Short-term treatment of golden retriever muscular dystrophy (GRMD) dogs with rAAVrh74.MCK.GALGT2 induces muscle glycosylation and utrophin expression but has no significant effect on muscle strength

We have examined the effects of intravenous (IV) delivery of
rAAVrh74.MHCK7.GALGT2 in the golden retriever muscular dystrophy (GRMD)
model of Duchenne Muscular Dystrophy (DMD). After baseline testing, GRMD
dogs were treated at 3 months of age and reassessed at 6 months. This 3-6
month age range is a period of rapid disease progression, thus offering a
relatively short window to establish treatment efficacy.
 Measures analyzed included muscle AAV transduction, GALGT2
transgene expression, GALGT2-induced glycosylation, muscle pathology, and
muscle function.  A total of five dogs were treated, 4 at
2x1014vg/kg and one at 6x1014vgkg. The 2x1014vg/kg dose led to
transduction of regions of the heart with 1-3 vector genomes (vg) per
nucleus, while most skeletal muscles were transduced with
0.25-0.5vg/nucleus. GALGT2-induced glycosylation paralleled levels of
myofiber vg transduction, with about 90% of cardiomyocytes having
increased glycosylation versus 20-35% of all myofibers across the skeletal
muscles tested. Conclusions from phenotypic testing were limited by the
small number of dogs. Treated dogs had less pronounced fibrosis and
overall lesion severity when compared to control groups, but surprisingly
no significant changes in limb muscle function measures.
 GALGT2-treated skeletal muscle and heart had elevated levels of
utrophin protein expression and GALGT2-induced expression of glycosylated
a dystroglycan, providing further evidence of a treatment effect.
 No abnormalities were seen on serum chemistry, hematology, and
cardiac testing, suggesting short-term safety. Cumulatively, these data
show that short-term intravenous treatment of GRMD dogs with
rAAVrh74.MHCK7.GALGT2 at high doses can induce muscle glycosylation and
utrophin expression and may be safe over a short 3-month interval, but
that such treatments have only modest effects on muscle pathology and do
not significantly improve muscle strength.