title: Histological effects of givinostat in boys with Duchenne muscular dystrophy.
abstract: Duchenne Muscular Dystrophy (DMD) is caused by mutations in the dystrophin gene leading to dystrophin deficiency, muscle fiber degeneration and progressive fibrotic replacement of muscles. Givinostat, a histone deacetylase (HDAC) inhibitor, significantly reduced fibrosis and promoted compensatory muscle regeneration in mdx mice. This study was conducted to evaluate whether the beneficial histological effects of Givinostat could be extended to DMD boys. Twenty ambulant DMD boys aged 7 to <11 years on stable corticosteroid treatment were enrolled in the study and treated for ≥12 months with Givinostat. A muscle biopsy was collected at the beginning and at the end of treatment to evaluate the amount of muscle and fibrotic tissue. Histological effects were the primary objectives of the study. Treatment with Givinostat significantly increased the fraction of muscle tissue in the biopsies and reduced the amount of fibrotic tissue. It also substantially reduced tissue necrosis and fatty replacement. Overall the drug was safe and tolerated. Improvement in functional tests was not observed in this study, but the sample size of the study was not sufficient to draw definitive conclusions. This study showed that treatment with Givinostat for more than 1 year significantly counteracted histological disease progression in ambulant DMD boys aged 7 to 10 years.
authors: Italfarmaco S.p.A., Milan, Italy. Electronic address: p.bettica@italfarmaco.com.
authors: Paolo
authors: P
authors: Bettica
authors: Research Laboratories, Confocal Microscopy Core Facility, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
authors: Stefania
authors: S
authors: Petrini
authors: Research Laboratories, Confocal Microscopy Core Facility, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
authors: Valentina
authors: V
authors: D'Oria
authors: Unit of Neuromuscular and Neurodegenerative Disorders, Laboratory of Molecular Medicine, Department of Neurosciences, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
authors: Adele
authors: A
authors: D'Amico
authors: Unit of Neuromuscular and Neurodegenerative Disorders, Laboratory of Molecular Medicine, Department of Neurosciences, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
authors: Michela
authors: M
authors: Catteruccia
authors: Department of Paediatric Neurology, Catholic University, Rome, Italy.
authors: Marika
authors: M
authors: Pane
authors: Department of Paediatric Neurology, Catholic University, Rome, Italy.
authors: Serena
authors: S
authors: Sivo
authors: Dino Ferrari Centre, Neuroscience Section, Department of Pathophysiology and Transplantation, Neurology Unit, IRCCS Foundation Ca'Granda Ospedale Maggiore Policlinico, University of Milan, Milan, Italy.
authors: Francesca
authors: F
authors: Magri
authors: Dino Ferrari Centre, Neuroscience Section, Department of Pathophysiology and Transplantation, Neurology Unit, IRCCS Foundation Ca'Granda Ospedale Maggiore Policlinico, University of Milan, Milan, Italy.
authors: Simona
authors: S
authors: Brajkovic
authors: Department of Neurosciences, University of Messina, Messina, Italy; NEMO SUD Clinical Centre for Neuromuscular Disorders, Messina, Italy.
authors: Sonia
authors: S
authors: Messina
authors: NEMO SUD Clinical Centre for Neuromuscular Disorders, Messina, Italy.
authors: Gian Luca
authors: GL
authors: Vita
authors: Italfarmaco S.p.A., Milan, Italy.
authors: Barbara
authors: B
authors: Gatti
authors: Neuromuscular and Rare Disease Unit, Department of Neuroscience, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Dino Ferrari Centre, University of Milan, Milan, Italy.
authors: Maurizio
authors: M
authors: Moggio
authors: Sanford-Burnham medical Research Institute, Sanford Children's Health Research Center, La Jolla, California, USA; IRCCS Fondazione Santa Lucia, Rome, Italy.
authors: Pier Lorenzo
authors: PL
authors: Puri
authors: Independent Consultant, Milan, Italy.
authors: Maurizio
authors: M
authors: Rocchetti
authors: Department of Electrical, Computer and Biomedical Engineering, University of Pavia, Pavia, Italy.
authors: Giuseppe
authors: G
authors: De Nicolao
authors: Department of Neurosciences, University of Messina, Messina, Italy; NEMO SUD Clinical Centre for Neuromuscular Disorders, Messina, Italy.
authors: Giuseppe
authors: G
authors: Vita
authors: Dino Ferrari Centre, Neuroscience Section, Department of Pathophysiology and Transplantation, Neurology Unit, IRCCS Foundation Ca'Granda Ospedale Maggiore Policlinico, University of Milan, Milan, Italy.
authors: Giacomo P
authors: GP
authors: Comi
authors: Unit of Neuromuscular and Neurodegenerative Disorders, Laboratory of Molecular Medicine, Department of Neurosciences, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
authors: Enrico
authors: E
authors: Bertini
authors: Department of Paediatric Neurology, Catholic University, Rome, Italy.
authors: Eugenio
authors: E
authors: Mercuri
mesh_terms: D000305:Adrenal Cortex Hormones / Q000627:therapeutic use; D002219:Carbamates / Q000009:adverse effects / Q000627:therapeutic use*; D002648:Child; D004305:Dose-Response Relationship, Drug; D056572:Histone Deacetylase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000473:pathology*; D020388:Muscular Dystrophy, Duchenne / Q000097:blood / Q000188:drug therapy* / Q000473:pathology*; D010976:Platelet Count; D016896:Treatment Outcome
chemical_list: D000305:Adrenal Cortex Hormones; D002219:Carbamates; D056572:Histone Deacetylase Inhibitors; C575255:givinostat
keywords: Clinical trial; Duchenne muscular dystrophy; Givinostat; Histology; Histone deacetylase inhibitor