A Simplified Immune Suppression Scheme Leads to Persistent Micro-dystrophin Expression in Duchenne Muscular Dystrophy Dogs
Year: 2011
Type: article
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 2.85×1012 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. Shin and colleagues develop and test a novel immune suppression scheme to allow for successful recombinant adeno-associated virus (AAV)-mediated microdystrophin gene transfer to dystrophic dogs. This shorter, simplified scheme uses readily available drugs such as cyclosporine and mycophenolate, administered over the course of 5 weeks. Adult dystrophic dog limb muscles injected with AAV encoding a canine dystrophin microgene under the new immune suppression protocol show sustained transduction for nearly half a year.
Source: Human Gene Therapy
DOI: 10.1089/hum.2011.147
Institutions: University of Missouri, University of Florida, Auburn University
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W1963954114