In:
PLOS ONE, Public Library of Science (PLoS), Vol. 16, No. 3 ( 2021-3-26), p. e0248721-
Abstract:
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 2x10 14 vg/kg and one at 6x10 14 vgkg. The 2x10 14 vg/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 α dystroglycan, providing further evidence of a treatment effect. Serum chemistry, hematology, and cardiac function measures were largely unchanged by treatment. 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 had only modest effects on muscle pathology and did not significantly improve muscle strength.
Type of Medium:
Online Resource
ISSN:
1932-6203
DOI:
10.1371/journal.pone.0248721
DOI:
10.1371/journal.pone.0248721.g001
DOI:
10.1371/journal.pone.0248721.g002
DOI:
10.1371/journal.pone.0248721.g003
DOI:
10.1371/journal.pone.0248721.g004
DOI:
10.1371/journal.pone.0248721.g005
DOI:
10.1371/journal.pone.0248721.g006
DOI:
10.1371/journal.pone.0248721.t001
DOI:
10.1371/journal.pone.0248721.t002
DOI:
10.1371/journal.pone.0248721.s001
DOI:
10.1371/journal.pone.0248721.s002
DOI:
10.1371/journal.pone.0248721.s003
DOI:
10.1371/journal.pone.0248721.s004
DOI:
10.1371/journal.pone.0248721.s005
DOI:
10.1371/journal.pone.0248721.s006
Language:
English
Publisher:
Public Library of Science (PLoS)
Publication Date:
2021
detail.hit.zdb_id:
2267670-3
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