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Funded Studies

Evaluation of the Oligomer Modulator anle138b in a Seeding-based Model of Parkinson’s Disease

Objective/Rationale:             
Mounting evidence indicates a crucial role of pathological aggregates of the protein alpha-synuclein in Parkinson’s disease (PD). Small aggregates termed oligomers seems to be toxic for nerve cells. Moreover, prion-like spread of pathological alpha-synuclein aggregation may cause progressive degeneration of brain areas. We recently developed the novel oligomer modulator anle138b that inhibits the formation of pathological alpha-synuclein oligomers and has shown therapeutic efficacy in several models of PD.

Project Description:
We will test anle138b in a novel, large PD model. First, we will test which doses are required to obtain relevant levels of anle138b in blood and tissue (“pharmacokinetics”) and whether there are any adverse effects of this compound at the required doses (“toxicology”). In parallel, we will obtain additional efficacy data in a PD model that is based on seeding pathology with extracts containing aggregated alpha-synuclein purified from PD brain tissue. In the second project phase, we will use these extracts to induce a PD-like disease in larger models, which have an alpha-synuclein protein that is identical to human alpha-synuclein. Using this recently established disease model, we will then test the therapeutic efficacy of anle138b.

Relevance to Diagnosis/Treatment of Parkinson’s Disease:                     
Accumulating evidences suggest that aggregation of alpha-synuclein and formation of toxic oligomers is a key process in PD. Small molecules such as anle138b that can prevent or even reverse the generation of alpha-synuclein oligomers, therefore have the potential to directly block disease progression.

Anticipated Outcome:          
The results of this study will be of crucial importance for assessing the therapeutic potential of anle138b and for moving it to clinical trials in humans. If successful, this therapeutic approach may be able to inhibit the progressive neurodegeneration.


Researchers

  • Christian Griesinger, PhD

    Gottingen Germany


  • Armin Giese, Prof. Dr. med., MD

    Wendelsheim Germany


  • Erwan Bezard, PhD

    Bordeaux France


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