Efficacy of Tomivosertib (MNK1/2 Inhibitor) in Mitigating RDEB Mice Pain

Recessive dystrophic epidermolysis bullosa (RDEB) is a skin disorder caused by pathogenic variants in the COL7A1 gene, resulting in a deficiency of functional collagen VII, which anchors the epidermis to the dermis. Without collagen VII, the skin is fragile and blisters easily, leading to severe pain, chronic wounds, and infection risk. However, effective, non-opioid pain treatments remain limited, highlighting the need for alternatives. MNK1/2 kinases are part of a known pain pathway that regulates pain-related protein translation. This study investigates the role of MNK1/2 signaling in RDEB pain and the effect of tomivosertib, an MNK1/2 inhibitor, on pain-related behaviors and gene expression in an RDEB mouse model with hypomorphic Col7a1 pathogenic variants. RDEB mice were treated with tomivosertib or DMSO control for two to four weeks. Pain behaviors (paw nibbling, grooming, grimacing) were assessed using behavioral assays, and gene expression (Bdnf, Eif4e) was quantified by RT-qPCR, which measures mRNA levels, along with immunostaining to assess MNK pathway activation. Tomivosertib reduces pain-related gene expression and alleviates pain behaviors in RDEB mice without significantly affecting itch. MNK inhibition decreased Bdnf expression in dorsal root ganglia, supporting MNK1/2 inhibition as a potential intervention for RDEB pain.