Gene correction for SCID-X1 in long-term hematopoietic stem cells

Mara Pavel-Dinu, Volker Wiebking, Beruh T. Dejene, Waracharee Srifa, Sruthi Mantri, Carmencita E. Nicolas, Ciaran Lee, Gang Bao, Eric J. Kildebeck, Niraj Punjya, Camille Sindhu, Matthew A. Inlay, Nivedita Saxena, Suk See DeRavin, Harry Malech, Maria Grazia Roncarolo, Kenneth I. Weinberg and Matthew H. Porteus ()
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Mara Pavel-Dinu: Stanford University
Volker Wiebking: Stanford University
Beruh T. Dejene: Stanford University
Waracharee Srifa: Stanford University
Sruthi Mantri: Stanford University
Carmencita E. Nicolas: Stanford University
Ciaran Lee: Rice University
Gang Bao: Rice University
Eric J. Kildebeck: University of Texas at Dallas
Niraj Punjya: Stanford University
Camille Sindhu: Stanford University
Matthew A. Inlay: University of California Irvine
Nivedita Saxena: Stanford University
Suk See DeRavin: National Institute of Health
Harry Malech: National Institute of Health
Maria Grazia Roncarolo: Stanford University
Kenneth I. Weinberg: Stanford University
Matthew H. Porteus: Stanford University

Nature Communications, 2019, vol. 10, issue 1, 1-15

Abstract: Abstract Gene correction in human long-term hematopoietic stem cells (LT-HSCs) could be an effective therapy for monogenic diseases of the blood and immune system. Here we describe an approach for X-linked sSevere cCombined iImmunodeficiency (SCID-X1) using targeted integration of a cDNA into the endogenous start codon to functionally correct disease-causing mutations throughout the gene. Using a CRISPR-Cas9/AAV6 based strategy, we achieve up to 20% targeted integration frequencies in LT-HSCs. As measures of the lack of toxicity we observe no evidence of abnormal hematopoiesis following transplantation and no evidence of off-target mutations using a high-fidelity Cas9 as a ribonucleoprotein complex. We achieve high levels of targeting frequencies (median 45%) in CD34+ HSPCs from six SCID-X1 patients and demonstrate rescue of lymphopoietic defect in a patient derived HSPC population in vitro and in vivo. In sum, our study provides specificity, toxicity and efficacy data supportive of clinical development of genome editing to treat SCID-Xl.

Date: 2019
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DOI: 10.1038/s41467-019-09614-y

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