Nitric oxide release combined with nonsteroidal antiinflammatory activity prevents muscular dystrophy pathology and enhances stem cell therapy.
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.
Brunelli
Silvia
S
Department of Experimental Medicine, University of Milano-Bicocca, 20052 Monza, Italy.
Sciorati
Clara
C
D'Antona
Giuseppe
G
Innocenzi
Anna
A
Covarello
Diego
D
Galvez
Beatriz G
BG
Perrotta
Cristiana
C
Monopoli
Angela
A
Sanvito
Francesca
F
Bottinelli
Roberto
R
Ongini
Ennio
E
Cossu
Giulio
G
Clementi
Emilio
E
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
D000894:Anti-Inflammatory Agents, Non-Steroidal; D020030:Nitric Oxide Donors; D049031:Sarcoglycans; C095631:nitroflurbiprofen; D005480:Flurbiprofen; D011239:Prednisolone; D003402:Creatine Kinase