Disruption of Plexin-A1 signaling by FTX-101: mode of action and effect on oligodendrocyte biology

Background and purpose: In the absence of effective remyelination therapies for neurodegenerative disorders, we have synthesized FTX-101, a therapeutic peptide rationally designed to enhance the recruitment and maturation of oligodendrocyte precursors.

Experimental approach: Given that Sema3A signaling through the NRP1/Plexin-A1 receptor complex inhibits remyelination, we employed FTX-101 to disrupt the assembly of this receptor complex at the transmembrane interface. We conducted in vitro analyses to assess the effects on the migration, differentiation, and myelination of oligodendrocytes. FTX-101 was evaluated in a murine oligodendroglial cell line as well as in oligodendrocytes derived from human fibroblasts.

Key results: FTX-101 functions as a membrane-targeting peptide with exceptional attributes. Notably, while of lipophilic nature it demonstrates water solubility, it is highly specific for the NRP1/Plexin-A1 receptor system and when lyophilized remains stable for an extended amount of time. Our findings indicated that FTX-101 effectively disrupts the NRP1/Plexin-A1 receptor complex and mitigated the inhibitory influence of Sema3A on oligodendrocyte migration and differentiation, thereby facilitating increased myelin sheathing around axons.

Conclusion and implications: FTX-101 enhanced the recruitment of oligodendrocytes and promoted myelination, addressing critical medical needs in demyelinating conditions. Specificity, solubility in water, and enduring stability render FTX-101 a highly promising candidate for a first-in-class therapeutic agent.

Myelin; Neuropilin; Plexin A1; Remyelination; Transmembrane peptide.