We suggest a novel approach for the treatment of Parkinson's disease based on anti-alpha-synuclein monoclonal antibodies. This treatment concept offers a preventive approach in combination with a diagnostics concept for healthy elderly people or genetically predisposed people prone to develop PD.
Anti-alpha-synuclein antibodies will be cloned and expressed in mammalian cells. The best recombinant antibody candidates (mAbs-Syn) will be selected in respect to their capacities to bind to synuclein and to brain tissue derived either from PD patients or transgenic mice expressing human alpha-synuclein. They will also be tested for their abilities to inhibit alpha-synuclein fibrillation and neurotoxicity and for their effect in an in vivo transgenic alpha-synuclein pre-clinical model.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
The goal of the proposed plan is to develop an approach for the efficient treatment and particularly for the prevention as well as the slowing of the progression of PD. The underlying treatment concept can be combined with a diagnostics concept for healthy elderly people or genetically predisposed people prone to develop PD. As it stops disease progression, this treatment will be applicable at all stages of the disease.
We expect that this project will yield the proof of concept of the treatment approach in the pre-clinical model within 21 months. We further expect that at the end of this project we will have a monoclonal antibody candidate for further preclinical and clinical development. Provided that this project will yield the proof of concept in the pre-clinical model, the aim is to develop the drug candidate through the end of clinical phase IIa within another five years.
Aggregates of alpha-synuclein are the major component of Lewy bodies associated with Parkinson’s disease. Recently, autoantibodies against alpha-synuclien were detected. We hypothesize that such autoantibodies against alpha-synuclein are involved in the metabolization of alpha-synuclein.
We were able to isolate naturally occurring, physiologic autoantibodies against alpha-synuclein from the serum of healthy individuals and from commercially available intravenous immunoglobulin preparations using an affinity column coated with alpha-synuclein. The autoantibodies display strong bonding affinities to alpha-synuclein as demonstrated by ELISA, immunoprecipitation and Western blotting analysis. Furthermore the affinity-purified autoantibodies had an inhibitory effect on alpha-synuclein fibril formation and were also able to specifically reverse the alpha-synuclein toxicity on neuroblastoma cells.
Our results emphasize the possible importance of naturally occurring autoantibodies against alpha-synuclein for the pathogenesis of PD. Since these autoantibodies are detectable in human serum and cerebrospinal fluid and interfere with pathological events associated with alpha-synuclien, and since their physiological role is far from being understood, further studies are necessary to investigate whether the autoantibodies may provide an innovative approach for the treatment of PD.