Adaptive Immune Response Impairs the Efficacy of Autologous Transplantation of Engineered Stem Cells in Dystrophic Dogs

Clementina Sitzia, Andrea Farini, Luciana Jardim, Paola Razini, Marzia Belicchi, Letizia Cassinelli, Chiara Villa, Silvia Erratico, Daniele Parolini, Pamela Bella, Joao Carlos da Silva Bizario, Luis Garcia, Marcelo Dias-Baruffi, Mirella Meregalli, Yvan Torrente

Research output: Contribution to journalArticlepeer-review

Abstract

Duchenne muscular dystrophy is the most common genetic muscular dystrophy. It is caused by mutations in the dystrophin gene, leading to absence of muscular dystrophin and to progressive degeneration of skeletal muscle. We have demonstrated that the exon skipping method safely and efficiently brings to the expression of a functional dystrophin in dystrophic CD133+ cells injected scid/mdx mice. Golden Retriever muscular dystrophic (GRMD) dogs represent the best preclinical model of Duchenne muscular dystrophy, mimicking the human pathology in genotypic and phenotypic aspects. Here, we assess the capacity of intra-arterial delivered autologous engineered canine CD133+ cells of restoring dystrophin expression in Golden Retriever muscular dystrophy. This is the first demonstration of five-year follow up study, showing initial clinical amelioration followed by stabilization in mild and severe affected Golden Retriever muscular dystrophy dogs. The occurrence of T-cell response in three Golden Retriever muscular dystrophy dogs, consistent with a memory response boosted by the exon skipped-dystrophin protein, suggests an adaptive immune response against dystrophin.Molecular Therapy (2016); doi:10.1038/mt.2016.163.

Original languageEnglish
Pages (from-to)1949-1964
Number of pages16
JournalMolecular Therapy
Volume24
Issue number11
DOIs
Publication statusPublished - 2016

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery

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