Lentivector cryptic splicing mediates increase in CD34+ clones expressing truncated HMGA2 in human X-linked severe combined immunodeficiency

Suk See Ravin (), Siyuan Liu, Colin L. Sweeney, Julie Brault, Narda Whiting-Theobald, Michelle Ma, Taylor Liu, Uimook Choi, Janet Lee, Sandra Anaya O’Brien, Priscilla Quackenbush, Tyra Estwick, Anita Karra, Ethan Docking, Nana Kwatemaa, Shuang Guo, Ling Su, Zhonghe Sun, Sheng Zhou, Jennifer Puck, Morton J. Cowan, Luigi D. Notarangelo, Elizabeth Kang, Harry L. Malech () and Xiaolin Wu ()
Additional contact information
Suk See Ravin: Laboratory of Clinical Immunology and Microbiology, NIAID, NIH
Siyuan Liu: Cancer Research Technology Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research
Colin L. Sweeney: Laboratory of Clinical Immunology and Microbiology, NIAID, NIH
Julie Brault: Laboratory of Clinical Immunology and Microbiology, NIAID, NIH
Narda Whiting-Theobald: Laboratory of Clinical Immunology and Microbiology, NIAID, NIH
Michelle Ma: Laboratory of Clinical Immunology and Microbiology, NIAID, NIH
Taylor Liu: Laboratory of Clinical Immunology and Microbiology, NIAID, NIH
Uimook Choi: Laboratory of Clinical Immunology and Microbiology, NIAID, NIH
Janet Lee: Laboratory of Clinical Immunology and Microbiology, NIAID, NIH
Sandra Anaya O’Brien: Laboratory of Clinical Immunology and Microbiology, NIAID, NIH
Priscilla Quackenbush: Laboratory of Clinical Immunology and Microbiology, NIAID, NIH
Tyra Estwick: Laboratory of Clinical Immunology and Microbiology, NIAID, NIH
Anita Karra: Laboratory of Clinical Immunology and Microbiology, NIAID, NIH
Ethan Docking: Laboratory of Clinical Immunology and Microbiology, NIAID, NIH
Nana Kwatemaa: Laboratory of Clinical Immunology and Microbiology, NIAID, NIH
Shuang Guo: Cancer Research Technology Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research
Ling Su: Cancer Research Technology Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research
Zhonghe Sun: Cancer Research Technology Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research
Sheng Zhou: Experimental Cell Therapeutics Lab, St. Jude Children’s Research Hospital
Jennifer Puck: Division of Allergy Immunology and Blood and Marrow Transplantation, Department of Pediatrics, University of California San Francisco and UCSF Benioff Children’s Hospital
Morton J. Cowan: Division of Allergy Immunology and Blood and Marrow Transplantation, Department of Pediatrics, University of California San Francisco and UCSF Benioff Children’s Hospital
Luigi D. Notarangelo: Laboratory of Clinical Immunology and Microbiology, NIAID, NIH
Elizabeth Kang: Laboratory of Clinical Immunology and Microbiology, NIAID, NIH
Harry L. Malech: Laboratory of Clinical Immunology and Microbiology, NIAID, NIH
Xiaolin Wu: Laboratory of Clinical Immunology and Microbiology, NIAID, NIH

Nature Communications, 2022, vol. 13, issue 1, 1-15

Abstract: Abstract X-linked Severe Combined Immunodeficiency (SCID-X1) due to IL2RG mutations is potentially fatal in infancy where ‘emergency’ life-saving stem cell transplant may only achieve incomplete immune reconstitution following transplant. Salvage therapy SCID-X1 patients over 2 years old (NCT01306019) is a non-randomized, open-label, phase I/II clinical trial for administration of lentiviral-transduced autologous hematopoietic stem cells following busulfan (6 mg/kg total) conditioning. The primary and secondary objectives assess efficacy in restoring immunity and safety by vector insertion site analysis (VISA). In this ongoing study (19 patients treated), we report VISA in blood lineages from first eight treated patients with longer follow up found a > 60-fold increase in frequency of forward-orientated VIS within intron 3 of the High Mobility Group AT-hook 2 gene. All eight patients demonstrated emergence of dominant HMGA2 VIS clones in progenitor and myeloid lineages, but without disturbance of hematopoiesis. Our molecular analysis demonstrated a cryptic splice site within the chicken β-globin hypersensitivity 4 insulator element in the vector generating truncated mRNA transcripts from many transcriptionally active gene containing forward-oriented intronic vector insert. A two base-pair change at the splice site within the lentiviral vector eliminated splicing activity while retaining vector functional capability. This highlights the importance of functional analysis of lentivectors for cryptic splicing for preclinical safety assessment and a redesign of clinical vectors to improve safety.

Date: 2022
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DOI: 10.1038/s41467-022-31344-x

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