For this reason, and also because it is probably preferable to have these trophic factors only target the area that has become susceptible to the disease, it is critical to develop innovative means for delivering them to the right areas and at the right levels to have a therapeutic effect. The two most common approaches to do this that are currently in development are direct protein therapy and gene therapy:
• In direct protein therapy, a catheter is used to directly infuse the trophic factor into the part of the brain affected by the disease.
• 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.
There are pros and cons to each method. With direct protein therapy you have the ability to better regulate dosing and stop the flow of the protein. The negative would be the constant presence of the catheter and the attached equipment that goes with it.
For gene therapy, the advantage is that it is a one-time surgery. Once the genetic vector itself is implanted the brain itself produces the therapy. The negative here is that it is impossible to turn the therapy off once it has begun, because once a gene is introduced into our bodies, we do not yet have a way to regulate it (turn it off and on again).
Both therapies have thus far proven to be safe. However, while both techniques have been shown to protect dopamine neurons in pre-clinical models, no one has yet successfully demonstrated this effect in a clinical trial in Parkinson’s patients.
MJFF: What exactly are Lilly and Medtronic announcing today and how might this announcement stand to shape future neurotrophic factor research?
Sherer: Most researchers believe there are a couple of high priority issues to focus on, one being the selection of the neurotrophic factor that might give the greatest potential biological benefit, and the other being improved delivery of these molecules at the right levels to the right regions of the brain.
Lilly and Medtronic are announcing new preclinical work that could potentially lead to progress on both the biology and the delivery fronts. Lilly has biosynthetically engineered a new GDNF variant with the goal of achieving increased distribution in targeted brain regions. They are pairing this with Medtronic’s drug pump and specially designed catheter that have been designed to hopefully enable precise delivery of the GDNF variant into a targeted area of the brain consistently over time. While it’s early days, the hope is that this combination of a novel GDNF variant, paired with an optimized delivery system, could help overcome some of the technical hurdles that have affected earlier trophic research.
Most importantly, it is encouraging to see well-established companies reaffirming a commitment to trophic factor research. MJFF has long been a leader in supporting trophic factor development and we continue to believe in their promise to yield a next-generation therapy for PD. But given the many challenges, the more shots on goal that are being taken, the better.
MJFF: What other trophic factor research is under way?
Sherer: MJFF is currently funding a Phase 1/2 clinical trial of a trophic factor called neurturin, which is closely related to GDNF. This trial is sponsored by the San Diego-based biotech Ceregene. We have been working with them on the development of their neurturin therapeutic since 2005. Another company, MedGenesis, is working on an approach called convection-enhanced delivery, or CED, to deliver GDNF to the putamen through an integrated approach based on four components, including a catheter system and MRI technology.
We are also funding a researcher named Mart Saarma who is working with a different neurotrophic factor called conserved dopamine neurotrophic factor (CDNF) in order to compare the effects between this protein and GDNF. The idea is to begin to prioritize which one might be most effective in the regions of the brain affected by Parkinson’s.
Of these projects, currently only Ceregene is in the clinic. Saarma and MedGenesis are still preclinical, but with short time horizons to the clinic if all goes well. Another GDNF study funded by the National Institute of Neurological Disorders and Stroke (NINDS) at the National Institutes of Health expects to enter the clinic in short order.
It is important to recognize that these are different, yet complementary efforts. Most Parkinson’s researchers believe that trophic factors hold a great deal of potential to improve treatment of PD, and what’s exciting is that there is now a wealth of studies intent on finding the best ways to implement them in the fight against Parkinson’s. Hopefully, if one such project is successful, there will be synergy among all of them. It is our hope that we can ultimately work together to successfully develop a disease-modifying therapy that would impact millions of lives.