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; 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 geometrics, and identified those eliciting the strongest signaling. The resulting designed agonists are able to stimulate transdifferentiated neurons and neuroblastoma cell lines, leading to outgrowth of neurites 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. RNA-seq profiling of SY5Y cells was performed between ag231 and PBS; and between ag237 and PBS.

神经生长因子（Nerve Growth Factor, NGF）用于神经再生的临床应用一直受限于痛觉致敏的不良反应。NGF通过受体酪氨酸激酶TrkA与共受体p75NTR介导信号转导；本研究旨在通过从头设计一种不结合p75的TrkA激动剂，以克服这一应用局限。我们构建了可通过多种几何构型结合两个TrkA亚基的同源二聚体TrkA结合元件，并筛选出了可引发最强信号响应的元件。所得的设计型激动剂能够刺激转分化神经元与神经母细胞瘤细胞系，促进神经突起生长与神经元分化，同时显著下调炎症与疼痛相关基因的转录水平。尽管仍需开展详细的体内表征工作以全面阐明其治疗潜力，但这些激动剂是有望实现低疼痛副作用的神经再生诱导候选药物。本研究针对SY5Y细胞开展了RNA-seq转录组谱分析，分别对比了ag231处理组与磷酸盐缓冲液（PBS）对照组，以及ag237处理组与PBS对照组的转录组特征。