CE18 - Innovation biomédicale

Extra cellular vesicles for intervertebral disc therapy – EXCELLDISC

Submission summary

Low back pain (LBP), affecting over 80% of adults during their lifetime and resulting in considerable disability and socioeconomic consequences, is often associated with intervertebral disc (IVD) degeneration. The IVD consists of a gel-like nucleus pulposus (NP) surrounded by a densely fibrous annulus fibrosus. IVD degeneration is characterized by NP cell dealth, extracellular matrix (ECM) changes and dehydration, increased expression of matrix metalloproteinases and inflammatory factors, culminating in failure of biomechanical properties, thereby leading to pain and disability. Current treatments, including pharmacotherapies for early degenerative stages and surgery for more advanced ones, only aim at controlling pain but do not address the underlying degenerative processes. Therefore, biologically-inspired regenerative strategies have recently gained increased attention. Stem cell-based therapies, consisting in NP supplementation with cells able to synthesize a functional ECM and tackle in situ inflammation, could contribute to revert the degenerative process and restore IVD biomechanical function. While promising outcomes have been reported with bone marrow or adipose Mesenchymal Stem/stromal Cells (MSCs), the regenerative mechanisms of MSCs after injection into a degenerated disc have not yet been fully elucidated. The regenerative potential of MSCs following IVD injection could depend on their in situ ability to secrete, either directly or mediated through the release of extracellular vesicles (EVs), a myriad of biofactors interacting with local NP cells. While this paracrine effect of MSCs has been evidenced in inflammation-associated degenerative diseases, including osteoarthritis, implementation of MSC-derived EVs in IVD regeneration still remains in its infancy. With EXCELLDISC, we hypothesize that MSC-derived EVs may represent a simpler alternative to IVD cell therapies, with cell-free strategy advantages: no risks of uncontrolled differentiation and extended “off-the-shelf” storage. In addition, we also hypothesize that EVs could be produced in response to IVD specific priming microenvironments (hypoxia, high osmolarity, acidic pH, nucleopulpogenic differentiation medium) that would mimic a degenerated disc, and that relevant recipient cells could internalize MSC-derived EVs in vitro and ex vivo. Finally, we hypothesize that MSC-derived EVs could contribute to slow down, halt or revert IVD degeneration in a clinically relevant established sheep model of disc degenerative disease.
To carry out the EXCELLDISC project, a 4-year period is planned and is divided into 3 main experimental work packages (WP), in addition to a management, communication and valorization one. Three academic partners are collaborating to achieve a successful completion of each stage of the project: INSERM UMRS 1229 (Regenerative Medicine and Skeleton, Partner 1 and coordinator), MSC CNRS 7087 (Matière et Systèmes Complexes, Partner 2) and Inserm U932 (Immunity and Cancer, Partner 3). Those academic partners have a strong collaborative track-record, and bring an impressive background in regenerative medicine, osteo-articular diseases and stem cell biology making them likely an appropriate scientific consortium to fulfill our ambitious objectives. The objectives of the EXCELLDISC proposal are thus: (i) to set-up production and characterization of clinical grade human bone marrow MSC-derived EVs using a high yield and cost-effective technology fully compatible with GMP-compliant bioreactors (WP1), (ii) to implement potency assays to assess the interactions of different MSC-derived EVs with target cells in vitro and in an ex vivo whole IVD culture system (WP2) and (iii) to perform a proof of concept to compare the MSC-derived EVs therapeutic activities with that of human bone marrow MSCs in a clinically relevant established sheep model of disc degeneration (WP3).

Project coordination

Catherine Le Visage (Regenerative Medicine and Skeleton)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

RMeS Regenerative Medicine and Skeleton
MSC Laboratoire Matière et Systèmes Complexes
IC INSTITUT CURIE - SIEGE
MSC Laboratoire Matière et Systèmes Complexes

Help of the ANR 678,240 euros
Beginning and duration of the scientific project: February 2020 - 48 Months

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