Reinvigorating drug development around NGF signaling for pain
Andi Wangzhou, Theodore J. Price
Andi Wangzhou, Theodore J. Price
Published February 17, 2025
Citation Information: J Clin Invest. 2025;135(4):e189029. https://doi.org/10.1172/JCI189029.
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Commentary

Reinvigorating drug development around NGF signaling for pain

Abstract

Nerve growth factor (NGF) signaling is a clinically validated target for the treatment of several prevalent types of chronic pain; however, addressing safety concerns remain a key challenge. In this issue of the JCI, Peach et al. take a major step forward in this area by deciphering complexities in the signaling of the NGF receptor TrkA, finding that neuropilin 1 (NRP1) acted as a coreceptor for NGF actions at TrkA and the receptor complex required scaffolding from GIPC1. Using a mix of techniques, including animal behavioral models, electrophysiology on mouse and human dorsal root ganglion (DRG) neurons, and elegant biochemical pharmacology, the authors demonstrated that this therapeutic target might more safely manipulate NGF signaling to achieve pain alleviation. While there are still important questions to answer, the innovative work paves the way for the development of nonopioid pain therapeutics.

Authors

Andi Wangzhou, Theodore J. Price

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Figure 1

TrkA/NGF/NRP1/GIPC1 targeting for pain treatment.

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TrkA/NGF/NRP1/GIPC1 targeting for pain treatment. The findings of Peach ...
The findings of Peach et al. demonstrate that interfering with the TrkA/NGF/NRP1 protein complex, or with GIPC1-mediated assembly and/or trafficking of this complex influences NGF-driven pain. Because many of the genes involved in this signaling pathway are ubiquitously expressed, developing safe therapeutics for this pathway remains a challenge. Previous strategies such as tanezumab blocks NGF actions everywhere and have had safety issues. Similarly, targeting NRP1, GIPC1, NGF, and p75 to some extent, would also have an effect in all tissues expressed. Notably, the TrkA/NGF/NRP1 protein complex can impart specificity because the intersection of the expression and function of these proteins is relatively specific for DRG neurons and their axons, which innervate peripheral tissues.