Phosphodiesterase 4D inhibition improves the functional and molecular outcome in a mouse and human model of Charcot Marie Tooth disease 1 A

Charcot-Marie-Tooth disease type 1A (CMT1A) is an inherited peripheral neuropathy caused by a duplication of the peripheral myelin protein 22 (PMP22) gene. It is primarily marked by Schwann cell dedifferentiation and demyelination, leading to motor and sensory deficits. Cyclic adenosine monophosphate (cAMP) is crucial for Schwann cell differentiation and maturation. Therefore, increasing cAMP by inhibiting its degraders, phosphodiesterases (PDE), is a potential therapeutic strategy for CMT1A. This study investigated the therapeutic potential of the specific PDE4D inhibitor Gebr32a using the C3-PMP22 mouse model for CMT1A and patient-induced Pluripotent Stem Cell (iPSC)-derived Schwann cells. C3-PMP22 mice, injected subcutaneously with Gebr32a twice a day for 10 weeks, showed significantly increased nerve conduction in sciatic nerves compared to vehicle-injected controls, indicating improved myelination. Additionally, Gebr32a-treated C3-PMP22 mice exhibited improved sensorimotor functions. Grip strength analysis revealed significantly increased strength in all limbs of Gebr32a-treated C3-PMP22 mice. Post-mortem histological and ultrastructural analysis confirmed enhanced myelination in the sciatic nerve of treated mice compared to controls. In primary mouse CMT1A Schwann cells, Gebr32a dose-dependently increased the expression of pro-myelinating genes such as oct6, Krox20, Mbp, Mpz, and Plp, while downregulating the dedifferentiation marker c-Jun and human PMP22. Similar effects on gene expression were observed in iPSC-derived Schwann cells from a CMT1A patient, highlighting the clinical relevance of our findings. In conclusion, inhibition of PDE4D with Gebr32a improves the functional and molecular outcomes in mouse and human models of CMT1A, highlighting its potential as a new therapeutic strategy for CMT1A disease management.