Bioinformatics and cell reprogramming to develop an in vitro platform to discover new drugs for progressive multiple sclerosis (BRAVEinMS)

BRAVEinMS rises from the joint efforts of laboratories from five
different countries in Europe and North America with the aim of
merging and synergizing unique competences to identify promising molecules that can counteract the progression of multiple sclerosis (MS). The project aims at detecting potential therapeutic
compounds to be rapidly translated into the clinic with a fast-forward step-wise process that can also, indirectly, unveil mechanisms controlling progressive neuronal damage or impaired
myelin regeneration.
A robust virtual network pharmacological screening on libraries
of registered and safe-in-human molecules will be performed and
hits with suggestive therapeutic potential will be tested in cellbased in-vitro experiments. Rodent as well as human neuro-glia
cells will be used as first line screening platform with attention to
robustly reproduce the data in the human cellular context and in
several laboratories to reduce false-negative hits. As a second
line screening system, induced pluripotent stem cell (iPSC)-
derived neural progenitors from MS patients will be used in order to have a disease-in-a-dish tool for human validation studies
essential for assessing the disease specificity of our results.
Finally, compounds found efficacious in vitro will be extensively
evaluated in vivo in several animal models each one representing
a clinical-pathological key aspect of the neurodegenerative process occurring in MS patients.
The process will leverage the unique expertise from each partner
group. Careful in vitro screening represents a main critical pillar
in the project and is designed to identify molecules with promising therapeutic potential whose efficacy will be ultimately tested
in innovative neurodegenerative and demyelinating preclinical
disease models. Within the goal of the Progressive MS Alliance
call, BRAVEinMS should pinpoint a limited number of previously
unidentified molecules with high chance of therapeutic power in
progressive MS patients, pharmacokinetic flexibility and minimal
side effects.
Compared to conventional drug-discovery pipeline or to previous
published work achieved with rodent cells, the approach proposed
by BRAVEinMS, focusing on modular and well controlled bioinformatics tools followed by stringent biological filtering criteria
as well as human neural cells from MS patients, will result in a
higher chance of robustness and disease specific relevance.