IPRIMYO: Immune-privileged, immortal, myogenic stem cells for gene therapy of Muscular Dystrophy
Dr. Marisa Jaconi, University of Geneva
Abstract (lay summary see below)
Duchenne muscular dystrophy (DMD) is a devastating incurable disease, affecting thousands with heavy burden on health systems. This project combines the development of a safe “immune‐privileged cell” with genetic engineering to correct many dystrophin gene mutations for an efficacious and cost affordable therapy. Systemic intra‐arterial transplantation of mesoangioblasts (blood vessel‐derived progenitors) proved safe in DMD patients and is now being implemented for efficacy in a phase II clinical trial. However, this personalized approach would prove prohibitively expensive for healthcare systems, as pricing of successful gene therapies is showing. We made the striking observation that human mesoangioblasts can be indefinitely expanded with a novel culture medium, even after genetic manipulation and cloning. Cells will be first engineered with a lentivector to silence endogenous HLA (β2‐microglubin and class II CTA) while inserting tolerogenic HLA‐E, fused to β2microglubin and, as safety device, the Herpes Simplex Thymidine Kinase suicide gene with truncated NGF receptor for selection. The vector will also express CD47 and PDL1 to further inhibit immune response to transplanted cells and a small nuclear RNA (U7) engineered to skip exon 51 of the dystrophin gene. Due to the syncytial nature of muscle fibers, the snRNA also enters and corrects the genetic defect in neighboring dystrophic nuclei, thus amplifying of one log the therapeutic effect. Five different cell lines would correct the mutation in 60% of DMD patients. Properly transduced and selected cells will be first checked for genome integrity and their capacity to generate muscle fibers in vitro. They will be then transplanted in humanized DMD mice (already available) and assessed for the ability to escape immune surveillance and to differentiate in dystrophin expressing myofibers, establishing pre‐clinical safety and efficacy for an off‐the‐shelf affordable product. Thanks to unique expertise to successfully complete this project, our strategy may be expanded to other recessive monogenic diseases, for a ground‐breaking impact in regenerative medicine.
Lay summary
Les dystrophies musculaires ne bénéficient toujours pas d'une thérapie efficace. Nous avons développé
une thérapie cellulaire permettant la correction génétique et une production élevée de dystrophine (dont
la mutation provoque la dystrophie musculaire de Duchenne, DMD). La distribution systémique de cellules
souches musculaires autologues génétiquement corrigées (mésoangioblastes) peut conduire à un bénéfice
clinique qui sera testé dans un essai clinique (San Raffaele, Milan). Néanmoins, même en cas de succès, le
coût d'un tel traitement individualisé resterait prohibitif, comme observé pour des protocoles réussis
d’autres maladies génétiques. Par conséquent, nous allons créer un unique lentivecteur spécifique qui
assurera aux mésoangioblastes de corriger le défaut génétique de la DMD et d’échapper à la destruction
par système immunitaire après transplantation. Ces cellules seront utilisées pour générer une banque
cellulaire permettant leur administration sur demande à n'importe quel patient atteint de DMD mais aussi
d'autres maladies génétiques.
German
Für Muskeldystrophien gibt es noch immer keine wirksame Therapie. Wir haben eine Zelltherapie
entwickelt, die eine genetische Korrektur und eine hohe Produktion von Dystrophin (dessen Mutation die
Duchenne‐Muskeldystrophie, DMD, verursacht) ermöglicht. Die systemische Verteilung von genetisch
korrigierten autologen Muskelstammzellen (Mesoangioblasten) könnte zu einem klinischen Nutzen
führen, der in einer klinischen Studie (San Raffaele, Mailand) getestet werden soll. Doch selbst wenn dies
gelänge, wären die Kosten für eine solche individualisierte Behandlung unerschwinglich, wie bei
erfolgreichen Protokollen für andere genetische Krankheiten zu beobachten ist. Deshalb werden wir einen
einzigen spezifischen Lentivor entwickeln, der sicherstellt, dass die Mesoangioblasten den DMD‐Gendefekt
korrigieren und nach der Transplantation der Zerstörung durch das Immunsystem entgehen. Diese Zellen
werden zur Erstellung einer Zellbank verwendet, die es ermöglicht, sie bei Bedarf jedem Patienten zu
verabreichen, der an DMD, aber auch an anderen genetischen Krankheiten leidet.
Italian
Le distrofie muscolari non hanno ancora una terapia efficace. Abbiamo sviluppato una terapia cellulare
che permette la correzione genetica e la produzione elevata di distrofina (la cui mutazione causa la distrofia
muscolare di Duchenne, DMD). La distribuzione sistemica di cellule staminali muscolari autologhe
geneticamente corrette (mesoangioblasti) può portare a un beneficio clinico che sarà testato in un trial
clinico (San Raffaele, Milano). Tuttavia, anche se avesse successo, il costo di un tale trattamento
individualizzato rimarrebbe proibitivo, come osservato in protocolli di successo per altre malattie
genetiche. Pertanto, creeremo un unico lentivettore specifico che assicurerà ai mesoangioblasti di
correggere il difetto genetico DMD e sfuggire alla distruzione da parte del sistema immunitario dopo il
trapianto. Queste cellule saranno utilizzate per generare una banca cellulare per la loro somministrazione
su richiesta a qualsiasi paziente affetto da DMD ma anche da altre malattie genetiche.
Projets
- Nouveaux projets de recherche dès 2024
- L'importance de la recherche
- Projets financés
- Unstructured proteins as therapeutic targets for neuromuscular diseases
- Open and reproducible pipeline for the acquisition and analysis of muscle MRI data in Facioscapulohumeral Muscular Dystrophy
- Dissecting lysosomal signals to fight Pompe disease
- Functional properties and epigenetic signature of quiescent and early activated human muscle reserve cells
- Activation of human skeletal muscle stem cells:role of Orai3 ans its partner AHNAK2 in physiological condition and in Duchenne Muscular Dystrophy
- Understanding the clinical spectrum associated with VMA21 deficiency
- ANTXR2 as a key player in Collagen VI signaling in muscle stem cells: new therapeutic perspectives for COL6-related myopathies.
- Molecular mechanisms of complement activation and neuromuscular disruption by combinations of autoantibodies from patients with Myasthenia Gravis
- From the investigation of the role of SRSF1 in ALS/FTD to its targeting as a therapeutic strategy
- Molecular crosstalk between muscles and motor neurons and its role in neuromuscular circuit formation
- Molecular Diagnosis and Coping Mechanisms in Mitochondrial Myopathies
- IPRIMYO: Immune-privileged, immortal, myogenic stem cells for gene therapy of Muscular Dystrophy
- Effect of RYR1 mutations on muscle spindle function and their impact on the musculoskeletal system
- Therapeutic potential of human myogenic reserve cells in Duchenne Muscular Dystrophy
- Glutamine metabolism as a potential target for Duchenne Muscular Dystrophy
- Targeting protein s-acylation during Tubular Aggregate Myopathy
- Aggravating the phenotype of dystrophic mice for improving preclinical research and clinical translation for Duchenne muscular dystrophy
- Characterization of autoreactive T cells in Guillain-Barré syndrome
- A vascularized human muscle-on-a-chip to elucidate the contribution of endothelial-mesenchymal transition on the progression of muscular dystrophies
- Characterization of a novel form of ALS associated with changes in the sphingolipid metabolism
- Pre-clinical treatment of mouse models carrying recessive Ryr1 mutations with HDAC/DNA methyltransferase inhibitors.
- New aspects of TGFβ signaling in muscle homeostasis and regeneration
- Inhibition of sphingolipid synthesis as a treatment strategy for Duchenne muscular dystrophy
- Tamoxifen in Duchenne muscular dystrophy (TAMDMD)
- DNA aptamers against the DUX4 protein reveal novel therapeutic implications for FSHD
- Facilitating diagnosis of critical illness myopathy using muscle excitability testing
- Rapid Exploratory Imaging for High-resolution and Whole Extremity Coverage in MR Neurography
- Deciphering novel mechanisms and effectors contributing to muscle dysfunction in Myotonic Dystrophy Type I
- Can HDAC/DNA methyltransferase inhibitors improve muscle function in a congenital myopathy caused by recessive RYR1 mutations?
- Identification of the critical regulators of protein synthesis and degradation in human muscle atrophy
- Exploring peripheral B-cell-helper T cell phenotypes in the blood of patients with Myasthenia gravis using mass cytometry (CyTOF)
- Molecular signature, metabolic profile and therapeutic potential of human myogenic reserve cells
- A multicenter cross-sectional and longitudinal study of the Swiss cohort of Merosin-negative congenital muscular dystrophy
- Targeting NADPH oxidase 4 in models of Duchenne muscular dystrophy
- Characterizing the role of ER stress in C9orf72-linked ALS pathology
- Inducing mitophagy with Urolithin A to restore mitochondrial and muscle function in muscular dystrophy
- Motor unit action potentials analysis in patients with myopathies with a new wireless portable and multichannel Surface EMG device (WPM-SEMG)
- Role and therapeutic potential of PLIN3 in neuromuscular diseases
- Changes in ventilation distribution in children with neuromuscular disease using the insufflator/exsufflator technique: An observational study
- Mechanism and function of genome organization in muscle development and integrity
- Role and therapeutic potential of NADPH oxidases in a mouse model of Duchenne Muscular Dystrophy
- Characterization of pathological pathways activated in muscles of patients with congenital myopathies with disturbed Ca2+ homeostasis
- Creation of a study team to conduct an SMA 1-clinical trial at the Centre for Neuromuscular Diseases of the University Children's Hospital Basel (UKBB)
- Novel treatment to stop progressive neuropathy and muscle weakness in multifocal motor neuropathy
- Understanding the pathomechanisms leading to muscle alterations in Myotonic Dystrophy type I
- Automated volumetry and quantitative MRI to diagnose peripheral nerve lesions – translational proposal for a new clinical diagnostic imaging tool
- Novel approaches against Spinal Muscular Atrophy by targeting splicing regulators
- Protective effects and mechanisms of action of tamoxifen in mice with severe muscular diseases
- Role of the receptor FgfrL1 in the development of slow muscle fibers
- Muscle velocity recovery cycles: A new tool for early diagnosis of critical illness myopathy
- Generation of uncommitted human IPSC derived muscle stem cells for therapeutic applications
- Transposable vectors for dystrophin-expression in a murine model for muscular dystrophy
- Cardiac involvement in patients with Duchenne/Becker Muscular Dystrophy; an observational study
- Deciphering the pathogenic mechanisms of C9ORF72 ALS
- Enhancing estrogenic signalling to fight muscular dystrophies: Mechanisms of action and repurposing clinically approved drugs
- Mechanisms and therapeutic potential of modulating PGC‐1α to alter neuromuscular junction morphology and function
- Triggering human myoblast differentiation: from EGFR to myogenic transcription factors
- Improving cellular therapies of muscle dystrophies by uncovering epigenetic and signaling pathways of muscle formation
- Protein engineering in an attempt to increase the mechanical, integrin dependent cytoskeleton-matrix linkage in muscle fibers
- Muscle velocity recovery cycles: a new tool for characterization of muscle disease in vivo
- Excessive neurotrypsin activation and agrin cleavage-a pathogenic condition leading to sarcopenia-like muscle atrophy?
- Evaluation of novel treatment strategies for dyspherlinopathies in mouse models
- Cell therapy of LGMD2D by donor HLA-characterized human mesoangioblasts (hMABs) produced in GMP conditions
- In search of small molecules targeting protein-RNA complex: a novel approach against Spinal Muscular Atrophy
- Restoration of autophagy as a new strategy for the treatment of congenital muscular dystrophies
- Development of magnetic resonance methods for functional imaging of the skeletal muscle
- Targeting ER stress response: a potential mechanism for neuroprotection in Amyotrophic Lateral Sclerosis
- Generation of uncommitted human IPSC derived muscle stem cells for therapeutic applications
- Brochure décrivant les projets
- SEAL Therapeutics AG
- Rencontres et séminaires
- Participation à des associations faîtières
- Les registres de patients
- Le réseau Myosuisse
FSRMM
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- philippe.rognon@fsrmm.ch