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

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.

In vivo correction of genetic defects of monocyte/ macrophages using attenuated Salmonella as oral vectors for targeted gene delivery

“…21 This aspect would need to be carefully addressed. In terms of clinical endpoints, even though the applications of gene therapy attempted to date have primarily been safety studies, clinical benefit has proved to be difficult to establish except for the gene therapy of adenosine deaminase deficiency 28,29 and cancer. 30 Here, we have shown the outcome of gene delivery in vivo in a knock-out model, which resembles to a good extent a genetic defect.…”

Absence of retroviral vector-mediated transformation of gene-modified T cells after long-term engraftment in mice

“…7 In addition, retrovirus has been used widely to transduce tumor cells and immune cells for cancer therapy. [8][9][10] Retroviral vectors have also been used successfully in human trials to correct gene deficiencies in diseases including ADA-SCID, [11][12][13][14] X-linked SCID 15,16 and chronic granulomatous disease. 17 Retroviruses insert their genes in a semirandom manner into host chromosomes, 18 and it is thought that retroviruses may integrate preferentially into transcriptionally active sites.…”

Lentivirus-mediated gene transfer in primary T cells is enhanced by a central DNA flap

“…[1][2][3][4] Moreover, transfer of wild-type genes into T cells with defects in enzymatic genes such as adenosine deaminase may allow the correction of these types of disorders. [5][6][7] At this time, the most widely used method for gene transfer into human T cells has involved Moloney murine leukemia virus (MuLV)-based vectors. MuLVbased vectors allow stable gene transfer as the genetic material contained within the vector is integrated into target cell genomes.…”