Biology subjects

Damo, E.

Publications and source records attributed to Damo, E..

4 recordsLinked to original sources

bioRxiv2026

Structural basis for direct NGF/TrkA blockade by an analgesic antibody

The NGF/TrkA signaling axis is a central mediator of inflammatory and chronic pain, where injury-induced NGF binds and activates TrkA on nociceptive neurons to drive peripheral sensitization and persistent pain states. Despite its therapeutic promise, targeting this pathway is limited by adverse effects of systemic NGF sequestration such as rapidly progressive osteoarthritis and poor isoform selectivity of Trk kinase inhibitors leading to off-target neurological effects. Targeting the TrkA extracellular domain (TrkAECD) offers a pathway to achieve high isoform selectivity while avoiding these complications. However, the precise structural basis for selective TrkA neutralization remains poorly understood. Monoclonal antibody (mAb) 42F5-15 inhibits TrkA-mediated signaling and increases pain threshold. Here, we report the high-resolution (2.60 [A]) cryo-EM structure of the TrkAECD in complex with the Fab region of the TrkA-neutralizing mAb 42F5-15. Structural analysis reveals that the antibody epitope overlaps the NGF-binding interface, consistent with orthosteric inhibition and distinct from previously proposed allosteric mechanisms. The epitope includes residues conserved in TrkA but divergent in TrkB and TrkC, providing a structural basis for receptor isoform selectivity. Furthermore, we demonstrate in vivo that the mAb 42F5-15 potently mitigates mechanical allodynia and nociceptive sensitization. These findings establish a structural framework for the development of selective extracellular TrkA-targeted therapies for safer, non-opioid chronic pain management.

neuroscience↗

bioRxiv2026

Targeting Synaptic Vesicle Endocytosis in Nociceptors Provides Sustained Pain Relief

Endocytosis replenishes synaptic vesicle (SV) pools that are required for persistent transmission of chronic pain signals within nociceptive spinal circuits. The nociceptor-specific contribution of SV endocytosis to pain and the therapeutic potential of endocytosis inhibitors are unclear. We identified SV endocytosis in nociceptors as a critical driver of ongoing pain and developed a gene-based strategy to target this mechanism. Nociceptor-specific adeno-associated virus-mediated knockdown of adaptor-associated kinase 1 (AAK1) or dynamin 1 (Dnm1) in dorsal root ganglia Nav1.8-positive neurons inhibited postoperative and neuropathic hypersensitivity without affecting baseline mechanical or thermal sensitivity, locomotion or spontaneous behavior. Electrophysiological recordings from spinal neurons combined with optogenetic activation of nociceptor afferents showed that AAK1 or Dnm1 downregulation blocked the sustained synaptic transmission between nociceptors and dorsal horn neurons by disrupting SV recycling and reducing neurotransmitter release probability. Lipid nanoparticle (LNP)-encapsulated CRISPR/dCas9-repressor mRNA constructs (dCas9-R) were engineered to achieve sustained and reversible transcriptional and epigenetic repression of Aak1 or Dnm1 following intrathecal delivery. LNP-mediated gene modulation produced sustained downregulation of Aak1 or Dnm1 mRNA in sensory neurons and resulted in robust and long-lasting analgesia in preclinical models of postoperative, inflammatory, neuropathic and osteoarthritis pain without impairing acute nociception or locomotor activity. Mechanistically, targeting endocytic machinery disrupted SV recycling at nociceptor terminals, thereby reducing excitatory neurotransmission within spinal pain circuits. Together, these findings establish presynaptic endocytic regulation as a convergent mechanism underlying chronic pain and demonstrate the translational potential of LNP-delivered CRISPR/dCas9-R as a durable, non-opioid pain therapy that surmounts inherent redundancy of pain signaling mechanisms. One Sentence SummarySynaptic vesicle endocytosis in nociceptors is a critical mechanism driving ongoing pain and targeting this process with intrathecal LNP-delivered CRISPR/dCas9-mediated gene repression produces durable, non-opioid analgesia across multiple chronic pain models.

neuroscience↗

bioRxiv2024

Genetic ablation of GABAB receptors from oligodendrocyte precursor cells protects against demyelination in the mouse spinal cord

GABAergic signaling and GABAB receptors play crucial roles in regulating the physiology of oligodendrocyte-lineage cells, including their proliferation, differentiation, and myelination. Therefore, they are promising targets for studying how spinal oligodendrocyte precursor cells (OPCs) respond to injuries and neurodegenerative diseases like multiple sclerosis. Taking advantage of the temporally controlled and cell-specific genetic removal of GABAB receptors from OPCs, our investigation addresses their specific influence on OPC behavior in the gray and white matter of the mouse spinal cord. Our results show that while GABAB receptors do not significantly alter OPC cell proliferation and differentiation under physiological conditions, they distinctly regulate the Ca2+ signaling of OPCs. In addition, we investigate the impact of OPC-GABAB receptors in two models of toxic demyelination, namely the cuprizone and the lysolecithin models. The genetic removal of OPC-GABAB receptors protects against demyelination and oligodendrocyte loss. Additionally, we observe enhanced resilience to cuprizone-induced pathological alterations in OPC Ca2+ signaling. Our results provide valuable insights into the potential therapeutic implications of manipulating GABAB receptors in spinal cord OPCs and deepen our understanding of the interplay between GABAergic signaling and spinal cord OPCs, providing a basis for future research.

neuroscience↗

bioRxiv2022

Activation of β2-adrenergic receptors in microglia alleviates neuropathic hypersensitivity in mice

Drugs enhancing the availability of noradrenaline are gaining prominence in the therapy of chronic neuropathic pain. However, underlying mechanisms are not well understood, and research has thus far focused on 2-adrenergic receptors and neuronal excitability. Adrenergic receptors are also expressed on glial cells, but their roles toward antinociception are not well deciphered. This study addresses the contribution of {beta}2-adrenergic receptors ({beta}2-ARs) to the therapeutic modulation of neuropathic pain in mice. We report that selective activation of {beta}2-ARs with Formoterol inhibits pro-inflammatory signaling in microglia ex-vivo and nerve injury-induced structural remodeling and functional activation of microglia in vivo. Systemic delivery of Formoterol inhibits behaviors related to neuropathic pain, such as mechanical hypersensitivity, cold allodynia and the aversive component of pain, and reverses chronically established neuropathic pain. Using conditional gene targeting for microglia-specific deletion of {beta}2-ARs, we demonstrate that the anti-allodynic effects of Formoterol are primarily mediated by microglia. Although Formoterol also reduces astrogliosis at late stages of neuropathic pain, these functions are unrelated to {beta}2-AR signaling in microglia. Our results underline the value of developing microglial {beta}2-AR agonists for relief from neuropathic pain and clarify mechanistic underpinnings. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=136 SRC="FIGDIR/small/520924v1_ufig1.gif" ALT="Figure 1"> View larger version (36K): org.highwire.dtl.DTLVardef@166c767org.highwire.dtl.DTLVardef@ad3be9org.highwire.dtl.DTLVardef@1383f5eorg.highwire.dtl.DTLVardef@1c852b1_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗