A simplified immune suppression scheme leads to persistent micro-dystrophin expression in Duchenne muscular dystrophy dogs

Hum Gene Ther. 2012 Feb;23(2):202-9. doi: 10.1089/hum.2011.147. Epub 2011 Dec 14.

Abstract

Highly abbreviated micro-dystrophin genes have been intensively studied for Duchenne muscular dystrophy (DMD) gene therapy. Following adeno-associated virus (AAV) gene transfer, robust microgene expression is achieved in murine DMD models in the absence of immune suppression. Interestingly, a recent study suggests that AAV gene transfer in dystrophic dogs may require up to 18 weeks' immune suppression using a combination of three different immune-suppressive drugs (cyclosporine, mycophenolate mofetil, and anti-dog thymocyte globulin). Continued immune suppression is not only costly but also may cause untoward reactions. Further, some of the drugs (such as anti-dog thymocyte globulin) are not readily available. To overcome these limitations, we developed a novel 5-week immune suppression scheme using only cyclosporine and mycophenolate mofetil. AAV vectors (either AV.RSV.AP that expresses the heat-resistant human alkaline phosphatase gene, or AV.CMV.μDys that expresses the canine R16-17/H3/ΔC microgene) at 2.85×10(12) vg particles were injected into adult dystrophic dog limb muscles under the new immune suppression protocol. Sustained transduction was observed for nearly half year (the end of the study). The simplified immune suppression strategy described here may facilitate preclinical studies in the dog model.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antilymphocyte Serum / administration & dosage
  • Cyclosporine / administration & dosage
  • Dependovirus / genetics*
  • Disease Models, Animal
  • Dogs
  • Dystrophin / genetics*
  • Dystrophin / immunology
  • Female
  • Gene Expression
  • Genetic Therapy*
  • Genetic Vectors
  • Humans
  • Immunosuppression
  • Immunosuppressive Agents / administration & dosage*
  • Injections, Intramuscular
  • Male
  • Mice
  • Muscle, Skeletal / metabolism*
  • Muscle, Skeletal / pathology
  • Muscular Dystrophy, Duchenne / immunology
  • Muscular Dystrophy, Duchenne / pathology
  • Muscular Dystrophy, Duchenne / therapy*
  • Mycophenolic Acid / administration & dosage
  • Mycophenolic Acid / analogs & derivatives
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism
  • Transgenes

Substances

  • Antilymphocyte Serum
  • Dystrophin
  • Immunosuppressive Agents
  • Cyclosporine
  • Mycophenolic Acid