Translational Challenges in Neuroscience Drug Development Rita Balice-Gordon Neuroscience Therapeutic Area, Sanofi, Inc., Boston, MA
Neurodegenerative diseases are underpinned by complex, multi-cellular, progressive and in some cases poorly understood pathophysiology, including chronic neuroinflammation, presenting significant challenges for the discovery and development of disease modifying therapeutics. Preclinical and clinical evidence supports the view that chronic neuroinflammation exacerbates neuron and glia dysfunction and ultimately disease progression. Many questions and challenges remain to be addressed, including whether acute neuroinflammation is beneficial or detrimental, dynamics and biomarkers of chronic neuroinflammation, timing of therapeutic interventions to abrogate neuroinflammation, and monitoring neuroinflammation in the clinic. Some of these challenges are tractable by individual labs and biopharma companies, others require long term commitments or pre-competitive consortia efforts. We have been working on neuroinflammation and neurodegeneration in Multiple Sclerosis (MS), a chronic, inflammatory, demyelinating disease of the CNS. Activated microglia and macrophages, among other cell types, play significant roles in mediating disease pathophysiology and progression. Sanofi teams are evaluating the therapeutic hypothesis that inhibition of a class III receptor tyrosine kinase, colony stimulating factor-1 receptor (CSF1R), modulates microglia and infiltrating macrophages, attenuates deleterious CNS inflammation, and reduces demyelination and neurodegeneration in MS. The CSF1R signaling pathway is altered in CNS tissue from MS patients and in preclinical models of neuroinflammation and neurodegeneration. In vitro assays utilizing primary microglia and macrophages demonstrated that CSF1R inhibition blocks receptor phosphorylation and downstream signaling, and alters cytokine production and microglial and macrophage activation. In vivo, CSF1R inhibition significantly improved neurological impairments in experimental autoimmune encephalomyelitis models of MS. Translational work is ongoing to support advancing CSF1R inhibition as a therapeutic for MS.
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