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. 2022 Dec 7;30(12):3587-3600.
doi: 10.1016/j.ymthe.2022.10.010. Epub 2022 Oct 25.

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

Paul Harmatz  1 , Carlos E Prada  2 , Barbara K Burton  3 , Heather Lau  4 , Craig M Kessler  5 , Liching Cao  6 , Marina Falaleeva  6 , Andres G Villegas  6 , Jennifer Zeitler  6 , Kathleen Meyer  6 , Weston Miller  6 , Cheryl Wong Po Foo  6 , Sagar Vaidya  6 , Wendy Swenson  6 , Lisa H Shiue  6 , Didier Rouy  6 , Joseph Muenzer  7
Affiliations

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

Paul Harmatz et al. Mol Ther. .

Abstract

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.

Trial registration: ClinicalTrials.gov NCT03041324 NCT02702115 NCT02695160.

Keywords: MPS I; MPS II; first-in-human; hemophilia; in vivo genome editing; mucopolysaccharidosis; zinc-finger nuclease.

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Conflict of interest statement

Declaration of interest Marina Falaleeva, Andres G. Villegas, Jennifer Zeitler, Kathleen Meyer, Wendy Swenson, and Lisa Shiue are employees and stockholders of Sangamo Therapeutics, Inc. Didier Rouy is a former employee of Sangamo Therapeutics, Inc. Liching Cao is an employee of Sangamo Therapeutics, Inc. and has a patent pending (16/534,483; WO 2020/05947; US 2020/0071743) for enzymatic assays supporting MPS studies. Cheryl Wong Po Foo is a former employee of Sangamo Therapeutics, Inc., and a current employee of Astellas Gene Therapies. Sagar Vaidya is a former employee of Sangamo Therapeutics, Inc., and has a patent pending for “Method for the treatment of mucopolysaccharidosis type II” and is a current employee of Travere Therapeutics. Weston Miller is a former employee of Sangamo Therapeutics, Inc., owns stock in Sangamo Therapeutics, Inc., and is a full-time employee of Astellas Gene Therapies. Paul Harmatz has received writing support, clinical trial support, and/or consulting fees from Sangamo Therapeutics, Inc., BioMarin Pharmaceutical Inc., Takeda/Shire, REGENXBIO, Denali Therapeutics Inc., Inventiva Pharma, QED Therapeutics, Ascendis Pharma, Orphazyme, Ultragenyx Pharmaceutical, Amicus, Aeglea BioTheraeutics, Homology, JCR Pharmaceuticals, Ltd, Paradigm, Audentes Therapeutics, and Chiesi; has received registry support from Genzyme, BioMarin Pharmaceutical Inc., and Shire (Takeda). Barbara Burton has served as a consultant for Biomarin, Shire (Takeda), Denali Therapeutics Inc., Genzyme, Ultragenyx, Moderna, Aeglea, Horizon, Alexion, Inventiva, Applied Therapeutics, SIO, and JCR Pharmaceuticals Co., Ltd. She has received clinical trial funding from Biomarin, Shire (Takeda), Ultragenyx, Sangamo Therapeutics, Inc., and Homology Medicines. Carlos Prada has served as a consultant for Sanofi-Genzyme and Shire (Takeda). Heather Lau is an employee of Ultragenyx Pharmaceutical, Inc., and reports grants and non-financial support from Sangamo Therapeutics, Inc.(.), during the conduct of the study. Outside the submitted work, Dr. Lau reports personal fees from Actelion, Ltd.; grants and personal fees from Amicus Therapeutics; grants and personal fees from Biomarin Pharmaceutical, Inc.; personal fees from Chiesi; grants from Denali Therapeutics, Inc.; grants from Mallinckrodt Pharmaceuticals; grants and personal fees from Orphazyme; grants from Intrabio, Ltd.; grants, personal fees, and non-financial support from Sanofi; grants, personal fees, and non-financial support from Takeda; grants, personal fees, non-financial support, and other from Ultragenyx Pharmaceutical, Inc.; grants from Pfizer, Inc.; grants and personal fees from Prevail Therapeutics, Inc.; grants, personal fees, and non-financial support from Aspa Therapeutics; grants from Protalix BioTherapeutics; personal fees and other from National Gaucher Foundation; personal fees from Taysha Therapeutics; personal fees and other from Muscular Disease Association; personal fees and other from National Fabry Disease Foundation; personal fees and other from MPS Society; grants, personal fees, and other from Adult Polyglucosan Body Disorder Disease Foundation; personal fees and other from National Fabry Disease Foundation; and grants, personal fees and other from National Tay Sachs and Allied Disease Foundation. Craig Kessler has served as an advisory board participant with an honorarium from Sangamo Therapeutics, Inc., and his university has received support from Sangamo Therapeutics, Inc., for clinical gene therapy research. He has also served as chair, DSMB for a FVIII gene therapy trial with Bayer. Joseph Muenzer has served as a principal investigator for Takeda clinical trials, received travel and speaking fees to speak at Takeda meetings, and served on Takeda advisory boards. He has participated in advisory boards and consulted for Genzyme, Bluebird Bio, Inc., Denali Therapeutics, Inc., and served as a consultant for REGENXBIO.

Figures

None
Graphical abstract
Figure 1
Figure 1
Enzyme, substrate, and ALT levels for study SB-913-1602 (MPS II) Notes: ALT, alanine aminotransferase; ERT, enzyme replacement therapy; GAG, glycosaminoglycan; HS, heparan sulfate; I2S, iduronate-2-sulfatase; ZFN in vivo editing, zinc-finger nuclease-based in vivo genome editing. Numbers indicate days post-ERT administration. Maximum plasma ALT level is labeled relative to study day in red. Data on dermatan sulfate (DS) and total GAGs (T-GAG) are presented in Figure S3. The lower limit of quantitation for this quantitative method was 0.78 nmol/mL/h of I2S enzyme activity.
Figure 2
Figure 2
Enzyme, substrate, and ALT levels for study SB-318-1502 (MPS I) Notes: ALT, alanine aminotransferase; ERT, enzyme replacement therapy; GAG, glycosaminoglycan; HS, heparan sulfate; iduronidase, α-L-iduronidase; ZFN in vivo editing, zinc-finger nuclease-based in vivo genome editing. Numbers indicate days post-ERT administration. Maximum plasma ALT level is labeled relative to study day in red. Leukocyte iduronidase activity was measured by a validated diagnostic test. Data on dermatan sulfate (DS) and total GAGs (T-GAG) are presented in Figure S4.
Figure 3
Figure 3
Enzyme and ALT levels for study SB-FIX-1501 (hemophilia B) Notes: ALT, alanine aminotransferase; FIX, factor IX; ZFN in vivo editing, zinc-finger nuclease-based in vivo genome editing. Numbers indicate days post-FIX administration.
Figure 4
Figure 4
Enzyme, substrate, and ALT levels for subject 6 in study SB-913-1602 (MPS II) Notes: ALT, alanine aminotransferase (normal: 7–55 U/L); ERT, enzyme replacement therapy; GAG, glycosaminoglycan; HS, heparan sulfate; I2S, iduronate-2-sulfatase; ZFN in vivo editing, zinc-finger nuclease-based in vivo genome editing. Numbers indicate days post-ERT administration. Maximum plasma ALT level is labeled relative to study day in red. Data on dermatan sulfate (DS) and total GAGs (T-GAG) are presented in Figure S3.
Figure 5
Figure 5
Clinical design schematics of the three clinical studies (A) Study SB-913-1602. (B) Study SB-318-1502. (C) Study SB-FIX-1501. NAbs, neutralizing antibodies to the AAV6 capsid; SMC, safety monitoring committee; SNPs, single-nucleotide polymorphisms.
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