Trophic Factors: Specialized Proteins that Nurture and Protect Neurons
What are trophic factors?
Trophic factors (also neurotrophic factors or growth factors) are proteins that promote the survival, growth and function of neurons in the brain. Because the degeneration of dopamine neurons is the pathological hallmark of Parkinson's disease, these proteins are of great interest to Parkinson's researchers. During normal brain development, trophic factors are critical for the correct wiring of the nervous system. Trophic factors that have received significant attention in Parkinson's research include GDNF and the closely related neurturin.
Why are trophic factors important?
The word "trophic" comes down to English from a Greek word meaning "to nourish." This goes a long way toward describing what neurotrophic factors do for neurons: enhance function and prevent death.
In preclinical models of Parkinson's disease, trophic factors have been shown to promote the survival of dopamine neurons, as well as to induce these neurons' regrowth, or sprouting. The molecular effects seen in the brain were accompanied by an outward improvement in motor symptoms. These promising preclinical results have led to the investigation of trophic factors as potential neuroprotective PD therapies.
What stands in the way of trophic factor therapies?
One of the greatest challenges to the development of trophic factor therapies is finding a viable delivery approach. Trophic factors are proteins, which cannot be given orally (in pill or liquid form) because they are degraded in the stomach or intestine. They also do not readily cross the blood-brain barrier. This barrier protects the brain by preventing certain molecules, including almost all proteins, from passing from the blood stream into brain tissue. However, it also creates an obstacle to peripheral administration of some neurological therapies, including trophic factors. Since trophic factors don't cross the blood-brain barrier, they can work only when injected into or produced inside of the brain. To advance trophic factors as a viable therapy, researchers must develop technologies to overcome the blood-brain barrier impediment.
What recent attempts have been made to deliver trophic factors to the brain?
Technologies that optimize the diffusion and spread of trophic factors into brain tissue are in varying stages of development, and some have already been tested in clinical trials in PD patients.
Direct brain infusion. Catheters are implanted directly into the brain. The catheters are attached to pumps that control infusion of the trophic factor. The most promising approaches involve direct infusion into the putamen, the brain region marked by loss of dopamine in PD. The rate of infusion can be closely controlled, and treatment can be discontinued if adverse events occur. The surgery is highly invasive, however, and patients must keep the catheters in place for the duration of treatment. Additionally, this approach is subject to possible immunological responses, primarily development of antibodies that might block the function of protein, resulting from protein leakage from the pumps and infusion of foreign proteins.
Direct brain infusion of the trophic factor GDNF has been tested in four separate clinical trials to date, with varying degrees of success. While positive clinical outcomes were observed in two open-label clinical studies, this result was not replicated in a subsequent double-blind study. Researchers are continuing to work to understand the differences in results between these studies and to optimize testing of future direct brain infusion approaches.
Gene therapy approaches. This approach involves injecting a "viral vector" (a virus that has been engineered not to cause illness) containing the gene that expresses the trophic factor directly into the patient's putamen, the part of the brain where dopamine neurons send their signals. If successful, this injection causes the patient's own brain tissue to begin producing the trophic factor. The extent of trophic factor expression in the brain is determined by the amount of virus injected and the location and number of these injections.
This approach can achieve high levels of localized trophic factor production. Additionally, having the patient's own cells produce the trophic factor reduces the risk of immunological responses to the treatment. But a major limitation of this approach is that with current technologies, there is no way to regulate expression of the trophic factor once the virus is injected. Additional efforts are under way to develop "regulatable" gene therapy approaches - which would make it possible to "turn off" or otherwise control a gene in case of adverse effects following implantation.
Additionally, The Michael J. Fox Foundation has provided funding for Ceregene Inc.'s Phase I and Phase II clinical trials to test gene therapy delivery of neurturin, a trophic factor closely related to GDNF. Following positive safety results from the Phase I trial, reported in fall 2006, the Foundation signed on to support the Phase II clinical trial, currently under way.
Stem-cell-based delivery. Stem cells are engineered to produce trophic factors and are then injected into the brain. An example of one such delivery approach uses neural stem cells engineered to produce GDNF, then injected into the putamen. This approach harbors certain advantages - neural stem cells may produce additional positive factors beyond GDNF, and once injected, stem cells may migrate in the brain to increase diffusion of GDNF into brain tissue. There are limitations to this approach, however, similar to those seen in gene therapy: Patients bodies' may reject the stem cells, and there is an overall lack of ability to control the stem cells once they are injected. This approach is currently in preclinical development working toward a clinical trial.
Encapsulated cell technology (ECT). A current LEAPS award from MJFF is funding exploration of ECT as an alternative delivery system for GDNF. How it works: Cells engineered to produce GDNF are enclosed in a non-biodegradable capsule, which is then implanted into the putamen. Because the capsule is non-biodegradable, the patient's brain is less likely to reject the foreign cells; the GDNF passes through the capsule, however, for the primary purpose of protecting dopamine neurons and stimulating their regeneration. This approach can achieve highly localized trophic factor production. An additional advantage is that the capsule can be removed if adverse events develop. Like other approaches, however, ECT is subject to possible immunological responses including rejection. It is also not clear whether sufficient levels of GDNF can be delivered through this approach.
What is the MJFF view on trophic factors?
Trophic factors represent one of the most promising approaches to develop neuroprotective and neurorestorative therapies in the short term. Determining the efficacy of trophic factors, as well as optimizing various delivery strategies, are research priorities for MJFF.
Compelling preclinical data supports clinical development of GDNF and neurturin. Additional trophic factors also have been discovered and should also be vigorously pursued as potential PD therapies. With the establishment of reliable and safe delivery approaches, we are optimistic that trophic factor therapy will become a viable treatment option for PD patients.
For more information on MJFF investments in trophic factor research, please search our Funded Studies Database.
April 12, 2007
