Nanoparticle-Based Imaging and Therapy of Chronic Pain in the Dorsal Root Ganglia (DRG)

Projektinformationen

PIANO

ID Finanzhilfevereinbarung: 956477

DOI

10.3030/956477

Projekt abgeschlossen

EK-Unterschriftsdatum 9 November 2020

Startdatum 1 März 2021

Enddatum 28 Februar 2025

Finanziert unter

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Gesamtkosten

€ 3 565 136,22

EU-Beitrag

€ 3 565 136,22

Koordiniert durch

KING'S COLLEGE LONDON
United Kingdom

Periodic Reporting for period 2 - PIANO (Nanoparticle-Based Imaging and Therapy of Chronic Pain in the Dorsal Root Ganglia (DRG))

Berichtszeitraum: 2023-03-01 bis 2025-02-28

Zusammenfassung vom Kontext und den Gesamtzielen des Projekts

Chronic neuropathic pain, which results from peripheral nerve damage, chemotherapy-induced neuropathy (CIPN) and spinal cord injury remains a clinical challenge. Since current pain killers are only partially effective and bring severe side effects, there is an urgent need for novel analgesic therapies.
PIANO-ITN has addressed the need for novel and more effective treatments for neuropathic pain through the delineation of novel pathways and identification of strategies to target both sensory neurons and macrophages within the dorsal root ganglia (DRG) in the pain pathways. Indeed, the DRG constitute an ideal site for our investigation as they contain the cell bodies of specialised neurons that transmit noxious signalling from the periphery to the spinal cord on their way to the brain, where pain is perceived. We have addressed the following objectives: i) to develop and characterise innovative biomaterials for use in controlled drug delivery and as contrast agents for imaging studies; ii) to identify novel modalities for neuron communication with macrophages in the DRG in the pain pathway; iii) to define specific roles of neuronal receptors involved in nociceptive processing in DRG.
With a focus on neurons and macrophages, the (10 - 15) Early Scientists Researchers (ESRs) have i) unravelled mechanisms involved in pain signalling and inflammatory processes in DRG, ii) synthesised compounds that inhibit pain-neuron activity, iii) developed targeted nanoparticles to enable sensory neuron visualisation and deliver analgesic compounds and iv) developed non-viral gene transfer technology to promote neuroregeneration in a model of spinal cord injury. The exploitation of our data will eventually lead to improvement of the quality of life of Europeans and impact positively on the health economy of EU countries.

Arbeit, die ab Beginn des Projekts bis zum Ende des durch den Bericht erfassten Berichtszeitraums geleistet wurde, und die wichtigsten bis dahin erzielten Ergebnisse

PIANO ITN has formulated drug-loaded nanoparticles to target sensory neurons and macrophages in DRG, hydrogel-nanoparticle patches for therapeutic application and modulators to target pain channels in sensory neurons. We have developed novel compounds which block pain channels TRPV1 and Nav1.7 in sensory neurons and are endowed with a safer profile compared to current therapeutic options. We have elucidated the function of sensory neuron expressed receptors, namely TRPV1, TRPM8, and TRPA1, in detection of thermal and chemical stimuli in chemotherapy (paclitaxel)- induced neuropathic pain. We have delineated mechanisms by which proinflammatory macrophages release extracellular vesicles (EVs) containing microRNA miR-155 which are taken-up by DRG neurons where miR-155 regulates neuronal activity and facilitates nociceptive signalling. We delineated mechanisms by which GABA-A receptor inhibits DRG neuron activity and GABA regulates macrophage polarisation. In this context, we have developed chemical technologies to target pro-inflammatory/pronociceptive (ATR2 positive) macrophages as a novel therapeutic approach for analgesia. Finaly, we have developed a novel formulation (polyplexes embedded into in situ gelling injectable hydrogels) for local and sustained release of a miR-155 antagomir at the site of the spinal cord injury (SCI).

DISSEMINATION:

We have collected several exploitable results including 1. availability of nanoparticles that polarise macrophages to anti-nociceptive phenotype. 2. Modulators of TRPV2 channel. 3. Hydrogel patches containing capsaicin for therapeutical applications 4. tools for macrophage ablation as a novel therapeutic approach for analgesia. 5. Soft TRPV1 antagonist-based topical formulation to attenuate symptoms of CIPN, and PROTAC-based antagonists of TRPV1 and Nav 1.7 receptors to treat neuropathic pain.

Fortschritte, die über den aktuellen Stand der Technik hinausgehen und voraussichtliche potenzielle Auswirkungen (einschließlich der bis dato erzielten sozioökonomischen Auswirkungen und weiter gefassten gesellschaftlichen Auswirkungen des Projekts)

PIANO-ITN has examined sensory neurons and immune cell activities which are associated with neuropathic pain to provide innovative approaches for pain relief. Our ambitious aims have resulted in synthesis of channel blocker compounds, and formulation of nanoparticles and nanoparticle patches to inhibit pain-neuron activity. We reveal novel chemical technologies to target macrophages and promote polarisation towards anti-inflammatory phenotypes. We have identified a macrophage to neuron communication pathway that entails release of extracellular vesicles that contain non-coding RNA and facilitates pain signalling and offer targets for innovative analgesic therapies.
The results of this project will be of interest to scientists working in neuroinflammation and chronic pain with a special focus on nanoparticle selective delivery to target cells. In addition, data will be of interest to clinicians who treat people with neuropathic pain and to pharmaceutical companies interested in developing better analgesics for treating chronic pain.

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