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ROScue Therapeutics - ROS-induced cell death signaling in neurons

Finding new substances to combat neurodegenerative diseases

The incidence of neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis (ALS) and stroke is continuously increasing in ageing societies, and thus represents not only a major health problem but also a growing socio-economic burden. Yet treatment strategies to combat many of these neurodegenerative diseases are inadequate or fail to exist entirely.
 
One major underlying factor is the wide diversity of aberrant cellular processes in neurons, which ultimately lead to their demise. However, new evidence is mounting that a high level of reactive oxygen species (ROS; also called oxidative stress) is a common denominator of virtually all neuronal dysfunction, ultimately resulting in neurodegeneration[1]. Although previously thought to be indiscriminate, oxidative stress-dependent cell death occurs frequently in a programmed fashion, called “necroptosis.”  This recent revelation - that ROS cause cell death through a distinct cell death signalling pathway[2] - allows for the first time the development of novel protective drugs to inhibit collective neurodegenerative cell death signaling pathways.



Figure 1:
ROS-induced cell death signaling in neurons. An increased level of ROS is a common denominator of many aberrant cellular processes in neurons. In stark contrast to previous assumptions, ROS have been shown to cause cell death via specific cell death signaling pathways, opening unique perspectives for the targeted treatment of neurodegenerative disease.

 
The goal of this proposal is to create commercial value through the identification and preliminary validation of potential neuroprotective drugs for neurological disease. As a basis for the discovery of novel compounds, we propose a cell-based model for ROS-dependent degenerative diseases established at the Helmholtz Zentrum München. This model is based on an inducible knockout system of one of the most central ROS regulating enzymes in mammals. Genetic ablation of this gene in cells triggers massive ROS generation and activates the aforementioned cell death pathway, making it highly amenable to early-stage drug discovery projects.
 
In the project first phase, cells are incorporated into a semi-automated robotic platform and screened against a disparate set of novel compounds for activity in inhibiting cell death, analogous to neurodegenerative disease. In the second and third phases, compounds (“hits”) identified by the primary screen will be validated for efficacy in neurodegenerative cell and mouse models, respectively. Successful candidates resulting from the third phase will be submitted for patent review and will serve as the basis for commercialization. It is expected that the value generated by this project will enable a viable enterprise for lead optimization and clinical trials in cooperation with pharmaceutical or biotech partners.


 
Figure 2:
The RỌScue group consists of Joel Schick, Marcus Conrad and Wolfgang Wurst. “RỌScue” is a portmanteau of “ROS” and “rescue” with an unpaired electron below the O.

 
[1] Lin, M.T. & Beal, M.F. Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature 443, 787-795 (2006).
[2] Vandenabeele, P., et al. Molecular mechanisms of necroptosis: an ordered cellular explosion. Nat Rev Mol Cell Biol 11, 700-714. (2010)
[3] Seiler, A., et al. Glutathione Peroxidase 4 Senses and Translates Oxidative Stress into 12/15-Lipoxygenase Dependent- and AIF-Mediated Cell Death. Cell Metab 8, 237-248 (2008).