Ms. Christiana Salami, Ms. Katie Jackson, Ms. Clarisse L. Jose, Mr. Laith Alyass, Mr. Georges-Ibrahim Cisse, Dr. Bishnu P De, Dr. Katie Stiles, Dr. Maria J. Chiuchiolo, Dr. Dolan Sondhi, Dr. Ronald G Crystal, and Dr. Stephen M. Kaminsky. Human Gene Therapy. Ahead of print doi:10.1089/hum.2019.363
The study was designed to create a mouse model for early FA disease relevant to the time for which a gene therapy would likely be most effective. To generate a cardiac-specific mouse model of FA cardiomyopathy similar to the human disease, we used a cardiac promoter (αMyhc) driving Cre-recombinase cardiac-specific excision of FXN exon 4 to generate a mild cardiac-specific FA model that is normal at rest but exhibits the cardiac phenotype with stress.
A one-time intravenous administration of 1011 genome copies of AAVrh.10hFXN, an adeno-associated virus serotype rh10 gene transfer vector expressing human FXN, corrected the stress-induced ejection fraction and fractional shortening phenotypes. Treated αMyhc mice exhibited exercise performance on a treadmill indistinguishable from littermate controls. These αMyhc mice provide an ideal model to study long-term cardiac complications due to FA and AAV-mediated gene therapy correction of stress-induced cardiac phenotypes typical of human FA.
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