Welcome to the ESID 2022 Meeting Interactive Programme
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Introduction
Gene Correction for IEI
CRISPR-Cas9 Genome Editing in IEI
Artificial Thymus - A Future Treatment Option in Primary Thymic IEI?
JAK-INHIBITOR TREATMENT OF INBORN ERRORS OF IMMUNITY WITH DYSREGULATED JAK/STAT SIGNALLING, AN ESID AND EBMT INBORN ERRORS WORKING PARTY STUDY
Abstract
Background and Aims
Inborn errors of immunity (IEI) with dysregulated JAK/STAT signalling can present with variable manifestations of severe immune dysregulation. Hematopoietic stem cell transplantation (HSCT) is potentially curative, however the reported treatment related mortality (TRM) of JAK/STAT patients is significant. Targeted therapies with JAK Inhibitors (JAKinib) offer a promising alternative and potentially TRM reducing bridging option. However, data on efficacy and adverse events (AE) of JAKinib treatment for IEI are limited.
Methods
Multicentre retrospective cohort study on patients with pathogenic variants in a JAK/STAT IEI-gene who have received JAKinib treatment for at least 3 months.
Results
66 patients (74% children) were included (41 STAT1-GOF, 21 STAT3-GOF, 1 STAT1-LOF, 1 STAT5B, 1 SOCS1, 1 JAK1-GOF). Ruxolitinib was the predominantly prescribed JAKinib (82%). Improvement of general well-being was observed in 91%. However, therapeutic responses varied among underlying diseases and disease manifestations. In 41% of patients, AE were observed (i.e. infections and weight gain). AE could generally be well controlled, leading to discontinuation of treatment in only 15% among patients who suffered AE. Currently, 76% patients are maintained on JAKinib (mean treatment observation 20 months) while 17% patients have received HSCT. Drug dosing and monitoring varies considerably between individual patients and centres.
Conclusions
Our study affirms that JAKinib are an effective and generally well tolerated therapy for patients with JAK/STAT-IEI. While there was variable efficacy for different disease manifestations, severe adverse events were rare. Our data will provide the basis for a consensus process to generate treatment recommendations and for the implementation of a prospective Jakinib treatment registry.
GENE EDITING OF APDS1 T CELLS
Abstract
Background and Aims
Activated PI3kinase Delta Syndrome type 1 (APDS1) is caused by gain of function mutations affecting the PIK3CD gene. The project aims to develop a gene editing approach to correct ex vivo patient T cells and reinfuse them. This treatment may be used to treat severe viral infections, or serve as a pre-requisite for a milder conditioning before hematopoietic stem cell transplantation.
Methods
T cells were modified using a nuclease targeting the PIK3CD gene and an AAV. Nuclease cleavage frequency was assessed by digital droplet PCR. Successful editing was analyzed by flow cytometry based on the expression of a reporter gene. Phospho-AKT level and cytotoxic activity were analyzed to evaluate the functional activity of corrected T cells.
Results
A highly specific nuclease achieved a reproducible cleavage efficiency of 80% and in conjunction with the AAV a gene editing efficiency of 20% at the PIK3CD locus. High basal level of phosphorylated AKT in APDS1 patient T cells was normalized in corrected patient cells. After T cell receptor activation phosphorylation of AKT could still be induced in corrected cells. Gene editing improved the impaired cytotoxic activity of repeatedly rechallenged APDS1 patient T cells towards lymphoblastoid B cell lines in the presence of blinatumomab.
Conclusions
We developed a protocol allowing efficient gene editing of APDS1 patient T cells. Corrected APDS1 T cells displayed normalized level of AKT phosphorylation and increased cytotoxic activity indicating the potential of our approach as a new treatment for ADPS1.