title: Multi-parametric MRI at 14T for muscular dystrophy mice treated with AAV vector-mediated gene therapy.
abstract: The objective of this study was to investigate the efficacy of using quantitative magnetic resonance imaging (MRI) as a non-invasive tool for the monitoring of gene therapy for muscular dystrophy. The clinical investigations for this family of diseases often involve surgical biopsy which limits the amount of information that can be obtained due to the invasive nature of the procedure. Thus, other non-invasive tools may provide more opportunities for disease assessment and treatment responses. In order to explore this, dystrophic mdx4cv mice were systemically treated with a recombinant adeno-associated viral (AAV) vector containing a codon-optimized micro-dystrophin gene. Multi-parametric MRI of T2, magnetization transfer, and diffusion effects alongside 3-D volume measurements were then utilized to monitor disease/treatment progression. Mice were imaged at 10 weeks of age for pre-treatment, then again post-treatment at 8, 16, and 24 week time points. The efficacy of treatment was assessed by physiological assays for improvements in function and quantification of expression. Tissues from the hindlimbs were collected for histological analysis after the final time point for comparison with MRI results. We found that introduction of the micro-dystrophin gene restored some aspects of normal muscle histology and pathology such as decreased necrosis and resistance to contraction-induced injury. T2 relaxation values showed percentage decreases across all muscle types measured (tibialis anterior, gastrocnemius, and soleus) when treated groups were compared to untreated groups. Additionally, the differences between groups were statistically significant for the tibialis anterior as well. The diffusion measurements showed a wider range of percentage changes and less statistical significance while the magnetization transfer effect measurements showed minimal change. MR images displayed hyper-intense regions of muscle that correlated with muscle pathology in histological sections. T2 relaxation, alongside diffusion and magnetization transfer effects provides useful data towards the goal of non-invasively monitoring the treatment of muscular dystrophy.
authors: Department of Radiology, University of Washington, Seattle, Washington, United States of America.
authors: Joshua
authors: J
authors: Park
authors: Department of Neurology, University of Washington, Seattle, Washington, United States of America.
authors: Jacqueline
authors: J
authors: Wicki
authors: Comparative Medicine Shared Resources, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors: Sue E
authors: SE
authors: Knoblaugh
authors: Department of Neurology, University of Washington, Seattle, Washington, United States of America; Department of Biochemistry, University of Washington, Seattle, Washington, United States of America; Department of Medicine, University of Washington, Seattle, Washington, United States of America.
authors: Jeffrey S
authors: JS
authors: Chamberlain
authors: Department of Radiology, University of Washington, Seattle, Washington, United States of America.
authors: Donghoon
authors: D
authors: Lee
mesh_terms: D000818:Animals; D003402:Creatine Kinase / Q000097:blood; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D016189:Dystrophin / Q000235:genetics; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics; D007091:Image Processing, Computer-Assisted; D008279:Magnetic Resonance Imaging / Q000379:methods*; D051379:Mice; D018101:Mice, Inbred mdx; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000502:physiology; D009137:Muscular Dystrophy, Animal / Q000235:genetics* / Q000473:pathology / Q000628:therapy*
chemical_list: D016189:Dystrophin; D003402:Creatine Kinase