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Expanding and extending gene therapy of monogenic diseases of the haematopoietic system

Periodic Reporting for period 4 - GENE FOR CURE (Expanding and extending gene therapy of monogenic diseases of the haematopoietic system)

Reporting period: 2021-04-01 to 2022-09-30

The present project seeks to further consolidate the rationale for replacing HLA-partially-matched HSCT with a gene therapy approach to treat PIDs and to explore new strategies of gene modification by gene-editing technology.
The main goals of this project are as follows:
- WP1: Immunological and haematological reconstitution after gene therapy in WAS patients: implications for the clinical outcome, with a particular focus on autoimmunity and microthrombocytopenia
- WP2: Gene therapy of a SCID caused by an Artemis mutation: implementation of the first clinical trial for this indication
- WP3: Gene therapy for IPEX syndrome
- WP4: Gene therapy of SCA
WP1 : Immunological and haematological reconstitution after gene therapy in W AS patients: implications for the clinical outcome, with a particular focus on autoimmunity and microthrombocytopenia
WP1 aims at investigating the long term follow up of our first gene therapy trial for WAS in terms of the correction of all blood lineages, with a particular focus on the long-term cure of autoimmunity and thrombocytopenia. The study of platelet function and autoimmunity is ongoing and will be completed by the end of the project.

WP2 : Gene therapy of a SCID caused by an Artemis mutation: implementation of the first clinical trial for this indication
The main objective of this work package is to open a phase I/II clinical trial to treat 5 patients with Artemis immune deficiency. We expect at the end of the grant to have opened and included the 5 patients to be treated.

WP3 : Gene therapy for IPEX syndrome
We shall then assess the ability of CD4SfFOXP3 cells to cure the scurfy mouse’s autoimmune symptoms by adoptive transfer in scurfy male recipients. We shall compare the efficiency of these CD4SfFOXP3 cells with that of eGFP Tregs in controlling the autoimmune manifestation of scurfy mice and define the cell dose required for a sustained effect. We shall analyse the long-term persistence of the corrected CD4SfFOXP3 cells over several months.

The stability of the generated Tregs is a critical parameter for robust suppressor function. Recent studies have also revealed the plasticity of the Treg lineage (Sawant and Vignali, 2014). Therefore, in addition to restoration of FOXP3 expression in IPEX cells, we shall explore their transcriptional signatures and (i) look for expression of other core suppression factors that act in synergy with Foxp3 to lock the regulatory signature (Fu et al., 2012) and (ii) define the whole signature by comparison with healthy Tregs (Ferraro et al., 2014).
Considering our preliminary data showing the feasibility of regulatory T cell engineering though lentiviral transduction of FOXP3 in diseased CD4 T cells, we expect to demonstrate the ability of transduced CD4SfFOXP3 to control the disease as efficiently as nTreg. We expect a reasonable stability of the cells allowing controlling the disease for a couple of months.

WP4 : Gene therapy of SCA
Compared to previously published studies, we have developed a novel high-titer vector expressing an anti-sickling transgene that will be use in a clinical trial expected to start at Necker Hospital in 2019. In parallel, we have developed a novel genome editing strategy to reactivate therapeutic HbF levels in vitro. Future experiments will aim at selecting guide RNAs specifically targeting the β-globin locus that lead to efficient HbF reactivation in the progeny of bona fide HSCs (as assessed by xenotransplantation in immunodeficient mice) without evidence of toxicity.