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

Paul Harmatz*, Carlos E. Prada, Barbara K. Burton, Heather Lau, Craig M. Kessler, Liching Cao, Marina Falaleeva, Andres G. Villegas, Jennifer Zeitler, Kathleen Meyer, Weston Miller, Cheryl Wong Po Foo, Sagar Vaidya, Wendy Swenson, Lisa H. Shiue, Didier Rouy, Joseph Muenzer

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

23 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)3587-3600
Number of pages14
JournalMolecular Therapy
Issue number12
StatePublished - Dec 7 2022


  • MPS I
  • MPS II
  • first-in-human
  • hemophilia
  • in vivo genome editing
  • mucopolysaccharidosis
  • zinc-finger nuclease

ASJC Scopus subject areas

  • Drug Discovery
  • Genetics
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology


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