Team 3

Targeted therapies for peripheral neuropathies

Director : Liliane MASSADE, PhD, DR2 CNRS
Deputy Director : David ADAMS, PU-PH, APHP

Researches Team 3

Our team is part of the Laboratories of Excellence in Nanosciences and Nanotechnologies (LaBEX Nanosaclay, http://nanosaclay.fr).
Our research goes from basic to translational research and involves close collaborations between clinicians and researchers with research programs structured around neuroprotection, neuroregeneration and myelin repair for peripheral neuropathies with unmet medical needs.
Therefore our aim is to develop new therapeutic approaches by:
the use of nanomedecine based on Small Interfering RNA (siRNA) nanoparticles for the treatment of monogenic peripheral neuropathies and the study of physiopathological mechanisms involved in disorders of peripheral nervous systems (PI: Liliane MASSADE, PhD).
the combination of microsurgery and small molecules or the use of viral vectors for the delivery of genes to tissues and cells to promote peripheral nerve regeneration (PI: Song LIU, MD, PhD).
To develop a murine model in order to evaluate new agents on the regeneration of the Autonomic Nervous system (PI: Thomas Bessede, MD, PhD)
To develop analgesic and anti-inflammatory molecules in pain models (PI: Dan BENHAMOU)
NB. The team wishes to be strengthened by permanent toxicologists or biochemists researchers. Contact: Liliane Massade

Staff members

Name
E-mail
Function
ORCID Number
Liliane MASSADE liliane.massade@inserm.frDR2 CNRS0000-0002-9636-4559

David ADAMS

david.adams@aphp.frPU-PH, APHP0000-0002-8722-4108
Thomas BESSEDEthomas.bessede@gmail.comMCU-PH, APHP0000-0003-3215-1332
Song LIUsong.liu@inserm.frCRCN INSERM0000-0003-3598-4823
Dan BENHAMOUdan.benhamou@aphp.frPU-PH, APHP0000-0001-9893-209X
Philippe SITBONphilippe.sitbon@gustaveroussy.frPH0000-0001-6117-5371
Clovis ADAMSclovis.adams@aphp.frPH, APHP0000-0003-1083-8379
Mévidette EL MADANImevidette.el-madani@inserm.frPost-doc0000-0002-2012-0929
Olivier MORASSIolivier.morassi@aphp.frITA, APHP0000-0003-1083-8379
Julien LOISEL-DUWATTEZjulien.loisel-duwattez@u-psud.frITA, UPud0000-0003-1083-8379
Suzan BOUTARYsuzan.boutary@inserm.frPhD Student0000-0001-7639-2256
Marie CAILLAUDmarie.caillaud@inserm.frPhD Student0000-0003-1588-1501
Krystel NYANGOH-TIMOHkrystel.nyangoh-timoh@univ-rennes1.frMD, PhD Student0000-0003-4751-9080
Laura RUSCIOlaura.ruscio@aphp.frMD, PhD Student 0000-0003-4721-9184
Mickaël SOUEDmickaelsoued@gmail.comMD, PhD Student0000-0002-6941-4071

Grants :

Nanosqualonc, ANR-P2N, https://anr.fr/Projet-ANR-11-NANO-0003
Nanoprotection: Labex NanoSaclay, reference: ANR-10-LABX-0035), supported by a public grant overseen by the French National Research Agency (ANR) as part of the “Investissements d’Avenir” program) http://nanosaclay.fr/Phocea/Vie_des_labos/Ast/ast_theme.php?id_ast=110

Targeted therapies for peripheral neuropathies

PI : Liliane Massade

Our research is focused on the use of nanomedecine based on small interfering RNA (siRNA) nanoparticles for the treatment of monogenic peripheral neuropathies. The strength of our team relies on complementary expertises in: 1) siRNA design, their characterization and optimization; 2) nanotechnologies, with the development of nanoparticle carriers for the delivery of siRNA and neuroactive molecules.

Recently, we investigated the regulation of a gene playing a key role in inherited demyelinating peripheral neuropathy by siRNA-squalene nanoparticles. The effect of these nanoparticles were tested in a mouse model, characterized by muscle weakness and atrophy and by slow nerve conduction velocity (European patent filed in September 2018). Importantly, we showed a normalization of the disease gene expression in this mouse model in addition of the reversal of the disease process and symptoms.

The figure below represents our projects for the next years. They consist of optimization of the treatment by siRNA-squalene nanoparticules and studying the mechanisms underlying the restoration of motor activity in the model of inherited demyelinating neuropathy. Our final aim is to reach clinical phases that will be done in the National reference center for Familial Amyloid Polyneuropathy and Other Rare Neuropathies, headed by Pr. David ADAMS.

This work is supported by a public grant overseen by the French National Research Agency (ANR) as part of the “Investissements d’Avenir” program (Labex NanoSaclay, reference: ANR-10-LABX-0035).

Promoting peripheral nerve regeneration by combining microsurgery

and neuroregenerative treatments

PI : Song Liu

A new surgical procedure for repairing the injured facial nerve with functional restoration has been developed using a rat model of facial nerve crush lesion. The method consists of hypoglossal–facial nerve ‘side’-to-side neurorrhaphy with a predegenerated nerve autograft for restoring functions after facial palsy. The method has then been successfully translated to the clinics and represents a major advance in the rehabilitation of facial nerve injury.

In preclinical studies, we test the usefulness of small molecules, in particular ligands of the tanslocator protein (TSPO), and of viral vectors delivering neurotrophic factors to promote the viability of sensory and motoneurons and the regeneration of axons after peripheral nerve injury.

Morphology and regeneration of the autonomic nervous system

PI : Thomas Bessede

Functional sequelae after abdomino-pelvic oncologic surgery are mainly related to nerve damage in the peripheral autonomic system. Because of anatomical, physiological and functional particularities, specific studies are required to try to improve its intraoperative nerve preservation and its postoperative nerve regeneration.

A Computer-Assisted Anatomical Dissection model was elaborated and is used to identify peripheral autonomic nerve fibers. Utilizing specific immunolabelings, we create 3D morphologic cartographies that are augmented with functional data. It is possible to analyse surgical dissection planes to better preserve vegetative functions.

As a second model, the recovery of erectile function was assessed after cavernous nerve injury in rats. Various techniques to promote cavernous neuroregeneration were assessed : pharmacologic treatments, support with silicone guide, autologous support, combined strategies.
Morphological and experimental data converge towards the objective of reducing functional sequelae after lesions of the autonomic nervous system. With new experimental and imaging models, it is possible to overpass surgical applications and collaborate in Neuroscience.

Preclinical development of analgesic

and anti-inflammatory molecules in pain models

PI : Dan Benhamou

The laboratory of anesthesia focus on preclinical development of analgesic and anti-inflammatory molecules such as Opiorphin (endogenous peptide inhibit NEP and APN) and Losmapimod (an inhibitor of p38 MAPK used as treatment of depression). We developed several murine models of neuropathic pain and showed that:
– Opiorphin as well as its stable derivate STR-324 have an analgesic effect and potentialize that of enkephalins.
– Losmapimod have analgesic and anti-inflammatory effects.

The future studies will consist to understand the mechanisms underlying these observations and to expend their studies on sever pains.