title: Human adipose-derived mesenchymal stromal cells injected systemically into GRMD dogs without immunosuppression are able to reach the host muscle and express human dystrophin.
abstract: Duchenne muscular dystrophy (DMD), a lethal X-linked disorder, is the most common and severe form of muscular dystrophies, affecting 1 in 3,500 male births. Mutations in the DMD gene lead to the absence of muscle dystrophin and a progressive degeneration of skeletal muscle. The possibility  to treat DMD through cell therapy has been widely investigated. We have previously shown that human adipose-derived stromal cells (hASCs) injected systemically in SJL mice are able to reach and engraft in the host muscle, express human muscle proteins, and ameliorate the functional  performance of injected animals without any immunosuppression. However, before starting clinical trials in humans many questions still need to be addressed in preclinical studies, in particular in larger animal models, when available. The best animal model to address these questions is the  golden retriever muscular dystrophy (GRMD) dog that reproduces the full spectrum of human DMD. Affected animals carry a mutation that predicts a premature termination codon in exon 8 and a peptide that is 5% the size of normal dystrophin. These dogs present clinical signs within the first  weeks and most of them do not survive beyond age two. Here we show the results of local and intravenous injections of hASCs into GRMD dogs, without immunosuppression. We observed that hASCs injected systemically into the dog cephalic vein are able to reach, engraft, and express human dystrophin  in the host GRMD dystrophic muscle up to 6 months after transplantation. Most importantly, we demonstrated that injecting a huge quantity of human mesenchymal cells in a large-animal model, without immunosuppression, is a safe procedure, which may have important applications for future therapy  in patients with different forms of muscular dystrophies.
authors.affiliation: Human Genome Research Center, Biosciences Institute, University of São Paulo, São Paulo, Brazil.
authors.forename: N M
authors.initials: NM
authors.lastname: Vieira
authors.forename: M
authors.initials: M
authors.lastname: Valadares
authors.forename: E
authors.initials: E
authors.lastname: Zucconi
authors.forename: M
authors.initials: M
authors.lastname: Secco
authors.forename: C R
authors.initials: CR
authors.lastname: Bueno
authors.forename: V
authors.initials: V
authors.lastname: Brandalise
authors.forename: A
authors.initials: A
authors.lastname: Assoni
authors.forename: J
authors.initials: J
authors.lastname: Gomes
authors.forename: V
authors.initials: V
authors.lastname: Landini
authors.forename: T
authors.initials: T
authors.lastname: Andrade
authors.forename: H V A
authors.initials: HV
authors.lastname: Caetano
authors.forename: M
authors.initials: M
authors.lastname: Vainzof
authors.forename: M
authors.initials: M
authors.lastname: Zatz
mesh_terms: D000273:Adipose Tissue / Q000166:cytology*; D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004285:Dogs; D016189:Dystrophin / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D007165:Immunosuppression Therapy; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D020388:Muscular Dystrophy, Duchenne / Q000628:therapy*
chemical_list: D016189:Dystrophin