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Severe hematopoietic stem cell inflammation compromises chronic granulomatous disease gene therapy

ABSTRACT: X-linked chronic granulomatous disease (CGD, caused by CYBB gene mutations) is associated with defective phagocytosis, life-threatening infections, and inflammatory complications. We performed a clinical trial of lentivirus-based gene therapy in four patients (NCT02757911). Two patients showed stable engraftment and clinical benefits, whereas the other two progressively lost gene-corrected cells. Single-cell transcriptomic analysis revealed a significantly lower frequency of the most immature hematopoietic stem cells (HSCs) in CGD patients, especially in the two patients with defective engraftment. The latter presented a profound change in HSCs status, a high interferon score, and elevated myeloid progenitor frequency. We used elastic-net logistic regression to identify a set of 51 interferon genes and transcription factors that predicted the failure of HSCs engraftment. In one patient, an aberrant HSCs state with elevated CEBPb expression drove HSCs exhaustion, as demonstrated by low repopulation in a xenotransplantation model. Targeted treatments that protect HSCs, coupled to targeted gene expression screening, might improve clinical outcomes in CGD.

ORGANISM(S): Homo sapiens (human)

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PROVIDER: S-BSST958 | biostudies-other |

REPOSITORIES: biostudies-other

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Severe hematopoietic stem cell inflammation compromises chronic granulomatous disease gene therapy.

Project description:X-linked chronic granulomatous disease (CGD) is associated with defective phagocytosis, life-threatening infections, and inflammatory complications. We performed a clinical trial of lentivirus-based gene therapy in four patients (NCT02757911). Two patients show stable engraftment and clinical benefits, whereas the other two have progressively lost gene-corrected cells. Single-cell transcriptomic analysis reveals a significantly lower frequency of hematopoietic stem cells (HSCs) in CGD patients, especially in the two patients with defective engraftment. These two present a profound change in HSC status, a high interferon score, and elevated myeloid progenitor frequency. We use elastic-net logistic regression to identify a set of 51 interferon genes and transcription factors that predict the failure of HSC engraftment. In one patient, an aberrant HSC state with elevated CEBPβ expression drives HSC exhaustion, as demonstrated by low repopulation in a xenotransplantation model. Targeted treatments to protect HSCs, coupled to targeted gene expression screening, might improve clinical outcomes in CGD.

| S-EPMC9975109 | biostudies-literature

Severe hematopoietic stem cell inflammation compromises chronic granulomatous disease gene therapy (Single Cell)

Project description: Not available

| S-BSST959 | biostudies-other

Granulocyte Transfusions in Patients with Chronic Granulomatous Disease Undergoing Hematopoietic Cell Transplantation or Gene Therapy.

Project description:Granulocyte transfusions are sometimes used as adjunctive therapy for the treatment of infection in patients with chronic granulomatous disease (CGD). However, granulocyte transfusions can be associated with a high rate of alloimmunization, and their role in CGD patients undergoing hematopoietic cell transplantation (HCT) or gene therapy (GT) is unknown. We identified 27 patients with CGD who received granulocyte transfusions pre- (within 6 months) and/or post-HCT or GT in a retrospective survey. Twelve patients received granulocyte transfusions as a bridge to cellular therapy. Six (50%) of these patients had a complete or partial response. However, six of 10 (60%) patients for whom testing was performed developed anti-HLA antibodies, and three of the patients also had severe immune-mediated cytopenia within the first 100 days post-HCT or GT. Fifteen patients received granulocyte transfusions post-HCT only. HLA antibodies were not checked for any of these 15 patients, but there were no cases of early immune-mediated cytopenia. Out of 25 patients who underwent HCT, there were 5 (20%) cases of primary graft failure. Three of the patients with primary graft failure had received granulocyte transfusions pre-HCT and were subsequently found to have anti-HLA antibodies. In this small cohort of patients with CGD, granulocyte transfusions pre-HCT or GT were associated with high rates of alloimmunization, primary graft failure, and early severe immune-mediated cytopenia post-HCT or GT. Granulocyte transfusions post-HCT do not appear to confer an increased risk of graft failure.

| S-EPMC9022412 | biostudies-literature

Lentiviral gene therapy for X-linked chronic granulomatous disease.

Project description:Chronic granulomatous disease (CGD) is a rare inherited disorder of phagocytic cells1,2. We report the initial results of nine severely affected X-linked CGD (X-CGD) patients who received ex vivo autologous CD34+ hematopoietic stem and progenitor cell-based lentiviral gene therapy following myeloablative conditioning in first-in-human studies (trial registry nos. NCT02234934 and NCT01855685). The primary objectives were to assess the safety and evaluate the efficacy and stability of biochemical and functional reconstitution in the progeny of engrafted cells at 12 months. The secondary objectives included the evaluation of augmented immunity against bacterial and fungal infection, as well as assessment of hematopoietic stem cell transduction and engraftment. Two enrolled patients died within 3 months of treatment from pre-existing comorbidities. At 12 months, six of the seven surviving patients demonstrated stable vector copy numbers (0.4-1.8 copies per neutrophil) and the persistence of 16-46% oxidase-positive neutrophils. There was no molecular evidence of either clonal dysregulation or transgene silencing. Surviving patients have had no new CGD-related infections, and six have been able to discontinue CGD-related antibiotic prophylaxis. The primary objective was met in six of the nine patients at 12 months follow-up, suggesting that autologous gene therapy is a promising approach for CGD patients.

| S-EPMC7115833 | biostudies-literature

Gene therapy of chronic granulomatous disease: the engraftment dilemma.

Project description:The potential of gene therapy as a curative treatment for monogenetic disorders has been clearly demonstrated in a series of recent Phase I/II clinical trials. Among primary immunodeficiencies, gene transfer into hematopoietic stem (HSC)/progenitor cells has resulted in the long-term correction of immune and metabolic defects in treated patients. In most cases, successes were augmented by a recognized biological selection for successfully treated cells in vivo, perhaps even to some extent at the HSC level. In contrast, similar achievements have not turned into reality for immunodeficiencies in which gene-transduced cells lack selective advantages in vivo. This is the case for chronic granulomatous disease (CGD), a primary immunodeficiency, characterized by deficient antimicrobial activity in phagocytic cells. Several attempts to correct CGD by gene transfer in combination with bone marrow conditioning have resulted in low-level long-term engraftment and transient clinical benefits despite high levels of gene marking and high numbers of reinfused cells. This review summarizes the data from clinical trials for CGD and provides some insights into treatment options that may lead to a successful application of gene therapy for CGD.

| S-EPMC3017455 | biostudies-other

Hematopoietic Tumors in a Mouse Model of X-linked Chronic Granulomatous Disease after Lentiviral Vector-Mediated Gene Therapy.

Project description:Chronic granulomatous disease (CGD) is a rare inherited disorder due to loss-of-function mutations in genes encoding the NADPH oxidase subunits. Hematopoietic stem and progenitor cell (HSPC) gene therapy (GT) using regulated lentiviral vectors (LVs) has emerged as a promising therapeutic option for CGD patients. We performed non-clinical Good Laboratory Practice (GLP) and laboratory-grade studies to assess the safety and genotoxicity of LV targeting myeloid-specific Gp91phox expression in X-linked chronic granulomatous disease (XCGD) mice. We found persistence of gene-corrected cells for up to 1 year, restoration of Gp91phox expression and NADPH oxidase activity in XCGD phagocytes, and reduced tissue inflammation after LV-mediated HSPC GT. Although most of the mice showed no hematological or biochemical toxicity, a small subset of XCGD GT mice developed T cell lymphoblastic lymphoma (2.94%) and myeloid leukemia (5.88%). No hematological malignancies were identified in C57BL/6 mice transplanted with transduced XCGD HSPCs. Integration pattern analysis revealed an oligoclonal composition with rare dominant clones harboring vector insertions near oncogenes in mice with tumors. Collectively, our data support the long-term efficacy of LV-mediated HSPC GT in XCGD mice and provide a safety warning because the chronic inflammatory XCGD background may contribute to oncogenesis.

| S-EPMC7791081 | biostudies-literature

Hematopoietic Cell Transplantation for Chronic Granulomatous Disease in Japan.

Project description:Hematopoietic cell transplantation (HCT) is established as a curative treatment for severe chronic granulomatous disease (CGD). However, outcomes of HCT for CGD in Japan had not been precisely reported. We evaluated the outcome of HCT for CGD in Japan by means of a nationwide survey. A total of 91 patients (86 males and 5 females) with CGD who received HCT between 1992 and 2013 was investigated. Their median age at HCT was 11 years (0-39). Sixty-four patients had X-linked CGD caused by CYBB gene mutations, 13 had autosomal recessive CGD (7 CYBA and 6 NCF2), and 14 were genetically undetermined. Seventy patients are still alive at a median follow-up of 38.9 (3.7-230) months. Three-year OS and EFS was 73.7 and 67.6%, respectively. Twenty-one patients died mainly from transplant-related mortality. The cumulative incidence of grade II to IV acute GVHD and extensive chronic GVHD was 27.2 and 17.9%, respectively. Risk factors for EFS after HCT for CGD were age >30 years (P < 0.01), non-CYBB gene mutations (P < 0.01) and CBT (P < 0.01). Regarding the reduced intensity conditioning (RIC) regimen, risk factors for EFS included anti-thymocyte globulin (P = 0.048) and not using low-dose irradiation therapy (P < 0.01), in addition to the preceding risk factors. We report outcomes of HCT for CGD in Japan. Future studies are needed to improve such outcomes, especially for patients harboring non-CYBB gene mutations and suffering from adult CGD. A RIC regimen including low-dose irradiation may be a good option to explore further.

| S-EPMC7403177 | biostudies-literature

Haematopoietic Stem Cell Transplantation for Chronic Granulomatous Disease.

Project description:Chronic granulomatous disease (CGD) is an inborn error of immunity due to defects in the transport or function of subunits of nicotinamide adenine dinucleotide phosphate oxidase, the enzyme that generates the phagocyte respiratory burst responsible for intracellular killing of engulfed micro-organisms. Patients present with infectious or inflammatory complications. Common bacterial pathogens include Staphylococcus aureus and Burkholderia cepacia complex. Fungal pathogens include Aspergillus species, particularly Aspergillus fumigatus. Inflammatory complications most commonly manifest as inflammatory bowel disease or lung disease. Granulomata are the distinguishing histological feature. Haematopoietic stem cell transplantation (HSCT) was first considered for CGD in the early 1970's. Since then, refinements in transplant technique, donor selection, conditioning regimens, and graft engineering have widened the option of HSCT to most patients with CGD. This review charts the progress made in HSCT for CGD.

| S-EPMC10532348 | biostudies-literature

Targeted gene addition in human CD34(+) hematopoietic cells for correction of X-linked chronic granulomatous disease.

Project description:Gene therapy with genetically modified human CD34(+) hematopoietic stem and progenitor cells (HSPCs) may be safer using targeted integration (TI) of transgenes into a genomic 'safe harbor' site rather than random viral integration. We demonstrate that temporally optimized delivery of zinc finger nuclease mRNA via electroporation and adeno-associated virus (AAV) 6 delivery of donor constructs in human HSPCs approaches clinically relevant levels of TI into the AAVS1 safe harbor locus. Up to 58% Venus(+) HSPCs with 6-16% human cell marking were observed following engraftment into mice. In HSPCs from patients with X-linked chronic granulomatous disease (X-CGD), caused by mutations in the gp91phox subunit of the NADPH oxidase, TI of a gp91phox transgene into AAVS1 resulted in ?15% gp91phox expression and increased NADPH oxidase activity in ex vivo-derived neutrophils. In mice transplanted with corrected HSPCs, 4-11% of human cells in the bone marrow expressed gp91phox. This method for TI into AAVS1 may be broadly applicable to correction of other monogenic diseases.

| S-EPMC4824656 | biostudies-literature

Failure to Prevent Severe Graft-Versus-Host Disease in Haploidentical Hematopoietic Cell Transplantation with Post-Transplant Cyclophosphamide in Chronic Granulomatous Disease.

Project description:PurposeHaploidentical related donor (HRD) transplantation was performed in 7 recipients with chronic granulomatous disease (CGD) who had no matched-related or unrelated donor.MethodsPeripheral blood cell (PBC) products were used with a conditioning regimen consisting of low-dose cyclophosphamide, fludarabine, total body irradiation, and busulfan. Graft-versus-host disease (GVHD) prophylaxis consisted of high-dose post-transplant cyclophosphamide and sirolimus. Recipients were ages 14-26 years, and 3 had severe infections active at transplant.ResultsAll 7 recipients achieved full engraftment with complete donor chimerism early in the post-transplant period. Acute GVHD occurred in all cases and was grade 3 or steroid refractory in 3. Two patients with steroid-refractory GVHD died. Three patients with severe infectious complications active at transplant, 1 Nocardia pneumonia and 2 extensive invasive fungal infections), survived and were cured of their infection at last follow-up. Bacterial disease occurred post-transplant in all recipients, and viral infections/reactivation were common, including 4 cases of BK virus-associated hemorrhagic cystitis.ConclusionsSeven patients with CGD achieved rapid and full-donor engraftment from HRDs utilizing PBCs and a conditioning regimen with PTCy and sirolimus GVHD prophylaxis. However, the incidence of grade 3 and steroid-refractory GVHD was high and led to 2 deaths. Patients with active infections at transplant had successful transplant courses and were cured of their disease. Although there was an initial success with this regimen, the cumulative experience does not support its use in CGD due to an unacceptable rate of severe GVHD.

| S-EPMC7507116 | biostudies-literature

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