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Normal IgH Repertoire Diversity in an Infant with ADA Deficiency After Gene Therapy

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Abstract

Purpose

Adenosine deaminase (ADA) deficiency causes severe combined immunodeficiency (SCID) through an accumulation of toxic metabolites within lymphocytes. Recently, ADA deficiency has been successfully treated using lentiviral-transduced autologous CD34+ cells carrying the ADA gene. T and B cell function appears to be fully restored, but in many patients’ B cell numbers remain low, and assessments of the immunoglobulin heavy (IgHV) repertoire following gene therapy are lacking.

Methods

We performed deep sequencing of IgHV repertoire in peripheral blood lymphocytes from a child following lentivirus-based gene therapy for ADA deficiency and compared to the IgHV repertoire in healthy infants and adults.

Results

After gene therapy, Ig diversity increased over time as evidenced by V, D, and J gene usage, N-additions, CDR3 length, extent of somatic hypermutation, and Ig class switching. There was the emergence of predominant IgHM, IgHG, and IgHA CDR3 lengths after gene therapy indicating successful oligoclonal expansion in response to antigens. This provides proof of concept for the feasibility and utility of molecular monitoring in following B cell reconstitution following gene therapy for ADA deficiency.

Conclusion

Based on deep sequencing, gene therapy resulted in an IgHV repertoire with molecular diversity similar to healthy infants.

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Availability of Data and Material

Sequencing data is available on dbGAP (Study Accession Number: phs002074.v1.p1).

Code Availability

Not applicable.

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Acknowledgements

We would like to thank the participants who volunteered to be included in this study.

Funding

This study was supported by R01 AI1001471 (JWS) and UO1 AI100801 (DK).

Funding for this study was in part provided by the Jeffrey Modell Foundation,

Leadiant Biosciences, and Orchard Therapeutics (MH).

NIH (NIAID) T32 training grant award number AI007062-38 (CB).

NIH (NHGRI) T32 training grant award number HG008955-01A1 (CB).

Author information

Author notes

  1. Suhag H. Parikh

    Present address: AFLAC Cancer Center & Blood Disorders Center, Children’s Healthcare of Atlanta, Emory University, Atlanta, Georgia

Authors and Affiliations

  1. Division of Allergy, Immunology and Pulmonary Medicine, Department of Pediatrics, Duke University School of Medicine, Durham, NC, USA

    Carolyn H. Baloh & John W. Sleasman

  2. Molecular HIV Host Interaction Section, National Institute of Allergy and Infectious Diseases, Bethesda, MD, USA

    Samiksha A. Borkar, Kai-Fen Chang, Maureen M. Goodenow & Li Yin

  3. Department of Biostatistics and bioinformatics, Moffitt Cancer Center, Tampa, FL, USA

    Jiqiang Yao

  4. Division of Rheumatology and Immunology, Department of Medicine, Duke University Medical Center, Durham, NC, USA

    Michael S. Hershfield

  5. Division of Blood and Marrow Transplantation, Department of Pediatrics, Duke University School of Medicine, Durham, NC, USA

    Suhag H. Parikh

  6. Division of Hematology & Oncology, Department of Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA

    Donald B. Kohn

  7. Department of Microbiology, Immunology, and Molecular Genetics, University of California Los Angeles, Los Angeles, CA, USA

    Donald B. Kohn

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  1. Carolyn H. Baloh
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Contributions

JS, LY, and MG contributed to the conception and design of the study. MH and DK contributed to the gene therapy protocol and monitoring of ADA. CB, MH, SP, DK, and JS contributed to patient care and obtaining clinical data. CB, SB, KC, JY, MG, JS, and LY contributed to the analysis and interpretation of sequencing data. CB wrote the first draft of the manuscript. All authors contributed to manuscript editing, read, and approved the final version.

Corresponding author

Correspondence to John W. Sleasman.

Ethics declarations

Ethics Approval

All study participants were enrolled with approvals by the Institutional Review Boards of the University of South Florida and Duke University.

Consent to Participate

Written informed consents were obtained from all participants or parents including the parents of the ADA-deficient child. Additional consent for publication of case report was obtained from the parents of the ADA-deficient child.

Consent for Publication

All authors provided consent for publication.

Conflict of Interest

MH receives funding support from Leadiant Biosciences and Orchard Therapeutics.

DK is an inventor on lentiviral gene therapy for ADA SCID licensed by the UC Regents to Orchard Therapeutics and serves as a member of the Orchard Scientific Advisory Board.

The other authors (CHB, SB, KC, JY, SP, MG, JS, LY) declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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Baloh, C.H., Borkar, S.A., Chang, KF. et al. Normal IgH Repertoire Diversity in an Infant with ADA Deficiency After Gene Therapy. J Clin Immunol 41, 1597–1606 (2021). https://doi.org/10.1007/s10875-021-01034-2

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  • DOI: https://doi.org/10.1007/s10875-021-01034-2

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