title: Nitric oxide release combined with nonsteroidal antiinflammatory activity prevents muscular dystrophy pathology and enhances stem cell therapy.
abstract: Duchenne muscular dystrophy is a relatively common disease that affects skeletal muscle, leading to progressive paralysis and death. There is currently no resolutive therapy. We have developed a treatment in which we combined the effects of nitric oxide with nonsteroidal antiinflammatory activity by using HCT 1026, a nitric oxide-releasing derivative of flurbiprofen. Here, we report the results of long-term (1-year) oral treatment with HCT 1026 of two murine models for limb girdle and Duchenne muscular dystrophies (alpha-sarcoglycan-null and mdx mice). In both models, HCT 1026 significantly ameliorated the morphological, biochemical, and functional phenotype in the absence of secondary effects, efficiently slowing down disease progression. HCT 1026 acted by reducing inflammation, preventing muscle damage, and preserving the number and function of satellite cells. HCT 1026 was significantly more effective than the corticosteroid prednisolone, which was analyzed in parallel. As an additional beneficial effect, HCT 1026 enhanced the therapeutic efficacy of arterially delivered donor stem cells, by increasing 4-fold their ability to migrate and reconstitute muscle fibers. The therapeutic strategy we propose is not selective for a subset of mutations; it provides ground for immediate clinical experimentation with HCT 1026 alone, which is approved for use in humans; and it sets the stage for combined therapies with donor or autologous, genetically corrected stem cells.
authors.affiliation: Department of Experimental Medicine, University of Milano-Bicocca, 20052 Monza, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Brunelli
authors.forename: Clara
authors.initials: C
authors.lastname: Sciorati
authors.forename: Giuseppe
authors.initials: G
authors.lastname: D'Antona
authors.forename: Anna
authors.initials: A
authors.lastname: Innocenzi
authors.forename: Diego
authors.initials: D
authors.lastname: Covarello
authors.forename: Beatriz G
authors.initials: BG
authors.lastname: Galvez
authors.forename: Cristiana
authors.initials: C
authors.lastname: Perrotta
authors.forename: Angela
authors.initials: A
authors.lastname: Monopoli
authors.forename: Francesca
authors.initials: F
authors.lastname: Sanvito
authors.forename: Roberto
authors.initials: R
authors.lastname: Bottinelli
authors.forename: Ennio
authors.initials: E
authors.lastname: Ongini
authors.forename: Giulio
authors.initials: G
authors.lastname: Cossu
authors.forename: Emilio
authors.initials: E
authors.lastname: Clementi
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D003131:Combined Modality Therapy; D003402:Creatine Kinase / Q000097:blood; D005480:Flurbiprofen / Q000031:analogs & derivatives* / Q000494:pharmacology; D051379:Mice; D018482:Muscle, Skeletal / Q000187:drug effects / Q000503:physiopathology; D009137:Muscular Dystrophy, Animal / Q000473:pathology / Q000628:therapy*; D020388:Muscular Dystrophy, Duchenne / Q000473:pathology / Q000628:therapy*; D020030:Nitric Oxide Donors / Q000627:therapeutic use*; D011239:Prednisolone / Q000494:pharmacology; D012038:Regeneration / Q000187:drug effects; D049031:Sarcoglycans / Q000502:physiology; D033581:Stem Cell Transplantation
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D020030:Nitric Oxide Donors; D049031:Sarcoglycans; C095631:nitroflurbiprofen; D005480:Flurbiprofen; D011239:Prednisolone; D003402:Creatine Kinase