دورية
First-in-human in vivogenome editing via AAV-zinc-finger nucleases for mucopolysaccharidosis I/II and hemophilia B
| العنوان: | First-in-human in vivogenome editing via AAV-zinc-finger nucleases for mucopolysaccharidosis I/II and hemophilia B |
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| المؤلفون: | Harmatz, Paul, Prada, Carlos E., Burton, Barbara K., Lau, Heather, Kessler, Craig M., Cao, Liching, Falaleeva, Marina, Villegas, Andres G., Zeitler, Jennifer, Meyer, Kathleen, Miller, Weston, Wong Po Foo, Cheryl, Vaidya, Sagar, Swenson, Wendy, Shiue, Lisa H., Rouy, Didier, Muenzer, Joseph |
| المصدر: | Molecular Therapy; December 2022, Vol. 30 Issue: 12 p3587-3600, 14p |
| مستخلص: | Zinc-finger nuclease (ZFN)-based in vivogenome editing is a novel treatment that can potentially provide lifelong protein replacement with single intravenous administration. Three first-in-human open-label ascending single-dose phase 1/2 studies were performed in parallel (starting November 2017) primarily to assess safety and tolerability of ZFN in vivoediting therapy in mucopolysaccharidosis I (MPS I) (n = 3), MPS II (n = 9), and hemophilia B (n = 1). Treatment was well tolerated with no serious treatment-related adverse events. At the 1e13 vg/kg dose, evidence of genome editing was detected through albumin-transgene fusion transcripts in liver for MPS II (n = 2) and MPS I (n = 1) subjects. The MPS I subject also had a transient increase in leukocyte iduronidase activity to the lower normal range. At the 5e13 vg/kg dose, one MPS II subject had a transient increase in plasma iduronate-2-sulfatase approaching normal levels and one MPS I subject approached mid-normal levels of leukocyte iduronidase activity with no evidence of genome editing. The hemophilia B subject was not able to decrease use of factor IX concentrate; genome editing could not be assessed. Overall, ZFN in vivoediting therapy had a favorable safety profile with evidence of targeted genome editing in liver, but no long-term enzyme expression in blood. |
| قاعدة البيانات: | Supplemental Index |
| تدمد: | 15250016 15250024 |
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| DOI: | 10.1016/j.ymthe.2022.10.010 |