Parkinson's Immunotherapy Targets α-Synuclein Aggregates
Immunotherapy that targets aggregates of α-synuclein protein in dopamine neurons points toward a potential pathway for treating Parkinson's disease, Dr. Eliezer Masliah reported at the annual meeting of the Society for Neuroscience.
Aggregates of oligomeric protofibrils of α-synuclein, which is highly concentrated in presynaptic boutons and plays an important role in neurotransmitter release, may contribute to the synaptic damage and degeneration found in disorders with Lewy bodies, such as Parkinson's disease. “There is a clear relationship between the distribution and aggregation of α-synuclein in cortical and subcortical regions and the patterns of clinical manifestations,” said Dr. Masliah of the University of California, San Diego.
He and his associates used human recombinant α-synuclein to vaccinate transgenic mice that express human α-synuclein and show the characteristic accumulation of abnormal α-synuclein oligomers in plasma and synaptic membranes and motor deficits of Lewy body disease and Parkinson's disease. The animals developed relatively high titers of antibodies to α-synuclein, which showed high affinity to α-synuclein aggregates in immunoblot assays and tissue sections. The mice that produced high-affinity antibodies accumulated fewer α-synuclein aggregates, which was associated with reduced neurodegeneration. The α-synuclein aggregates appear to be degraded via lysosomal pathways. The results suggest that α-synuclein antibodies might directly interact with oligomers of α-synuclein at the synaptic membrane or they might bind to receptors, resulting in the endocytosis of the antibodies with the α-synuclein complex, Dr. Masliah said.
No effects were seen on endogenous murine α-synuclein or on other α-synuclein-related markers that are present in the synapse, such as β-synuclein. No severe inflammatory effects were observed in the mice during the experiments, but because of the risk of using active immunization in humans, Dr. Masliah and his colleagues have been developing a passive immunization protocol for future experiments.
Dr. Caselli's comment: The strategy employed by Masliah and colleagues is reminiscent of the amyloid vaccination strategy also initially tested in a transgenic mouse model, and then extended into human trials. Masliah et al. are wisely taking the next step based on the Alzheimer's vaccination experience in which 5% of vaccine recipients developed an autoimmune meningoencephalitis and cerebral vasculitis that resulted in clinical deterioration and prompted premature termination of the trial. A passive vaccination strategy is now underway for Alzheimer's disease, and given the groundbreaking work of Masliah and colleagues, we may anticipate a similar trial for Parkinson's disease in the future. This is a powerful new approach, but clinical efficacy and safety still await further experience.
Protein-Stimulated Neural Stem Cell Repair in Parkinson's Model
The protein compound sNN0031 restored nearly all function and normalized dopamine transporter levels in a rat model of Parkinson's disease for at least 10 weeks by activating endogenous stem cell repair in the striatum, Olof Zachrisson, Ph.D., reported at the annual meeting of the Society for Neuroscience.
To mimic the effects of Parkinson's disease, Dr. Zachrisson of NeuroNova, Stockholm, and his associates injected 6-hydroxy dopamine unilaterally into the right median forebrain bundle of rats, which reduced dopamine transporter binding by 75% in the striatum. When the lesioned rats were given amphetamine, they rotated toward their lesioned side, a sign of an imbalanced dopamine system.
Five weeks later, lesioned rats and those that were given a sham injection received an intracerebroventricular infusion of sNN0031 or a vehicle for 2 weeks. Afterward, lesioned rats on sNN0031 showed significantly more improvement in rotational behavior than rats given vehicle; improvement continued up to 10 weeks after the drug had been administered. Lesioned rats on sNN0031 had a significantly improved level of striatal dopamine transporter binding 10 weeks after treatment, Dr. Zachrisson said.
sNN0031 induced endogenous stem cell proliferation in the ventricular wall adjacent to the medial striatum and neurogenesis in the striatum; the investigators have not yet determined if the new neurons are producing dopamine. At a press conference, one of the investigators, Dr. Anders Haegerstrand, also of NeuroNova, said that sNN0031 is already approved by the Food and Drug Administration for a non-CNS indication, albeit in a different form and dose. He would not say what disease the drug is normally used to treat or what its composition is for proprietary reasons.
Dr. Caselli's comment: That an existing compound has demonstrated neuroregenerative potential in this rat model is encouraging and warrants further exploration, although there is also some reason for caution. First, the lesioned rats in this study are not a model for progressive degenerative parkinsonism, but rather for a static basal ganglia lesion. Second, intracerebroventricular delivery of the agent is not an ideal access point for clinical therapy, especially after the failed adrenocortical transplantation trials. Third, much more work needs to be done to elucidate how the behavioral changes in the rats came about. Fourth, the long-term effects of enhancing CNS stem cell activity (or potentially encouraging other cellular populations as well) need to be determined. For example, is there a long-term risk of brain tumors? Fifth, given that this compound is FDA approved, much more information must be available about its clinical properties, side effects, and appropriateness for the intended patient population. These and other caveats aside, the results of this study are exciting for patients and researchers alike.