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Designed NGF mimetics with reduced nociceptive signatures in neurons

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE292792 | GEO | 2025/04/15

REPOSITORIES: GEO

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Designed NGF mimetics with reduced nociceptive signatures in neurons

Project description: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.

2025-04-30 | GSE295544 | GEO

Fingerprinting of the hNGF P61R100E gene expression in rat Dorsal Root Ganglion detected by microarray analysis

Project description:Nerve Growth Factor (NGF) is being considered as a therapeutic candidate for Alzheimer's disease (AD) treatment, not merely as a long-lasting cholinergic maintainer and neuroprotective agent but also as a direct anti-amyloidogenic factor. However, the development of a NGF-based therapy for neurodegenerative diseases is limited by the partial access of NGF to the brain and to its potent nociceptive actions in animals and humans. Indeed, NGF is involved in pain transmission and perception. The nociceptive activity of NGF is mediated through the activation of TrkA and p75NTR receptors on sensory nerve endings. Our group recently studied forms of NGF, mutated at residue R100, inspired by the human genetic disease HSAN V (Hereditary Sensory Autonomic Neuropathy Type V), which would allow increasing the dose of NGF without triggering pain. This “painless” hNGF hNGFP61S/R100E displays full neurotrophic and anti-amyloidogenic activities in neuronal cultures, and a reduced nociceptive activity in vivo, via a selective alteration of TrkA versus p75NTR binding and signaling. The molecular mechanism through which pNGF reduces nociceptive activity has never been investigated, therefore we performed gene expression microarray analysis to investigated the effect of hNGF hNGFP61S/R100E delivery in rat Dorsal Root Ganglia.

2017-04-18 | GSE80257 | GEO

Transcription profiling of mouse Bax null versus NGF-Bax double null animals

Project description:We report that developmental competition between sympathetic neurons for survival is critically dependent on a sensitization process initiated by target innervation and mediated by a series of feedback loops. Target-derived nerve growth factor (NGF) promoted expression of its receptor TrkA in neurons and prolonged TrkA-mediated signals. NGF also controlled expression of brain derived neurotrophic factor (BDNF) and neurotrophin-4 (NT4), which, through the receptor p75, can kill neighboring neurons with low retrograde NGFâ??TrkA signaling whereas neurons with high NGFâ??TrkA signaling are protected. Perturbation of any of these feedback loops disrupts the dynamics of competition. We suggest that three target-initiated events are essential for rapid and robust competition between neurons: sensitization, paracrine apoptotic signaling, and protection from such effects. Experiment Overall Design: This experiment examine gene expression differences in superior cervical ganglia fro P0 bax null versus NGF-Bax double null animals. The Bax genotype was used in order to prevent the neuronal cell death normally observed in the NGF null animal.

2008-06-11 | E-GEOD-10498 | biostudies-arrayexpress

Comparison of SCG expression profiles from Bax null versus NGF-Bax double null mice

Project description:We report that developmental competition between sympathetic neurons for survival is critically dependent on a sensitization process initiated by target innervation and mediated by a series of feedback loops. Target-derived nerve growth factor (NGF) promoted expression of its receptor TrkA in neurons and prolonged TrkA-mediated signals. NGF also controlled expression of brain derived neurotrophic factor (BDNF) and neurotrophin-4 (NT4), which, through the receptor p75, can kill neighboring neurons with low retrograde NGF–TrkA signaling whereas neurons with high NGF–TrkA signaling are protected. Perturbation of any of these feedback loops disrupts the dynamics of competition. We suggest that three target-initiated events are essential for rapid and robust competition between neurons: sensitization, paracrine apoptotic signaling, and protection from such effects. Keywords: comparative gene expression analysis

2008-04-09 | GSE10498 | GEO

Multifactorial neuroprotective effects of BNN27, a Nerve Growth Factor mimetic, in the 5xFAD mouse model of Alzheimer’s Disease

Project description:Neurotrophic factors consist major regulatory molecules and their decline in Alzheimer's disease is considered as an important cause of disease progression. Novel pharmacological approaches are targeting the downstream pathways controlled by neurotrophins, such as nerve growth factor (NGF) receptors, TrkA and p75NTR, which enhance hippocampal neurogenic capacity and neuroprotective mechanisms, and potentially counteract the neurotoxic effects of amyloid depositions. In this context, BNN27 is a newly developed 17-spiro-steroid analog that have previously shown to mimic the neuroprotective effects of NGF, acting as selective activator of its receptors, both TrkA and p75NTR, promoting neuronal survival. Our present research work aims at determining whether and which aspects of the AD-related pathology, BNN27 is able to alleviate, exploring the cellular and molecular components and link these changes with improvements in the cognitive performance of a mouse AD model. Our results clearly indicate that BNN27 administration significantly reduced amyloid-β load in whole brain, enhanced adult hippocampal neurogenesis, restored cholinergic neurons function and synaptogenesis, reducing inflammatory activation and leading to significant restoration of cognitive functions.

2024-11-25 | PXD044699 | Pride

Breaking through NGF-TrkA immunosuppression in melanoma sensitizes immunotherapy for durable memory T cell protection [scRNA-Seq]

Project description:Melanomas are generated from melanocytes, the neural crest derivatives sharing a neuroectodermal origin with the nervous system. In investigating whether immune privilege of the nervous system might be exploited by melanoma, we found that nerve growth factor (NGF) exerts both melanoma cell-intrinsic and -extrinsic immunosuppression. In melanoma cells, autocrine NGF engages TrkA receptor to desensitize IFN-gammasignaling, leading to T and NK cell exclusion. In effector T cells, which upregulate surface TrkA expression upon T cell receptor (TCR) activation, paracrine NGF dampens TCR signaling and effector function. Targeting NGF genetically or pharmacologically with larotrectinib sensitizes melanoma responsiveness to immune checkpoint blockade (ICB) therapy for tumor eradication and induces durable protection by eliciting robust memory of low-affinity T cells. Together, these findings uncover a comprehensive mechanism through which the NGF-TrkA axis suppresses anti-tumor T cell immunity, thus providing a novel mode of action to repurpose larotrectinib for immune sensitization. Moreover, by enlisting low-affinity tumor-specific T cells, anti-NGF reduces acquired resistance to ICB therapy and prevents melanoma recurrence.

2023-11-02 | GSE236680 | GEO

Breaking through NGF-TrkA immunosuppression in melanoma sensitizes immunotherapy for durable memory T cell protection [RNA-Seq 2]

2023-11-02 | GSE236674 | GEO

Breaking through NGF-TrkA immunosuppression in melanoma sensitizes immunotherapy for durable memory T cell protection [RNA-Seq 1]

Project description:Melanomas are generated from melanocytes, the neural crest derivatives sharing a neuroectodermal origin with the nervous system. In investigating whether immune privilege of the nervous system might be exploited by melanoma, we found that nerve growth factor (NGF) exerts both melanoma cell-intrinsic and -extrinsic immunosuppression. In melanoma cells, autocrine NGF engages TrkA receptor to desensitize IFN-gamma signaling, leading to T and NK cell exclusion. In effector T cells, which upregulate surface TrkA expression upon T cell receptor (TCR) activation, paracrine NGF dampens TCR signaling and effector function. Targeting NGF genetically or pharmacologically with larotrectinib sensitizes melanoma responsiveness to immune checkpoint blockade (ICB) therapy for tumor eradication and induces durable protection by eliciting robust memory of low-affinity T cells. Together, these findings uncover a comprehensive mechanism through which the NGF-TrkA axis suppresses anti-tumor T cell immunity, thus providing a novel mode of action to repurpose larotrectinib for immune sensitization. Moreover, by enlisting low-affinity tumor-specific T cells, anti-NGF reduces acquired resistance to ICB therapy and prevents melanoma recurrence.

2023-11-02 | GSE236673 | GEO

Breaking through NGF-TrkA immunosuppression in melanoma sensitizes immunotherapy for durable memory T cell protection [TCR-seq]

2023-11-02 | GSE243814 | GEO

Transcriptional programs controlled by NGF signaling in developing mouse dorsal root ganglia neurons

Project description:During embryogenesis, nociceptive sensory neurons of the dorsal root ganglia depend intimately on Nerve Growth Factor (NGF) for neuronal survival, maturation and target innervation. NGF is a secreted molecular signal synthesized by neuronal target tissues. In developing nociceptors, NGF engages the receptor tyrosine kinase TrkA to activate a gene transcriptional program involving the regulation of hundreds of transcripts. To identify NGF-dependent genes in developing mouse nociceptors, we have designed and performed two separate microarray screens to compare gene expression profiles of DRG neurons either with or lacking NGF signaling.

2013-11-01 | GSE25611 | GEO

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