Forschungsprojekte der AG Molekulare Pharmakologie
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1. Alzheimer's Disease: Testing of new drug candidates in tau-transgenic mice
Project leader: Prof. F. Theuring
Coworkers: Dr. S. Dietze, scientist; M. Magbagbeolu, B. Seelhorst, both are Technicians; V. Melis, PhD guest; A. Thoma, Animal Care Taker; Dr. C. Zabke, scientist.
Funding: TauRx Therapeutics, WisTa Laboratories, Singapore
Collaboration: Prof. C. Wischik, University of Aberdeen, Scotland
Tau transgenic mouse lines had been established to further analyse the functional role this protein and its aggregates, the so-called tau tangles play in clinical dementia, i.e. Alzheimer's Disease and to test putative new drug candidates in a preclinical setting to fight this neurodegenerative and terminal brain disease. In a most fruitful scientific collaboration with Prof. Wischik's group from the University of Aberdeen for the last 12 years these mice had been pivotal in establishing a relevant transgenic tau-based Alzheimer mouse model. Several dozens of newly discovered and synthesized drug candidates had been tested in vivo for their activity in reducing tau pathology and to enhance cognitive behaviour and motor skills in the drug-treated animals.
By teaming up with TauRx Pharma - a Singapore-based company spun out of the University of Aberdeen and the Charité - it is now our great pleasure to reveal a major breakthrough in the treatment of Alzheimer's disease. A total of 321 patients with mild and moderate Alzheimer's Disease were treated in a phase II clinical trial with Rember® a novel form of methylthioninium chloride (MTC). Patients receiving the study treatment experienced an 81% reduction in cognitive decline over one year, and did not experience a significant decline in their mental function over 24 months. In addition patients had repeated brain scans at the start of the study and after 25 weeks. These showed that the treatment effect was greatest in the memory-critical brain regions where the density of Alzheimer tangles is greatest. In the control group, there was a significant decline from the starting score in cognitive testing and on brain scans.
By employing our transgenic mice a group of second-generation rember® derivatives had been discovered and successfully tested. These compounds have the same mechanism of action as rember® acting as Tau Aggregation Inhibitors, with potential utility in the treatment of Alzheimer's disease and other neurodegenerative disorders. TauRx has now initiated preparations for Phase 3 studies in mild and moderate AD, and also in orphan indications such as Fronto-Temporal Dementia and provisionally Progressive Supranuclear Palsy.
These data underline the importance of generating relevant transgenic mouse models and their use in identification and validation of new drug candidates for human diseases, which then are planned to enter into clinical testing.
2. Parkinson's Disease: Testing of new drug candidates in α-synuclein transgenic mice
Project leader: Prof. F. Theuring
Coworkers: Dr. S. Dietze, scientist; M. Magbagbeolu, B. Seelhorst, both are Technicians; ; A. Thoma, Animal Care Taker; Dr. C. Zabke, Karima Schwab, scientist.
Funding: WisTa Laboratories, Singapore
Collaboration: Prof. C. M. Wischik, University of Aberdeen, Scotland
Parkinson's disease (PD) is a common human neurodegenerative movement disorder and affects 1% of the elderly population. PD is neuropathologically characterized by a marked and progressive degeneration of dopaminergic neurons and by the presence of fibrillar cytoplasmic inclusions (Lewy bodies [LBs]) and dystrophic neurites (Lewy neurites [LNs]) in the substantia nigra and other regions of the brain. Although the loss of dopamine neurons is certainly related to the major clinical symptoms of PD, the causes and the pathogenesis of this multifactorial disease as well as that of related "synucleinopathies" are still largely unknown.
The major components of both LBs and LNs are fibrillar aggregates of α-synuclein. α Synuclein is a widely expressed, neuronal presynaptic protein that appears to play a role in membrane-associated processes and synaptic plasticity and has been linked to learning and development processes. While the mechanism(s) of formation of LBs and LNs and their association with PD are yet not understood, several lines of evidence suggest that α synuclein fibrillization is associated with PD and that α-synuclein fibrillization causes toxicity. Thus the inhibition or reversal of synuclein aggregation is believed to be of therapeutic benefit.
The development of drugs that prevent this aggregation form the basis for the scientific rationale for this project. The aim is to model the molecular processes of α-synuclein aggregation in an animal model to test and evaluate new therapeutic drug candidates for PD.
Consequently α-synuclein transgenic mice had been generated carrying different transgenic constructs. These mice are currently being characterized in more detail and will be used to study basic mechanisms of the pathogenesis underlying PD. Most importantly, these mice will then be used to screen for α-synuclein aggregation inhibitors to facilitate the development of a new therapeutic intervention for this disease.