This LEAPS team (representing seven academic institutions, a research foundation, and a private company) is seeking to develop a novel therapy for Parkinson's disease based on the implantation of encapsulated GDNF-producing cells into the brain. GDNF is widely recognized as a potent, protective, 'neurotrophic factor' for the dopaminergic neurons that degenerate in PD. It also induces regeneration of dopaminergic cells and increases dopamine release from remaining neurons. Unfortunately, GDNF does not cross the 'blood-brain-barrier', so it cannot be given orally or by injection. This inability to efficiently deliver GDNF to where it is needed in the brain has greatly limited the impact of this important molecule.
Lindvall and colleagues believe the use of encapsulated cell technology (ECT) will enable localized, sustained delivery of GDNF to the brain. The team's approach consists of several steps that will take ECT delivery of GDNF from a concept to a therapeutic reality. First, they will generate human cell lines capable of steadily secreting small amounts of GDNF; then they will place these cells in fiber capsules. Once created, these capsules will be tested to assess cell viability and level and duration of GDNF secretion, diffusion of GDNF into the brain, and neuroprotective efficacy in PD models. They will also be tested for their potential to cause side effects and for their ability to be removed from the brain, if needed. This last step, retrievability, is an essential aspect of ECT-based therapy, as it allows the capsules to be removed in the event that unexpected results occur.
If encapsulated delivery of GDNF is successful in pre-clinical models of PD, twelve patients will be enrolled in a clinical trial in Sweden. The patients will be assessed clinically for at least 24 months after implantation of the encapsulated cells. We expect this LEAPS project to produce two important outcomes. First, the team will bring a neurotrophic factor therapy for neuroprotection in PD to the clinic. If encapsulated cell technology works with GDNF, it will also provide a way to deliver other molecules to the brains of PD patients. Using this approach it may be possible to evaluate the effectiveness of GDNF at slowing, halting, or even reversing the degenerative effects of PD. If GDNF is successful, it may be possible to develop conventional drugs that will have the same effects when administered in pill form.
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.