title: Intra-arterial transplantation of HLA-matched donor mesoangioblasts in Duchenne muscular dystrophy.
abstract: Intra-arterial transplantation of mesoangioblasts proved safe and partially efficacious in preclinical models of muscular dystrophy. We now report the first-in-human, exploratory, non-randomized open-label phase I-IIa clinical trial of intra-arterial HLA-matched donor cell transplantation in 5 Duchenne patients. We administered escalating doses of donor-derived mesoangioblasts in limb arteries under immunosuppressive therapy (tacrolimus). Four consecutive infusions were performed at 2-month intervals, preceded and followed by clinical, laboratory, and muscular MRI analyses. Two months after the last infusion, a muscle biopsy was performed. Safety was the primary endpoint. The study was relatively safe: One patient developed a thalamic stroke with no clinical consequences and whose correlation with mesoangioblast infusion remained unclear. MRI documented the progression of the disease in 4/5 patients. Functional measures were transiently stabilized in 2/3 ambulant patients, but no functional improvements were observed. Low level of donor DNA was detected in muscle biopsies of 4/5 patients and donor-derived dystrophin in 1. Intra-arterial transplantation of donor mesoangioblasts in human proved to be feasible and relatively safe. Future implementation of the protocol, together with a younger age of patients, will be needed to approach efficacy.
authors.affiliation: Institute of Inflammation and Repair, University of Manchester, Manchester, UK giulio.cossu@manchester.ac.uk previtali.stefano@hsr.it yvan.torrente@unimi.it ciceri.fabio@hsr.it.
authors.forename: Giulio
authors.initials: G
authors.lastname: Cossu
authors.affiliation: Institute of Experimental Neurology (InSpe), Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy Department of Neurology, IRCCS San Raffaele Scientific Institute, Milan, Italy giulio.cossu@manchester.ac.uk previtali.stefano@hsr.it yvan.torrente@unimi.it ciceri.fabio@hsr.it.
authors.forename: Stefano C
authors.initials: SC
authors.lastname: Previtali
authors.affiliation: HSR/TIGET Pediatric Clinical Research Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy Hematology and BMT Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Napolitano
authors.affiliation: HSR/TIGET Pediatric Clinical Research Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy Hematology and BMT Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Maria Pia
authors.initials: MP
authors.lastname: Cicalese
authors.affiliation: Department of Cell and Developmental Biology, University College London, London, UK.
authors.forename: Francesco Saverio
authors.initials: FS
authors.lastname: Tedesco
authors.affiliation: Laboratory of Analysis and Rehabilitation of Motor Function, Division of Neurosciences, IRCCS San Raffaele Scientific Institute, Milan, Italy Stem Cell Laboratory, Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Nicastro
authors.affiliation: Experimental Hematology Unit, Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Maddalena
authors.initials: M
authors.lastname: Noviello
authors.affiliation: Institute of Inflammation and Repair, University of Manchester, Manchester, UK.
authors.forename: Urmas
authors.initials: U
authors.lastname: Roostalu
authors.affiliation: Department of Neurology, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Natali Sora
authors.affiliation: Department of Neurology, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Marina
authors.initials: M
authors.lastname: Scarlato
authors.affiliation: Unit of Orthopaedics, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: De Pellegrin
authors.affiliation: Stem Cell Laboratory, Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy Neuroradiology Department and Neuroradiology Research Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Godi
authors.affiliation: Hematology and BMT Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Serena
authors.initials: S
authors.lastname: Giuliani
authors.affiliation: Hematology and BMT Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Ciotti
authors.affiliation: Institute of Experimental Neurology (InSpe), Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Rossana
authors.initials: R
authors.lastname: Tonlorenzi
authors.affiliation: Institute of Experimental Neurology (InSpe), Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Isabella
authors.initials: I
authors.lastname: Lorenzetti
authors.affiliation: Institute of Experimental Neurology (InSpe), Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Rivellini
authors.affiliation: Department of Cell and Developmental Biology, University College London, London, UK.
authors.forename: Sara
authors.initials: S
authors.lastname: Benedetti
authors.affiliation: Laboratory of Analysis and Rehabilitation of Motor Function, Division of Neurosciences, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Gatti
authors.affiliation: Hematology and BMT Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Sarah
authors.initials: S
authors.lastname: Marktel
authors.affiliation: Immunogenetics Laboratory, Department of Immunohematology & Blood Transfusion, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Benedetta
authors.initials: B
authors.lastname: Mazzi
authors.affiliation: Laboratory of Analysis and Rehabilitation of Motor Function, Division of Neurosciences, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Tettamanti
authors.affiliation: Department of Cell and Developmental Biology, University College London, London, UK.
authors.forename: Martina
authors.initials: M
authors.lastname: Ragazzi
authors.affiliation: MolMed S.p.A., Milan, Italy.
authors.forename: Maria Adele
authors.initials: MA
authors.lastname: Imro
authors.affiliation: MolMed S.p.A., Milan, Italy.
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Marano
authors.affiliation: University San Raffaele Vita e Salute, Milan, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Ambrosi
authors.affiliation: Unit of Anesthesiology, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Rossana
authors.initials: R
authors.lastname: Fiori
authors.affiliation: Department of Health Sciences, University of Genoa, Genoa, Italy.
authors.forename: Maria Pia
authors.initials: MP
authors.lastname: Sormani
authors.affiliation: Experimental Hematology Unit, Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Bonini
authors.affiliation: Department of Radiology, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Venturini
authors.affiliation: Neuroradiology Department and Neuroradiology Research Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Letterio S
authors.initials: LS
authors.lastname: Politi
authors.affiliation: Stem Cell Laboratory, Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy giulio.cossu@manchester.ac.uk previtali.stefano@hsr.it yvan.torrente@unimi.it ciceri.fabio@hsr.it.
authors.forename: Yvan
authors.initials: Y
authors.lastname: Torrente
authors.affiliation: HSR/TIGET Pediatric Clinical Research Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy giulio.cossu@manchester.ac.uk previtali.stefano@hsr.it yvan.torrente@unimi.it ciceri.fabio@hsr.it.
authors.forename: Fabio
authors.initials: F
authors.lastname: Ciceri
mesh_terms: D064987:Cell- and Tissue-Based Therapy; D006650:Histocompatibility Testing; D006801:Humans; D007261:Infusions, Intra-Arterial / Q000706:statistics & numerical data*; D020388:Muscular Dystrophy, Duchenne / Q000601:surgery* / Q000628:therapy*
keywords: Duchenne; MRI; cell therapy; dystrophin; mesoangioblast