Next generation drug connectivity mapping for acquiring therapeutic agents to differentially regulate myelination

The need for new therapeutic approaches:Conventional drug discovery is a lengthy and expensive process,taking decades and billions of dollars to get a drug from bench to bedside.Much of the costs incurred are at the pre-clinical stages,between drug design and synthesis to delineating the cellular“Mechanisms of Action”(MoA).Notably,there is a very high risk of failure,and only a very small proportion of therapeutic agents reach later-phase clinical trials.Accordingly,drug repositioning has become a valuable strategy aimed at fast-tracking treatments into clinical use and improving the chances of therapeutic success.A novel addition to this approach is connectivity mapping,which defines cell-specific transcriptional responses to small molecules in disease-dependent contexts.This commentary outlines how some of the latest innovations in connectivity mapping can be exploited for drug repurposing.

Resolving the age-related decline in central nervous system myelin turnover and drug discovery for oligodendroglial rejuvenation

Myel i n genes are amongst the most dysregulated genes in the aged brain:Just over half of the weight of an entire adult human brain is attributed to myelin,which wraps around neuronal axons and is essential for superfast axonal conduction and neuronal integrity.In the central nervous system,it is the function of specialized cells called oligodendrocytes(OLs)to make myelin,which is made up of lipids and proteins.OLs are generated throughout life by a significant population of oligodendrocyte progenitor cells(OPCs)that are responsible for the lifelong generation of OLs and myelin,essential for learning,as well as repair following pathological insults(i.e.in demyelinating diseases that include multiple sclerosis)(Simons and Nave,2015;Philips and Rothstein,2017).Changes in myelin content in the human brain over the lifespan of individuals have been well documented,as well as evidence of myelin loss in rodent models using classical histological approaches(Bartzokis et al.,2012;Soreq et al.,2017).