Gene therapy with adeno-associated viral vectors to increase bone XYLT2 (xylosyl transferase 2) increases bone density in mice — ASN Events
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Gene therapy with adeno-associated viral vectors to increase bone XYLT2 (xylosyl transferase 2) increases bone density in mice (#324)

Nicholas Dwyer 1
  1. CDOER, WIMR, The University of Sydney, Riverview, NSW, Australia

Nicholas Dwyer, Alexandra O’Donohue, Julian Chu, Nicholas Norris, Aaron Schindeler, Jenny Gunton

Homozygous XYLT2 (xylosyl-transferase 2) mutations in humans cause a brittle-bone disorder called spondylo-occular syndrome, complicated by multiple minimal-trauma fractures. This project investigated the safety and effects of increasing human-XYLT2 in bones in mice.

METHODS: Recombinant adeno-associated viral vectors were used as control (control-AAV) or expressing human XYLT2 under control of bone-promoters (AAV-XYLT2) were injected intraperitoneally into mice at 8w. Mice were followed for 6-months with dual energy X-ray absorptiometry (DEXA). At sacrifice, bones were collected for micro-CT and mechanical load-testing. In this study, 6 controls and 9 AAV-XYLT2 mice were studied.

RESULTS: Mice treated with control-AAV or XYLT2-AAV gained weight as usual, without significant difference between groups. Mice continue to grow, and consistent with that, bone mineral density measured by DEXA increased over 6 months in the controls from 0.073 to 0.077, an increase of 5.4%. In the XYLT2-AAV group, bone density increased from 0.072 to 0.082, an increase of 13.8%, p=0.01.

There were no significant differences on micro-CT between groups, with numerically higher values in the XYLT2-AAV group at both spines and tibiae. There were no differences in mechanical load test to failure for the spines (medians 43 and 43) or the tibiae (median control-AAV 14.0 versus XYLT-AAV 13.3).

CONCLUSIONS: AAV-mediated increase in XYLT2 in bone significantly increased bone density over 6 months. However, tThere were no significant differences in load strength or microCT analysis. DEXA data was serially tested, and paired testing provides greater statistical power. Usual group numbers for micro-CT and load testing are at least 12 /group for adequate statistical power. A second cohort of mice to increase N is currently approaching 6 months.

Expressing human XYLT2 in bone appears safe, and caused significant increase in bone density in mice with normal XYLT2.