Immunodeficiency: primary or acquired

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Lentiviral-mediated foxp3 Gene Transfer and foxp3 Gene Editing: Developing Novel Treatment Options for Ipex Syndrome

Wednesday, June 14
6:15 PM - 7:45 PM

FOXP3 is a key transcription factor for the maintenance of immune tolerance. FOXP3 mutations result in dysfunction of FOXP3+ regulatory Treg cells (Tregs) causing Immune dysregulation, Polyendocrinopathy, Enteropathy, X-linked (IPEX) syndrome, a severe autoimmune disease. Current therapies for IPEX syndrome are limited to immunosuppression and allogenic hematopoietic stem cell (HSC) transplantation, both with side effects and limited efficacy. To develop better treatments for IPEX patients we have investigated lentiviral FOXP3 gene transfer (LV-FOXP3) in T cells and FOXP3 gene editing in HSC.


LV-FOXP3 successfully converts IPEX patients-derived CD4+ effector T cells (Teff) into Treg-like cells (CD4LV-FOXP3 T cells) with stable suppressive capacity in vitro and in vivo (Passerini, Sci Transl Med, 2013). Recently, we could generate nominal- and allo-antigen-specific CD4LV-FOXP3 T cells. These results clearly demonstrated the potential clinical benefit of CD4LV-FOXP3 T cells, which could be applied not only in IPEX but also in immune mediated diseases of different origin.


We are currently pursuing a CRISPR-Cas9 based gene editing approach in HSC. The site-specific gene correction of FOXP3 would permit the regulated expression of the functional FOXP3 protein not only in Treg but also in Teff cells, which transiently express FOXP3 upon activation. To edit FOXP3, we used CRISPR-Cas9 protein combined with an AAV6 packaged donor DNA template, and showed that the system effectively targets FOXP3 in HSCs. Moreover, gene-edited HSPCs can be transplanted into NSG mice for long-term multilineage reconstitution.


Our data indicates that both LV-FOXP3 and FOXP3 gene editing hold promises for the cure of IPEX syndrome.

Marianne Goodwin

Department of Pediatrics, Division of Stem Cell Transplantation and Regenerative Medicine, Stanford University

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    Laura Passerini

    San Raffaele Telethon Institute for Gene Therapy, Division of Regenerative Medicine, Stem Cells and Gene Therapy, San Raffaele Scientific Institute

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      Yohei Sato

      Department of Pediatrics, Division of Stem Cell Transplantation and Regenerative Medicine, Stanford University

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        Suzette Shipp

        Department of Pediatrics, Division of Stem Cell Transplantation and Regenerative Medicine, Stanford University.

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          Louise Froessl

          Department of Pediatrics, Division of Stem Cell Transplantation and Regenerative Medicine, Stanford University

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            Matthew Porteus

            Department of Pediatrics, Division of Stem Cell Transplantation and Regenerative Medicine, Stanford University

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              Maria-Grazia Roncarolo

              Professor
              Department of Pediatrics, Division of Stem Cell Transplantation and Regenerative Medicine, Stanford University

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                Rosa Bacchetta

                Associate Professor
                Department of Pediatrics, Division of Stem Cell Transplantation and Regenerative Medicine, Stanford University

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