JAK inhibitor treatment for inborn errors of JAK/STAT signaling: An ESID/EBMT-IEWP retrospective study.

BACKGROUND: Inborn errors of immunity (IEI) with dysregulated JAK/STAT signaling present with variable manifestations of immune dysregulation and infections. Hematopoietic stem cell transplantation (HSCT) is potentially curative, but initially reported outcomes were poor. JAK inhibitors (JAKi) offer a targeted treatment option that may be an alternative or bridge to HSCT. However, data on their current use, treatment efficacy and adverse events are limited. OBJECTIVE: We evaluated the current off-label JAKi treatment experience for JAK/STAT inborn errors of immunity (IEI) among European Society for Immunodeficiencies (ESID)/European Society for Blood and Marrow Transplantation (EBMT) Inborn Errors Working Party (IEWP) centers. METHODS: We conducted a multicenter retrospective study on patients with a genetic disorder of hyperactive JAK/STAT signaling who received JAKi treatment for at least 3 months. RESULTS: Sixty-nine patients (72% children) were evaluated (45 STAT1 gain of function [GOF], 21 STAT3-GOF, 1 STAT5B-GOF, 1 suppressor of cytokine signaling 1 [aka SOCS1] loss of function, 1 JAK1-GOF). Ruxolitinib was the predominantly prescribed JAKi (80%). Overall, treatment resulted in improvement (partial or complete remission) of clinical symptoms in 87% of STAT1-GOF and in 90% of STAT3-GOF patients. We documented highly heterogeneous dosing and monitoring regimens. The response rate and time to response varied across different diseases and manifestations. Adverse events including infection and weight gain were frequent (38% of patients) but were mild (grade I-II) and transient in most patients. At last follow-up, 52 (74%) of 69 patients were still receiving JAKi treatment, and 11 patients eventually underwent HSCT after receipt of previous JAKi bridging therapy, with 91% overall survival. CONCLUSIONS: Our study suggests that JAKi may be highly effective to treat symptomatic JAK/STAT IEI patients. Prospective studies to define optimal JAKi dosing for the variable clinical presentations and age ranges should be pursued.

Case report: Novel treatment regimen for enterovirus encephalitis in SCID.

Most non-polio enterovirus infections in immunocompetent individuals are acute and self-limiting in nature; however, infection can be severe, chronic and have devastating outcomes in immunocompromised hosts. Therapeutic strategies have predominantly involved supportive care, with the lack of approved antiviral treatments proving challenging for management. We report a case of an 8-month-old child who presented with severe enterovirus encephalitis following gene therapy for X-linked severe combined immunodeficiency (X-SCID) and who demonstrated clinical and microbiological improvement after a novel regimen of favipiravir, fluoxetine, and high-dose intravenous immunoglobulin (IVIg). The patient presented 6 weeks post-gene therapy with rapid neurological deterioration in the context of incomplete immune reconstitution, with microbiological and radiological evidence confirming enterovirus encephalitis. His neurologic examination stabilised 8 weeks after treatment, and he subsequently demonstrated excellent immune recovery. This is the first case report of combined therapy with favipiravir, fluoxetine, and high-dose IVIg in the context of severe enterovirus encephalitis in an immunocompromised host. This case highlights the importance of considering enterovirus encephalitis in immunocompromised patients presenting with both acute and chronic neurological signs, as well as developmental regression. The demonstrated treatment success and the associated low risk of toxicity warrant further investigation of this therapeutic regimen.

Gene Therapy for Inborn Errors of Immunity: Severe Combined Immunodeficiencies.

Severe combined immune deficiency (SCID) causes profound deficiency in T cells and variable deficiencies in B and NK cells. Untreated, the condition is fatal within the first 2 years of life. HSCT has traditionally been the only curative approach; however, success rates are suboptimal in those lacking an HLA-matched donor and conditioning regimens can cause significant toxicity. Gene therapy was pioneered for adenosine deaminase (ADA-SCID) over 3 decades ago and has produced highly successful results. Encouraging data for X-SCID and preclinical work for Artemis-SCID and RAG1-SCID are paving the way for the therapy to become a viable curative treatment option.

Gene therapy for primary immunodeficiencies: up-to-date.

INTRODUCTION: Primary immunodeficiencies (PIDs) are monogenic disorders of the immune system associated with increased susceptibility to life-threatening infection. Curative treatment has been limited to hematopoietic stem cell transplant (HSCT), however toxic immunosuppression, graft failure, and graft versus host disease greatly reduce overall survival rates. Gene therapy is a targeted curative therapy that reduces these risks by utilizing autologous hematopoietic stem cells. The treatment has found significant success and is anticipated to become the standard of care in a number of PIDs. AREAS COVERED: This review is a summary of the developments in gene therapy, gene editing, and current gene therapy approaches in specific PIDs. EXPERT OPINION: The field of gene therapy has rapidly developed over the last three decades, with the first licensed pharmaceutical gene therapy product now available. After initial clinical trials discovered serious adverse events in the form of insertional oncogenesis, significant improvements in vector design have made the treatment a viable curative therapy. Cryopreservation has expanded the scope of gene therapy by increasing accessibility of the product to wider geographic locations. Targeted gene editing using engineered nucleases, while still in early stages of development, will further add to the repertoire of potential treatments available for PIDs.