Designed NGF mimetics with reduced nociceptive signatures in neurons
The clinical use of Nerve Growth Factor (NGF) for neural regeneration has been hampered by pain sensitization side effects. NGF signals through the receptor tyrosine kinase TrkA and the co-receptor p75NTR; pain sensitization is thought to involve p75NTR. We sought to overcome this limitation by de novo design of a TrkA agonist that does not bind p75. We designed homodimeric TrkA engaging constructs that bring together two TrkA subunits in a variety of geometries, and identified those eliciting the strongest signaling. The resulting designed agonists are able to stimulate transdifferentiated neurons and neuroblastoma cell lines, leading to neurite outgrowth and neuronal differentiation, with considerably reduced transcription of inflammation and pain related genes. Although detailed in vivo characterization will be required to fully understand their therapeutic potential, these agonists are promising candidates for inducing neural regeneration with reduced pain side effects. Overall design: RNA-seq profile for total RNA for two-weeks transdifferentiated neurons (iNs) treated for 48h with vehicle, 10 nM NGF or 10 nM 237 desgined agonist