Gene Therapy in Peripheral Blood Lymphocytes and Bone Marrow for ADA ⁻ Immunodeficient Patients

TLDR

Adenosine deaminase deficiency causes severe combined immunodeficiency, the first genetic disorder treated by gene therapy. Two retroviral vectors were used to transfer an ex vivo human ADA minigene into bone marrow cells and peripheral blood lymphocytes from two patients receiving enzyme replacement therapy. After two years, long‑term survival of T and B lymphocytes, marrow cells, and granulocytes expressing the transferred ADA gene was observed, normalizing the immune repertoire and restoring cellular and humoral immunity; following treatment cessation, T cells derived from transduced peripheral blood lymphocytes were progressively replaced by marrow‑derived T cells, demonstrating successful gene transfer into long‑lasting progenitor cells that produce functional multilineage progeny.

Abstract

Adenosine deaminase (ADA) deficiency results in severe combined immunodeficiency, the first genetic disorder treated by gene therapy. Two different retroviral vectors were used to transfer ex vivo the human ADA minigene into bone marrow cells and peripheral blood lymphocytes from two patients undergoing exogenous enzyme replacement therapy. After 2 years of treatment, long-term survival of T and B lymphocytes, marrow cells, and granulocytes expressing the transferred ADA gene was demonstrated and resulted in normalization of the immune repertoire and restoration of cellular and humoral immunity. After discontinuation of treatment, T lymphocytes, derived from transduced peripheral blood lymphocytes, were progressively replaced by marrow-derived T cells in both patients. These results indicate successful gene transfer into long-lasting progenitor cells, producing a functional multilineage progeny.