First-in-human in vivo genome editing via AAV-zinc-finger nucleases for mucopolysaccharidosis I/II and hemophilia B

• Published in: Molecular therapy Vol. 30; no. 12; pp. 3587 - 3600
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 07.12.2022; American Society of Gene & Cell Therapy
• Subjects: first-in-human; hemophilia; Humans; in vivo genome editing; MPS I; MPS II; mucopolysaccharidosis; Original; Zinc Finger Nucleases; zinc-finger nuclease; hemophilia; MPS II; zinc-finger nuclease; first-in-human; in vivo genome editing; mucopolysaccharidosis; MPS I
• ISSN: 1525-0016; 1525-0024; 1525-0024
• DOI: 10.1016/j.ymthe.2022.10.010

Zinc-finger nuclease (ZFN)-based in vivo genome 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 vivo editing 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 vivo editing therapy had a favorable safety profile with evidence of targeted genome editing in liver, but no long-term enzyme expression in blood. [Display omitted] In these first-in-human studies, ZFN in vivo editing had a favorable safety profile with evidence of targeted genome editing, but no long-term sustained enzyme expression, for subjects with MPS I, MPS II, and hemophilia B at doses up to 5e13 vg/kg.