EMBO Molecular Medicine (Nov 2015)
Intra‐arterial transplantation of HLA‐matched donor mesoangioblasts in Duchenne muscular dystrophy
- Giulio Cossu,
- Stefano C Previtali,
- Sara Napolitano,
- Maria Pia Cicalese,
- Francesco Saverio Tedesco,
- Francesca Nicastro,
- Maddalena Noviello,
- Urmas Roostalu,
- Maria Grazia Natali Sora,
- Marina Scarlato,
- Maurizio De Pellegrin,
- Claudia Godi,
- Serena Giuliani,
- Francesca Ciotti,
- Rossana Tonlorenzi,
- Isabella Lorenzetti,
- Cristina Rivellini,
- Sara Benedetti,
- Roberto Gatti,
- Sarah Marktel,
- Benedetta Mazzi,
- Andrea Tettamanti,
- Martina Ragazzi,
- Maria Adele Imro,
- Giuseppina Marano,
- Alessandro Ambrosi,
- Rossana Fiori,
- Maria Pia Sormani,
- Chiara Bonini,
- Massimo Venturini,
- Letterio S Politi,
- Yvan Torrente,
- Fabio Ciceri
Affiliations
- Giulio Cossu
- Institute of Inflammation and Repair, University of Manchester
- Stefano C Previtali
- Institute of Experimental Neurology (InSpe), Division of Neuroscience, IRCCS San Raffaele Scientific Institute
- Sara Napolitano
- HSR/TIGET Pediatric Clinical Research Unit, IRCCS San Raffaele Scientific Institute
- Maria Pia Cicalese
- HSR/TIGET Pediatric Clinical Research Unit, IRCCS San Raffaele Scientific Institute
- Francesco Saverio Tedesco
- Department of Cell and Developmental Biology, University College London
- Francesca Nicastro
- Laboratory of Analysis and Rehabilitation of Motor Function, Division of Neurosciences, IRCCS San Raffaele Scientific Institute
- Maddalena Noviello
- Experimental Hematology Unit, Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute
- Urmas Roostalu
- Institute of Inflammation and Repair, University of Manchester
- Maria Grazia Natali Sora
- Department of Neurology, IRCCS San Raffaele Scientific Institute
- Marina Scarlato
- Department of Neurology, IRCCS San Raffaele Scientific Institute
- Maurizio De Pellegrin
- Unit of Orthopaedics, IRCCS San Raffaele Scientific Institute
- Claudia Godi
- Stem Cell Laboratory, Department of Pathophysiology and Transplantation, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano
- Serena Giuliani
- Hematology and BMT Unit, IRCCS San Raffaele Scientific Institute
- Francesca Ciotti
- Hematology and BMT Unit, IRCCS San Raffaele Scientific Institute
- Rossana Tonlorenzi
- Institute of Experimental Neurology (InSpe), Division of Neuroscience, IRCCS San Raffaele Scientific Institute
- Isabella Lorenzetti
- Institute of Experimental Neurology (InSpe), Division of Neuroscience, IRCCS San Raffaele Scientific Institute
- Cristina Rivellini
- Institute of Experimental Neurology (InSpe), Division of Neuroscience, IRCCS San Raffaele Scientific Institute
- Sara Benedetti
- Department of Cell and Developmental Biology, University College London
- Roberto Gatti
- Laboratory of Analysis and Rehabilitation of Motor Function, Division of Neurosciences, IRCCS San Raffaele Scientific Institute
- Sarah Marktel
- Hematology and BMT Unit, IRCCS San Raffaele Scientific Institute
- Benedetta Mazzi
- Immunogenetics Laboratory, Department of Immunohematology & Blood Transfusion, IRCCS San Raffaele Scientific Institute
- Andrea Tettamanti
- Laboratory of Analysis and Rehabilitation of Motor Function, Division of Neurosciences, IRCCS San Raffaele Scientific Institute
- Martina Ragazzi
- Department of Cell and Developmental Biology, University College London
- Maria Adele Imro
- MolMed S.p.A.
- Giuseppina Marano
- MolMed S.p.A.
- Alessandro Ambrosi
- University San Raffaele Vita e Salute
- Rossana Fiori
- Unit of Anesthesiology, IRCCS San Raffaele Scientific Institute
- Maria Pia Sormani
- Department of Health Sciences, University of Genoa
- Chiara Bonini
- Experimental Hematology Unit, Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute
- Massimo Venturini
- Department of Radiology, IRCCS San Raffaele Scientific Institute
- Letterio S Politi
- Neuroradiology Department and Neuroradiology Research Unit, IRCCS San Raffaele Scientific Institute
- Yvan Torrente
- Stem Cell Laboratory, Department of Pathophysiology and Transplantation, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano
- Fabio Ciceri
- HSR/TIGET Pediatric Clinical Research Unit, IRCCS San Raffaele Scientific Institute
- DOI
- https://doi.org/10.15252/emmm.201505636
- Journal volume & issue
-
Vol. 7,
no. 12
pp. 1513 – 1528
Abstract
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.
Keywords