RARE DISEASE
Chronic granulomatous disease
Chronic granulomatous disease
Chronic granulomatous disease
Synonyms: CGD, Chronic septic granulomatosis
Synonyms: CGD, Chronic septic granulomatosis
Synonyms: CGD, Chronic septic granulomatosis
Drug discovery
10
drugs
With orphan designations
Overview
Chronic granulomatous disease (CGD) is a rare genetic immunodeficiency caused by defects in phagocyte NADPH oxidase, impairing bacterial/fungal killing [1][2][3]. Patients experience recurrent life-threatening infections (commonly Staphylococcus aureus and Aspergillus spp.) and granulomatous inflammation affecting lungs, lymph nodes, GI tract, and skin [2][6][9]. X-linked (CYBB mutations) and autosomal recessive forms exist [2][11]. Management includes prophylactic antimicrobials, interferon-gamma immunotherapy, and hematopoietic stem cell transplantation [3][7][12].
Burden
Mortality: 2-5% annual infection-related mortality despite prophylaxis [2][7]
Morbidity: Granuloma-related complications (GI obstruction, IBD) in 50% of patients [2][6][10]
Healthcare utilization: Frequent hospitalizations for abscess drainage (+35% require surgery) and IV antifungals for invasive aspergillosis [3][7][12]
Categories: rare gastroenterological diseases, rare genetic diseases, rare immunological diseases, rare ophthalmic disorders, rare respiratory diseases, rare skin diseases, rare transplant-related disorders
Research Papers
1,020 drug discovery papers about Chronic granulomatous disease, with 5 first-in-class and 6 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
1,020 drug discovery papers about Chronic granulomatous disease, with 5 first-in-class and 6 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-08-14 | First report of Rhinocladiella mackenziei osteomyelitis with CNS dissemination in a pediatric CGD patient post-HSCT: A case report and literature review.
Rhinocladiella mackenziei is a rare neurotropic dematiaceous fungus that causes cerebral phaeohyphomycosis, predominantly in immunocompetent adults with a geographical predilection to the Middle East. Pediatric infection is exceptionally rare, and to our knowledge, no cases of combined osseous and central nervous system involvement following hematopoietic stem cell transplantation (HSCT) have been reported. We report a male child with autosomal recessive chronic granulomatous disease (CGD) who developed traumatic forearm osteomyelitis due to R. mackenziei several months after haploidentical HSCT. Subsequent neuroimaging demonstrated intracerebral abscesses despite immune reconstitution. The infection persisted despite prolonged combination antifungal therapy with voriconazole and amphotericin B and ultimately required neurosurgical excision. The patient recovered without neurological sequelae and continues on long-term posaconazole therapy. This case highlights R. mackenziei as a cause of severe, invasive, disseminated fungal disease in pediatric post-bone marrow transplant patients and demonstrates extracerebral inoculation with subsequent CNS dissemination. It also underscores the importance of early recognition and a combined medical-surgical approach in management of refractory disease.
2026-08-03 | Prospective Study of Targeted Busulfan-Fludarabine Conditioning for Hematopoietic Stem Cell Transplantation in Genetic Rare Diseases.
Genetic rare diseases (GRDs), including chronic granulomatous disease, familial hemophagocytic lymphohistiocytosis, and congenital neutropenia, often require hematopoietic stem cell transplantation (HSCT) as the only curative option. Conventional myeloablative regimens are associated with considerable toxicity, whereas reduced-intensity regimens carry an increased risk of graft failure. To address the narrow therapeutic window of busulfan, we developed a pharmacokinetic-guided dosing strategy and evaluated it in a prospective study. Children with GRDs undergoing HSCT received a conditioning regimen comprising fludarabine 40 mg/m2 (days -8 to -4), anti-thymocyte globulin 2.5 mg/kg (days -4 to -2), and once-daily busulfan (days -9 to -6), with intensive pharmacokinetic monitoring and dose adjustments to achieve target exposure. Twenty patients with GRDs (median age, 3.6 years) received HSCT with a targeted busulfan-based myeloablative regimen. No engraftment failure occurred. Cumulative incidences of Grade II-IV and Grade III-IV acute graft-versus-host disease and moderate-to-severe chronic graft-versus-host disease were 25%, 5%, and 23%, respectively. Ten-year overall survival, event-free survival, and transplant-related mortality rates were 90%, 90%, and 5%, respectively. Pharmacokinetic-guided busulfan-fludarabine conditioning achieved reliable engraftment with acceptable toxicity in children with GRDs, supporting its use as a safe, effective HSCT conditioning strategy in vulnerable populations.
2026-07-19 | NADPH oxidase 2 (NOX2)-independent inducers of neutrophil extracellular traps promote resolution of chronic inflammation.
Reactive oxygen species (ROS) generated by NADPH oxidase 2 (NOX2) are essential for antimicrobial defense but also for the resolution of inflammation. NOX2 deficiency, as observed in chronic granulomatous disease (CGD), predisposes to persistent sterile inflammation. Current therapeutic strategies largely rely on nonspecific immunosuppression or require residual NOX2 activity, while systemic ROS-inducing therapies are limited by toxicity. Here, we present a NOX2-independent approach to restore inflammation-resolving ROS signaling using N-alkylaminoferrocene-based prodrugs (pro-NAAFs), which amplify pre-existing ROS rather than generating ROS indiscriminately. Among several candidates, prodrug 1 emerged as the most potent and well-tolerated ROS amplifier. In human neutrophils, prodrug 1 induced strong ROS production and neutrophil extracellular trap (NET) formation. These responses occurred independently of NOX2 and were maintained in CGD-derived neutrophils. Similar NOX2-independent ROS induction and NET formation were observed in immune cells from wild-type and NOX2-dysfunctional Ncf1∗∗ mice. Prodrug 1-induced NETs aggregated into high-density structures (aggNETs) capable of degrading pro-inflammatory mediators in vitro. Prodrug 1 also inhibited neutrophil inflammasome activation. In vivo, subcutaneous administration of prodrug 1 reduced inflammatory mediator levels in air pouches, promoted resolution of chronic arthritis in Ncf1∗∗ mice, and protected from bone destruction. Transcriptomic analyses indicated early suppression of inflammatory pathways and restoration of neutrophil maturation trajectories towards a wild-type-like state. While prodrug 1 increased protein oxidation markers, it shifted systemic oxysterol profiles towards an inflammation-resolving phenotype. These findings identify pro-NAAFs as NOX2-independent ROS amplifiers capable of restoring inflammatory resolution and highlight their therapeutic potential for chronic inflammatory conditions linked to NOX2-dysfunction.
2026-06-25 | Thalidomide for CGD-related inflammatory bowel disease: A randomized, double-blind trial.
Chronic granulomatous disease-related inflammatory bowel disease (CGD-IBD) requires effective and safe therapies, as conventional immunosuppressants increase infection risk. Thalidomide, with anti-inflammatory and immunomodulatory effects, may represent a therapeutic option. This study was conducted to explore the preliminary efficacy and safety of thalidomide for CGD-IBD in a multicenter, randomized, double-blind, placebo-controlled, parallel-group phase II trial. Patients were randomized to thalidomide or placebo for a 12-wk blinded phase, followed by a 12-wk extension thalidomide phase. The primary endpoint was achievement of remission or a ≥20-point reduction in the Pediatric Ulcerative Colitis Activity Index. Eight male patients were randomized and analyzed. The primary endpoint was achieved by 1/3 of thalidomide patients versus 0/5 in the placebo group during the blinded phase, and by 5/8 in the extension phase. Secondary endpoints and exploratory endoscopy showed improvements. CGD-related infection rates were comparable before and after treatment. Thalidomide met the prespecified efficacy criterion with an acceptable safety profile in CGD-IBD, suggesting a promising therapeutic option that warrants further clinical studies.
2026-06-18 | Case Report: Invasive pulmonary aspergillosis caused by Aspergillus lentulus in a boy with chronic granulomatous disease.
Aspergillus lentulus is a slow-growing and drug-resistant fungus, which has been primarily reported in adults, usually immunocompromised ones, suffering from invasive pulmonary aspergillosis (IPA). This condition is rare in children. Here, we report a case of invasive pulmonary aspergillosis due to Aspergillus lentulus in a boy with no history of recurrent infections who presented with a prolonged fever of unknown origin. Based on chest CT scan findings showing typical halo signs, a fungal infection was strongly suspected. Empirical antifungal therapy was initiated at early admission but failed to resolve the persistent fever in this case. The causative pathogen was confirmed by blood metagenomic next-generation sequencing (mNGS). Subsequent genetic analysis identified a pathogenic mutation in the X-linked CYBB gene, confirming chronic granulomatous disease (CGD). Eventually, following a combination therapy of voriconazole and micafungin, the boy became afebrile and was discharged, pending hematopoietic stem cell transplantation (HSCT). To our knowledge, no previous cases of Aspergillus lentulus infection in children with CGD have been reported in the literature. This case underscores the critical importance of identifying the causative microorganism. It also highlights the value of emerging detection methods, such as mNGS. At present, there is no consensus for the optimal antifungal regimen against pediatric Aspergillus lentulus infections. Clinical improvement was achieved in this patient following combination therapy with voriconazole and micafungin, offering a practical therapeutic reference for managing this refractory fungal infection.
cell therapies
2026-07-09 | Clinical analysis and follow up study of chronic granulomatous disease with neonatal onset
Objective To address the existing gap in knowledge regarding the small subset of chronic granulomatous disease (CGD) patients who present during the neonatal period, this study aimed to characterize their clinical features, genetic profiles, and long-term prognosis. Methods This study retrospectively selected CGD patients with neonatal onset who were diagnosed using neutrophil respiratory burst tests and genetic analysis at the Guangzhou Women and Children's Medical Center, Guangzhou Medical University, between January 2018 and September 2024. Results This study included nine male patients diagnosed with CGD presenting with neonatal onset. The median age at onset was 20 days (7–23 days). Pneumonia was observed in eight patients (88.9%), with Aspergillus species detected in five of these cases (62.5%). The stimulation index (SI) in the neutrophil oxidative burst assay was significantly reduced. All nine patients exhibited hemizygous variants in the CYBB gene. The median hospital stay was 42 days (15.5–48 days). Three patients died due to disease progression during their initial hospitalization. Regarding long-term prognosis, one patient was lost to follow-up at six months of age, and three patients died from severe infections during infancy. The remaining two patients underwent hematopoietic stem cell transplantation (HSCT) and achieved complete clinical remission. Conclusion Patients with CGD presenting in the neonatal period predominantly harbor mutations in the CYBB gene, which are associated with severe clinical manifestations. Aspergillus species are the most common pathogens in these patients. Although the prognosis is generally poor, it may be improved by hematopoietic stem cell transplantation (HSCT).
2026-06-20 | Expansion and CAR engineering of granulocyte-monocyte progenitors for cellular immunotherapy.
Engineered macrophages are promising for tumor immunotherapy but are limited by poor ex vivo expansion, genetic tractability, and biodistribution after transfer. Here, we develop defined culture conditions that enable long-term expansion of mouse and human granulocyte-monocyte progenitors (GMPs) while preserving progenitor identity and myeloid potential, establishing GMPs as a renewable engineering platform. Mechanistically, we identify myeloperoxidase as a regulator of GMP proliferation. Expanded GMPs are readily engineered and, after transfer, seed hematopoietic niches and generate donor-derived myelopoiesis that restores antibacterial defense in chronic granulomatous disease mice and yields abundant tumor-infiltrating macrophages. GMPs engineered with chimeric antigen receptors (CARs) suppress CD19-positive leukemia and human epidermal growth factor receptor 2 (HER2)-positive solid tumors. We further introduce a CAR incorporating an immunoglobulin G (IgG) Fc domain that recruits host Fc receptor-expressing phagocytes, enables T cell priming across major histocompatibility complex (MHC) mismatch, and enhances efficacy in immunocompetent allogeneic cancer models. Together, these findings establish expandable GMPs as a scalable platform for engineered immunotherapy.
2026-05-22 | Non-cryopreserved Kx negative packed red cell concentrates to support hematopoietic stem cell transplantation in McLeod contiguous gene deletion syndrome.
Transfusion management of Kx- individuals with McLeod phenotype (MLP) is highly challenging, particularly as cryopreservation affects red blood cell (RBC) concentrate quality. We developed a concept to provide non-cryopreserved Kx- RBCs over the complete period of hematopoietic stem cell transplantation (HSCT) for treatment of X-linked chronic granulomatous disease (X-CGD) with MLP. An infant with a large deletion affecting 12 protein-coding genes, including DMD, PRRG1, LANCL3, XK, CYBB, and DYNLT3, leading to CGD, Duchenne muscular dystrophy, and MLP, was scheduled for HSCT with the need of Kx- blood supply. No Kx- and RhD compatible donors were identified by rare donor programs, and autologous blood collection was not possible. In an interdisciplinary multicenter effort pre- and post-HSCT blood management, including procurement of non-cryopreserved allogeneic Kx- RBCs from an individual with MLP, was orchestrated, balancing donations, storage, pediatric RBC preparation, and irradiation with the clinical schedule. Our concept ensured compatible blood supply from 100 days prior HSCT to the peritransplant phase. The patient received 5 non-cryopreserved Kx- pediatric RBCs and was discharged with complete chimerism at day +68. The screen was repeatedly negative for antibodies to high frequency RBC antigens. After 2.8 years, the patient remained independent of transfusions and was without signs of graft-versus-host disease. Close coordination between institutions and disciplines and process optimization allow readily available provision of non-cryopreserved Kx- RBCs to support HSCT to a patient with unique contiguous gene deletion syndrome of X chromosome.
2026-05-22 | Hematopoietic stem cell transplantation following invasive mold infection in chronic granulomatous disease: Insights from a case series and literature review.
Chronic granulomatous disease (CGD) is an inborn error of immunity leading to severe invasive mold infections (IMIs). Questions remain regarding the safety of hematopoietic stem cell transplantation (HSCT) in patients following IMI. We retrospectively collected data from CGD patients undergoing HSCT within 2 years after a diagnosis of probable or proven IMI in France. The primary endpoint was to describe 1-year overall survival (OS). 14 patients were included, with aspergillosis (n = 10), mucormycosis (N = 2), scedosporiosis, or lomentosporiosis (n = 1 each). IMI status at time of HCST included four in complete response, four in partial response (PR), one in stable response (SR), and five with disease progression (DP). 1-year OS was 86 % (12/14). Two patients with scedosporiosis and lomentosporiosis died before engraftment. The remaining patients all achieved engraftment followed by prolonged clinical response of IMI. HSCT appears safe in patients with complete response or PR of IMI and could be a promising curative option for progressive IMI, specifically in those with invasive aspergillosis.
2026-05-22 | How I Treat: Chronic granulomatous disease.
Chronic granulomatous disease (CGD) is a rare inborn error of immunity with both high risk of invasive bacterial and fungal infections as well as inflammatory complications. Though diagnostic testing via the dihydrorhodamine assay is widely available, disease recognition can be challenging due to the broad range of initial clinical presentations. Preventative antimicrobial therapy is the backbone of management, while treatment of inflammatory disease remains a challenge. Definitive therapy via hematopoietic stem cell transplantation is increasingly favored for resolution of long-term disease risks, while gene therapy remains a promising but investigational treatment. Here, we present our consensus approach to diagnosis and management of CGD.
proteins
2025-12-01 | Mitigating chronic granulomatous disease (CGD) through mutational analysis and de novo drug design targeting the CYBA gene through different approaches
Chronic Granulomatous Disease (CGD) is a rare genetic immunodeficiency disorder that arises from mutations in genes responsible for encoding the NADPH oxidase complex, including the CYBA. Such genetic alterations impair the production of reactive oxygen species (ROS), which culminates in impaired microbial eradication, recurrent infections, and the formation of granulomas. This study aimed to conduct an in silico mutational analysis of the CYBA gene and design a novel therapeutic candidate to mitigate Chronic Granulomatous disease. The FASTA sequence of the protein Cytochrome b-245 light chain was retrieved from the UniProt. Mutational analysis was performed using BLASTp and UniProt to identify and confirm the possible mutations. AlphaFold server 3 was utilized to generate the mutated 3D structure of the CYBA protein. The pharmacokinetics and toxicity profiles performed using ADMET AI and ProToxII indicated that the drug compound is nontoxic with medium solubility. Finally, the molecular dynamics simulation studies were carried out using the OpenMM engine with the AMBER force field. The mutated protein structure was validated and assessed for quality using Ramachandran and ERRAT analysis which showed a quality factor of 98.5 according to ERRAT and 98.6 % of residues within favorable regions. For drug design, the ELEA-3D tool was utilized to synthesize the 20 ligands against the targeted protein from which the best one was selected based on a confidence score of 81.23 %. The molecular docking and interaction analysis was carried out utilizing HDock yielding a docking score of −165.5 and Ligplot+ and Discovery studio. The quality, validity, interaction analysis, and non-toxicity nature of the designed drug compound suggest it is a promising candidate for Chronic Granulomatous disease.
2025-07-17 | Interferon gamma rebalances immunopathological signatures in chronic granulomatous disease through metabolic rewiring.
Chronic granulomatous disease (CGD) is a primary immunodeficiency characterized by recurrent life-threatening infections and hyperinflammatory complications. It is caused by mutations in the reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex and the consequent loss of reactive oxygen species (ROS) production. Recombinant human interferon gamma (rIFN-γ) prophylaxis reduces the risk of severe infections, but the mechanisms behind its efficacy in CGD are still an open question, as it does not restore NADPH oxidase-dependent ROS production. Here, we demonstrate that the innate immune cells of patients with CGD are transcriptionally and functionally reprogrammed to a hyperactive inflammatory status, displaying an impaired in vitro induction of trained immunity. CGD monocytes have reduced intracellular amino acid concentrations and profound functional metabolic defects, both at the level of glycolysis and mitochondrial respiration. Ex vivo and in vivo treatments with IFN-γ restored these metabolic defects and reduced excessive interleukin 1β (IL-1β) and IL-6 production in response to fungal stimuli in CGD monocytes. These data suggest that prophylactic rIFN-γ modulates the metabolic status of innate immune cells in CGD. These data shed light on the effects of NADPH oxidase-derived ROS deficiency to the metabolic programs of immune cells and pose the basis for targeting this immunometabolic axis, potentially beyond CGD, with IFN-γ immunotherapy.
2024-07-07 | Self-extinguishing relay waves enable homeostatic control of human neutrophil swarming.
Neutrophils collectively migrate to sites of injury and infection. How these swarms are coordinated to ensure the proper level of recruitment is unknown. Using an ex vivo model of infection, we show that human neutrophil swarming is organized by multiple pulsatile chemoattractant waves. These waves propagate through active relay in which stimulated neutrophils trigger their neighbors to release additional swarming cues. Unlike canonical active relays, we find these waves to be self-terminating, limiting the spatial range of cell recruitment. We identify an NADPH-oxidase-based negative feedback loop that is needed for this self-terminating behavior. We observe near-constant levels of neutrophil recruitment over a wide range of starting conditions, revealing surprising robustness in the swarming process. This homeostatic control is achieved by larger and more numerous swarming waves at lower cell densities. We link defective wave termination to a broken recruitment homeostat in the context of human chronic granulomatous disease.
2023-02-24 | Recent topics and advanced therapies in chronic granulomatous disease.
Chronic granulomatous disease (CGD) is a primary immunodeficiency characterized by the inability of phagocytes to produce reactive oxygen species (ROS) owing to a defect in any of the five components (CYBB/gp91phox, CYBA/p22phox, NCF1/p47phox, NCF2/p67phox, and NCF4/p40phox) and a concomitant regulatory component of Rac1/2 and CYBC1/Eros of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex. Patients with CGD are at an increased risk of life-threatening infections caused by catalase-positive bacteria and fungi and of inflammatory complications such as CGD colitis. Antimicrobial and azole antifungal prophylaxes have considerably reduced the incidence and severity of bacterial and improved fungal infections and overall survival. CGD studies have revealed the precise epidemiology and role of NADPH oxidase in innate immunity which has led to a new understanding of the importance of phagocyte oxygen metabolism in various host-defense systems and the fields leading to cell death processes. Moreover, ROS plays central roles in the determination of cell fate as secondary messengers and by modifying of various signaling molecules. According to this increasing knowledge about the effects of ROS on the inflammasomal system, immunomodulatory treatments, such as IFN-γ and anti-IL-1 antibodies, have been established. This review covers the current topics in CGD and the relationship between ROS and ROS-mediated pathophysiological phenomena. In addition to the shirt summary of hematopoietic stem cell transplantation and gene therapy, we introduce a novel ROS-producing enzyme replacement therapy using PEG-fDAO to compensate for NADPH oxidase deficiency.
2022-06-16 | Treatment with Polyethylene Glycol-Conjugated Fungal D-Amino Acid Oxidase Reduces Lung Inflammation in a Mouse Model of Chronic Granulomatous Disease.
Chronic granulomatous disease (CGD) is a primary immunodeficiency wherein phagocytes are unable to produce reactive oxygen species (ROS) owing to a defect in the nicotinamide adenine dinucleotide phosphate oxidase (NADPH) complex. Patients with CGD experience bacterial and fungal infections and excessive inflammatory disorders. Bone marrow transplantation and gene therapy are theoretically curative; however, residual pathogenic components cause inflammation and/or organic damage in patients. Moreover, antibiotic treatments may not help in preventing excessive inflammation due to the residual presence of fungal cell wall β-glucan. Thus, better treatment strategies against CGD are urgently required. Polyethylene glycol-conjugated recombinant porcine D-amino acid oxidase (PEG-pDAO) supplies ROS to defective NADPH oxidase in neutrophils of patients with CGD, following which the neutrophils regain bactericidal activity in vitro. In this study, we employed an in vivo nonviable Candida albicans (nCA)-induced lung inflammation model of gp91-phox knockout CGD mice and supplied novel PEG conjugates of Fusarium spp. D-amino acid oxidase (PEG-fDAO), as it exhibits higher enzyme activity than PEG-pDAO. The body weight, lung weight, and lung pathology were evaluated using three experimental strategies with the in vivo lung inflammation model to test the efficacy of the ROS-generating enzyme replacement therapy with PEG-fDAO. The lung weight and pathological findings suggest the condition was ameliorated by administration PEG-fDAO, followed by intraperitoneal injection of D-phenylalanine or D-proline. Although a more precise protocol is essential, these data reveal the targeted delivery of PEG-fDAO to the nCA-induced inflammation site and show that PEG-fDAO can be used to treat inflammation in CGD in vivo.
gene therapies
2026-09-25 | Prime Editing and Its Delivery: Recent Advances in Gene Correction for Genetic Diseases.
Prime editing (PE), as a transformative genome-editing technology, overcomes many of the limitations of CRISPR-Cas9, particularly by enabling high-fidelity base conversions independent of double-strand breaks (DSBs). This unique mechanism significantly reduces unintended insertions, deletions, and chromosomal rearrangements, positioning PE as a safer and more precise tool for therapeutic gene correction. Recently, the world's first FDA-approved PE clinical trial (PM359 for chronic granulomatous disease) was officially launched, representing a major milestone in the field and highlighting the growing clinical translational potential of PE for treating human genetic disorders. Since the introduction of PE technology, extensive research efforts have been devoted to improving its gene correction efficiency, expanding the editing window, broadening target-site compatibility, reducing the size of the editing protein, and optimizing in vivo delivery vector systems. This review systematically summarizes the key improvements and evolutionary progress in the prime editor design and its updated delivery systems, with a particular focus on innovative modifications that have successfully overcome technical barriers. This study also highlights recent advances in engineered PE variants and their derivative systems, which have collectively expanded the scope and precision of PE-mediated gene correction. Additionally, this study critically discusses the remaining limitations and challenges associated with its application.
2026-07-25 | Gene therapy approaches for inborn errors of immunity: from bench to bedside.
Inborn errors of immunity (IEI) are rare genetic defects that disrupt immune function, often resulting in life-threatening infections, malignancies, and immune dysregulation. Allogeneic hematopoietic stem cell transplantation (HSCT), a curative option for some diagnoses, is limited by donor availability and the risks of graft-versus-host disease. This review explores the 30-year evolution of autologous gene therapy as a vital alternative to allogeneic HSCT for IEIs. Literature search using PubMed for gene therapy for IEI in the last 20 years. We trace the transition from early gamma-retroviral gene addition, which successfully restored immunity in severe combined immunodeficiency (SCID) but carried high risks of insertional mutagenesis and leukemogenesis, to the adoption of safer self-inactivating lentiviral vectors. The field is rapidly advancing beyond viral gene addition toward highly precise gene‑editing technologies, including CRISPR/Cas9 and base/prime editing, which offer targeted correction with minimized genotoxicity. Recent milestones in diseases such as Wiskott -Aldrich syndrome (WAS) and chronic granulomatous disease (CGD) highlight enormous scientific success, yet significant barriers to accessibility, manufacturing, and affordability remain. Overcoming this requires innovative regulatory frameworks and collaborative funding models. Streamlining development and ensuring equitable access are essential next steps to establishing gene therapy as a safe alternative.
2026-07-08 | Chronic granulomatous disease: A multicenter study from the MENA region.
To study chronic granulomatous disease (CGD) in the Middle East and North Africa (MENA) region, we conducted a retrospective multicenter study to investigate the clinical features, infections, microorganisms, management, mortality, and survival of patients with CGDs. A total of 322 patients were included; the M:F ratio was 1.8, and the median ages at disease onset and diagnosis were 6.0 and 20.0 mo, respectively. The most common infections included pneumonia (58.0%), lymphadenitis (49.1%), skin abscesses/cellulitis (40.7%), and invasive pulmonary aspergillosis (17.7%). The most commonly isolated microorganisms were Staphylococcus spp. (22%), Aspergillus spp. (19.3%), and Pseudomonas spp. (11.2%). The genetic diagnosis was established in 108 (30.4%) patients: AR inheritance in 84.3% and X-linked in 15.7%. The median survival age is 8.5 years, and the estimated 10-year survival rate is 77.3%. CGD represents a significant disease burden in the MENA region, necessitating early intervention with molecular/genetic testing and HSCT availability.
2026-03-14 | The New Wave of Gene and Cell Therapies Across Diseases.
Recent years have seen rapid progress in biological treatments for genetic diseases, as well as conditions like type 1 diabetes that lack an obvious genetic component. The authors sought to explain why this progress has emerged at this particular moment. The best way to illustrate this is by showcasing a wide range of therapies targeting diverse diseases. This progress has been driven by technological advances in genetically modified CAR-T and CAR-NK cells (e.g., using CRISPR or transgenes), which have led to significant improvements in cancer therapy. A key trend now is the emergence of "off-the-shelf" approaches aimed at generating cellular therapies compatible with a range of recipients by mitigating alloreactivity and immune rejection. Different diseases impose distinct biological and logistical limitations; thus, treatment of each patient requires an appropriate strategy. Emerging advances include the modification of therapeutic cells, either ex vivo or in vivo. Current options for transgene delivery mainly comprise lipid nanoparticles (LNPs), adeno-associated virus (AAV) vectors, and lentiviral vectors. Researchers also focus on selecting suitable promoters for specific expression in selected cell types. Altogether, these advances have led to remarkable progress in treating various diseases in recent years. This publication discusses the development of biological therapies, with particular emphasis on cell and gene therapies, illustrated by viable examples across various disorders. It covers implemented solutions for several types of cancer, as well as selected hereditary diseases and syndromes, including Huntington's disease, carbamoyl phosphate synthetase 1 (CPS1) deficiency, hemiplegia, epidermolysis bullosa, chronic granulomatous disease, and congenital deafness. Emerging applications in heart diseases and diabetes are also summarized, along with therapeutic strategies involving tRNA gene editing. Although numerous strategies exist, only the most representative, practical, and up-to-date examples are emphasized.
2026-02-22 | Human infections caused by pathogenic Burkholderia: current clinical challenges and future perspectives.
The genus Burkholderia comprises diverse environmental bacteria, although only a limited number of species are clinically significant. Among these, Burkholderia mallei, Burkholderia pseudomallei, and the Burkholderia cepacia complex (Bcc) are the primary human pathogens associated with severe infections. This review aims to synthesize current knowledge on these species, focusing on their epidemiology, pathogenicity, diagnostic approaches, and treatment challenges, while identifying key gaps and future research directions. A narrative synthesis of the literature was conducted, integrating findings from microbiological, clinical, and genomic studies addressing major pathogenic Burkholderia species and their management. B. mallei causes glanders, a zoonotic infection transmitted through contact with infected animals. B. pseudomallei, an environmental organism endemic to tropical and subtropical regions, causes melioidosis, particularly in individuals with risk factors such as diabetes. The Bcc, comprising over 20 species, poses significant risks in patients with cystic fibrosis and chronic granulomatous disease, where it may lead to severe outcomes including "cepacia syndrome" and nosocomial outbreaks linked to contaminated medical products. Pathogenic Burkholderia species exhibit highly dynamic genomes shaped by horizontal gene transfer, contributing to virulence and intrinsic resistance to multiple antimicrobials, including polymyxins and many β-lactams. Advances in laboratory diagnosis include the use of molecular techniques, mass spectrometry, and whole-genome sequencing alongside conventional methods. Treatment remains challenging due to multidrug resistance, often requiring prolonged and intensive therapeutic regimens. Clinically significant Burkholderia species present substantial diagnostic and therapeutic challenges due to their virulence and intrinsic antimicrobial resistance. Improved diagnostic strategies, optimized treatment protocols, and further research into prevention and control measures are essential to mitigate their clinical impact.
other
2026-06-04 | Severe Colitis in X-Linked Chronic Granulomatous Disease Bridged to Hematopoietic Cell Transplantation with Tacrolimus and Biologic Agents
Case A 22-month-old boy presented with hematochezia beginning in infancy. He had a history of lymphadenitis after Bacille Calmette-Guérin vaccination. Based on absent neutrophil oxidative burst activity, absent gp91phox expression (0%), and a CYBB variant (c.252G>A), he was diagnosed with X-linked chronic granulomatous disease (X-CGD). Colonoscopy revealed ulcerative colitis-like pancolitis characterized by diffuse loss of the vascular pattern, fine mucosal granularity, and friability, without perianal fistula. Histopathology showed neither foamy histiocytes nor granulomas. Treatment with 5-aminosalicylic acid (5-ASA) was discontinued because of intolerance. Vedolizumab (VED) was insufficiently effective, and prednisolone (PSL) and tacrolimus (Tac) were added. Although Tac induced remission at higher trough concentrations, relapse recurred as the trough concentration was lowered. After mirikizumab (MRK) was introduced, clinical remission could be maintained at lower Tac trough concentrations. However, colitis remained difficult to fully control, and prolonged Tac use led to renal dysfunction and septic shock secondary to a catheter-related infection. He therefore underwent unrelated donor bone marrow transplantation at 32 months of age. Conditioning consisted of fludarabine, dose-adjusted busulfan, antithymocyte globulin, and 3-Gy total body irradiation. For graft-versus-host disease (GVHD) prophylaxis, Tac and short-course methotrexate were used. At the start of conditioning, MRK was replaced with VED. Neutrophil engraftment was achieved on day 17 after transplantation, and hematochezia resolved. Although skin GVHD and vomiting developed, endoscopy showed improvement of colitis. Erythema in the stomach and duodenum prompted the addition of PSL while VED was continued, resulting in prompt symptom improvement. VED was discontinued 4 months after transplantation, Tac 9 months after transplantation. He remains alive without recurrence of colitis 1 year after transplantation. Discussion Anti-tumor necrosis factor-alpha agents are generally avoided in chronic granulomatous disease-associated colitis because fatal cases have been reported. The efficacy of VED and ustekinumab, an anti–interleukin-12/23 antibody, has been described in case series, but an optimal treatment strategy for refractory cases has not been established. In this case, MRK reduced the Tac requirement, and VED was safely continued before and after transplantation as bridging therapy. Careful selection of biologic agents with attention to infection risk may facilitate bridging to transplantation in refractory X-CGD–associated colitis. Further accumulation of cases is needed to establish an optimal treatment strategy.
2025-12-29 | Incidence, risk factors and outcomes of BCGosis following BCG vaccination in infants: a systematic review and meta-analyses.
The Bacille Calmette-Guerin (BCG) vaccine is widely administered in countries with high tuberculosis (TB) prevalence to protect against severe forms of childhood TB. Despite its efficacy, the vaccine can lead to adverse effects like BCGosis, a severe but rare condition marked by systemic granulomatous inflammation. This is because the vaccine is comprised of attenuated BCG bacteria which has the potential to cause uncontrolled dissemination beyond the injection site. Immunocompromised children are particularly vulnerable to this side effect. Through a systematic review of the current literature, this analysis seeks to determine the global incidence of BCGosis and identify critical risk factors associated with its onset. The review was conducted in accordance with the PRISMA-2020 guidelines (Preferred Reporting Items for Systematic Reviews and Meta-Analyses). The review's objectives and scope were framed using the PICOS (Population, Intervention, Comparison, Outcomes and Study Design) framework. Not surprisingly, BCGosis is most prevalent in infants with underlying genetic immunodeficiencies such as severe combined immunodeficiency (SCID) and chronic granulomatous disease (CGD). We found a high correlation between the development of BCGosis and genetic mutations affecting certain immune processes, notably those involved in NADPH oxidase function and interferon-gamma signalling. The risks of developing these mutations also correlated with the prevalence of consanguinity, a common practice in certain populations. Factors like early neonatal vaccination (often within the first week of life) and variations in BCG strains may also influence BCGosis risk. There is an urgent need for enhanced pre-vaccination screening for genetic and immunologic vulnerabilities in infants at hight risk for BCGosis, particularly in populations with high consanguinity rates. Alternatively, considerations should be made as to modifying existing vaccination schedules or postponing BCG immunization until immune competency can be confirmed in these high risk groups.
2025-10-09 | Antisense phosphorodiamidate morpholino oligomers retain activity in Burkholderia cepacia complex biofilm.
Members of the Burkholderia cepacia complex (Bcc) are known to cause severe pulmonary infections in immunocompromised hosts, namely individuals with cystic fibrosis (CF) and chronic granulomatous disease (CGD). Due to innate antibiotic-resistant phenotypes and the formation of protective biofilms, Bcc bacteria are difficult to eradicate from colonized lungs using traditional antibiotics. An alternative therapeutic approach involves the use of antisense molecules, specifically peptide-conjugated phosphorodiamidate morpholino oligomers (PPMOs). Previously, we found that PPMOs targeting the acyl carrier protein (AcpP) can reduce the burden of planktonic Bcc bacteria. Antimicrobial activities of AcpP PPMOs were assessed against established biofilms produced by Bcc clinical isolates, in which viable cells, biomass, and metabolic activity were enumerated. Bactericidal effects were further evaluated by microscopy. Cytotoxicity of these molecules was tested in human pulmonary cell lines. AcpP PPMO treatment resulted in over three-log reductions (p < 0.0001) in biofilm burden across five clinical isolates of Bcc that were tested. A dose-dependent effect was observed (5-40 μΜ). This effect was visualized using confocal and scanning electron microscopy. We further demonstrated that PPMOs associate with bacterial cells in a time-dependent fashion using a fluorescently labeled AcpP PPMO with B. cenocepacia K56-2 DsRed. Finally, alveolar cells retained viability with AcpP PPMOs at bactericidal dosages. The Bcc biofilm setting is not a deterrent against PPMO delivery or antimicrobial activity. This is supported by the colocalization of AcpP PPMOs with cells, membrane destruction, loss of cell viability, and biomass reduction. Collectively, these data provide evidence that AcpP PPMOs are a promising therapeutic strategy in the treatment of Bcc infections.
2025-09-23 | A 10-year-old Girl with an 8-Month History of Progressive Photophobia and Hemeralopia.
To report a case of nonparaneoplastic autoimmune retinopathy in a 10-year-old female with chronic granulomatous disease (CGD) due to compound heterozygous mutations in NCF1. The patient was evaluated at Columbia University Irving Medical Center using a comprehensive multimodal imaging protocol that included color fundus photography, short-wave autofluorescence (SW-AF), and spectral-domain optical coherence tomography (SD-OCT). Functional assessments were conducted using Goldmann visual fields and full-field electroretinography (ERG) were completed on-site and followed the ISCEV standard protocols to ensure consistent and reproducible measurements of photoreceptor activity. A 10-year-old female presented with decreased visual acuity, light sensitivity, and decreased color vision over the past 8 months with no improvement upon refraction. Upon detection of anti-retinal antibodies, treatment was initiated with stabilization and improvement of visual acuity and ERG responses with rituximab treatment. Whole genome sequencing revealed two mutations in NCF1 causing chronic granulomatous disease. We present a case of autoimmune retinopathy in a CGD patient with compound heterozygous mutations in the NCF1 gene. This novel association may suggest that autoimmunity may be involved the development of the chorioretinal lesions seen in CGD patients. It also supports the use of rituximab in the management of autoimmune retinopathy.
2025-09-04 | Importance of BCG Vaccination at birth in Pediatric Patients with Chronic Granulomatous Disease after Hematopoietic Stem Cell Transplantation in Developing Countries.
Recent advances in hematopoietic stem cell transplantation (HSCT) have improved clinical outcomes; however, various factors continue to influence HSCT success, especially vaccination in immunocompromised patients who receive vaccination at birth. While several studies have investigated the efficacy of vaccines in Chronic Granulomatous Disease (CGD) patients, the specific impact of vaccination on HSCT outcomes in these patients has not yet been studied. This study aimed to address an important gap in the current literature by investigating the effects of BCG vaccination on HSCT outcomes in patients with CGD. In this prospective study, 24 pediatric patients with CGD were enrolled from 2016 to 2022, all of whom received the same reduced-intensity conditioning (RIC) regimen before HSCT. Of these, 12 patients received the Bacillus Calmette-Guérin (BCG) vaccine, while 14 patients were not vaccinated. Contrary to other studies, our results showed that CGD patients who received the BCG vaccine before HSCT experienced varying degrees of BCGosis and BCGitis. Specifically, 8 patients showed symptoms of BCGosis, while 4 patients showed symptoms of BCGitis. In addition, our findings revealed no significant differences in graft-versus-host disease (GvHD) and other complications of HSCT between BCG-vaccinated and non-BCG-vaccinated CGD patients, although the overall survival (OS) rate was lower in the vaccinated group. This may be attributed to the reduced-intensity conditioning regimen applied to all patients which can balance HSCT outcome in CGD patients. Our study emphasizes the importance of screening and diagnosing immunodeficient patients at birth, especially in developing countries where BCG vaccine is administered at birth, as post- vaccination complications can significantly affect HSCT outcomes and subsequent treatments. BCG vaccination can significantly affect HSCT outcomes and subsequent treatments.
small molecules
2026-08-14 | First report of Rhinocladiella mackenziei osteomyelitis with CNS dissemination in a pediatric CGD patient post-HSCT: A case report and literature review.
Rhinocladiella mackenziei is a rare neurotropic dematiaceous fungus that causes cerebral phaeohyphomycosis, predominantly in immunocompetent adults with a geographical predilection to the Middle East. Pediatric infection is exceptionally rare, and to our knowledge, no cases of combined osseous and central nervous system involvement following hematopoietic stem cell transplantation (HSCT) have been reported. We report a male child with autosomal recessive chronic granulomatous disease (CGD) who developed traumatic forearm osteomyelitis due to R. mackenziei several months after haploidentical HSCT. Subsequent neuroimaging demonstrated intracerebral abscesses despite immune reconstitution. The infection persisted despite prolonged combination antifungal therapy with voriconazole and amphotericin B and ultimately required neurosurgical excision. The patient recovered without neurological sequelae and continues on long-term posaconazole therapy. This case highlights R. mackenziei as a cause of severe, invasive, disseminated fungal disease in pediatric post-bone marrow transplant patients and demonstrates extracerebral inoculation with subsequent CNS dissemination. It also underscores the importance of early recognition and a combined medical-surgical approach in management of refractory disease.
2026-08-03 | Prospective Study of Targeted Busulfan-Fludarabine Conditioning for Hematopoietic Stem Cell Transplantation in Genetic Rare Diseases.
Genetic rare diseases (GRDs), including chronic granulomatous disease, familial hemophagocytic lymphohistiocytosis, and congenital neutropenia, often require hematopoietic stem cell transplantation (HSCT) as the only curative option. Conventional myeloablative regimens are associated with considerable toxicity, whereas reduced-intensity regimens carry an increased risk of graft failure. To address the narrow therapeutic window of busulfan, we developed a pharmacokinetic-guided dosing strategy and evaluated it in a prospective study. Children with GRDs undergoing HSCT received a conditioning regimen comprising fludarabine 40 mg/m2 (days -8 to -4), anti-thymocyte globulin 2.5 mg/kg (days -4 to -2), and once-daily busulfan (days -9 to -6), with intensive pharmacokinetic monitoring and dose adjustments to achieve target exposure. Twenty patients with GRDs (median age, 3.6 years) received HSCT with a targeted busulfan-based myeloablative regimen. No engraftment failure occurred. Cumulative incidences of Grade II-IV and Grade III-IV acute graft-versus-host disease and moderate-to-severe chronic graft-versus-host disease were 25%, 5%, and 23%, respectively. Ten-year overall survival, event-free survival, and transplant-related mortality rates were 90%, 90%, and 5%, respectively. Pharmacokinetic-guided busulfan-fludarabine conditioning achieved reliable engraftment with acceptable toxicity in children with GRDs, supporting its use as a safe, effective HSCT conditioning strategy in vulnerable populations.
2026-07-19 | NADPH oxidase 2 (NOX2)-independent inducers of neutrophil extracellular traps promote resolution of chronic inflammation.
Reactive oxygen species (ROS) generated by NADPH oxidase 2 (NOX2) are essential for antimicrobial defense but also for the resolution of inflammation. NOX2 deficiency, as observed in chronic granulomatous disease (CGD), predisposes to persistent sterile inflammation. Current therapeutic strategies largely rely on nonspecific immunosuppression or require residual NOX2 activity, while systemic ROS-inducing therapies are limited by toxicity. Here, we present a NOX2-independent approach to restore inflammation-resolving ROS signaling using N-alkylaminoferrocene-based prodrugs (pro-NAAFs), which amplify pre-existing ROS rather than generating ROS indiscriminately. Among several candidates, prodrug 1 emerged as the most potent and well-tolerated ROS amplifier. In human neutrophils, prodrug 1 induced strong ROS production and neutrophil extracellular trap (NET) formation. These responses occurred independently of NOX2 and were maintained in CGD-derived neutrophils. Similar NOX2-independent ROS induction and NET formation were observed in immune cells from wild-type and NOX2-dysfunctional Ncf1∗∗ mice. Prodrug 1-induced NETs aggregated into high-density structures (aggNETs) capable of degrading pro-inflammatory mediators in vitro. Prodrug 1 also inhibited neutrophil inflammasome activation. In vivo, subcutaneous administration of prodrug 1 reduced inflammatory mediator levels in air pouches, promoted resolution of chronic arthritis in Ncf1∗∗ mice, and protected from bone destruction. Transcriptomic analyses indicated early suppression of inflammatory pathways and restoration of neutrophil maturation trajectories towards a wild-type-like state. While prodrug 1 increased protein oxidation markers, it shifted systemic oxysterol profiles towards an inflammation-resolving phenotype. These findings identify pro-NAAFs as NOX2-independent ROS amplifiers capable of restoring inflammatory resolution and highlight their therapeutic potential for chronic inflammatory conditions linked to NOX2-dysfunction.
2026-06-25 | Thalidomide for CGD-related inflammatory bowel disease: A randomized, double-blind trial.
Chronic granulomatous disease-related inflammatory bowel disease (CGD-IBD) requires effective and safe therapies, as conventional immunosuppressants increase infection risk. Thalidomide, with anti-inflammatory and immunomodulatory effects, may represent a therapeutic option. This study was conducted to explore the preliminary efficacy and safety of thalidomide for CGD-IBD in a multicenter, randomized, double-blind, placebo-controlled, parallel-group phase II trial. Patients were randomized to thalidomide or placebo for a 12-wk blinded phase, followed by a 12-wk extension thalidomide phase. The primary endpoint was achievement of remission or a ≥20-point reduction in the Pediatric Ulcerative Colitis Activity Index. Eight male patients were randomized and analyzed. The primary endpoint was achieved by 1/3 of thalidomide patients versus 0/5 in the placebo group during the blinded phase, and by 5/8 in the extension phase. Secondary endpoints and exploratory endoscopy showed improvements. CGD-related infection rates were comparable before and after treatment. Thalidomide met the prespecified efficacy criterion with an acceptable safety profile in CGD-IBD, suggesting a promising therapeutic option that warrants further clinical studies.
2026-06-18 | Case Report: Invasive pulmonary aspergillosis caused by Aspergillus lentulus in a boy with chronic granulomatous disease.
Aspergillus lentulus is a slow-growing and drug-resistant fungus, which has been primarily reported in adults, usually immunocompromised ones, suffering from invasive pulmonary aspergillosis (IPA). This condition is rare in children. Here, we report a case of invasive pulmonary aspergillosis due to Aspergillus lentulus in a boy with no history of recurrent infections who presented with a prolonged fever of unknown origin. Based on chest CT scan findings showing typical halo signs, a fungal infection was strongly suspected. Empirical antifungal therapy was initiated at early admission but failed to resolve the persistent fever in this case. The causative pathogen was confirmed by blood metagenomic next-generation sequencing (mNGS). Subsequent genetic analysis identified a pathogenic mutation in the X-linked CYBB gene, confirming chronic granulomatous disease (CGD). Eventually, following a combination therapy of voriconazole and micafungin, the boy became afebrile and was discharged, pending hematopoietic stem cell transplantation (HSCT). To our knowledge, no previous cases of Aspergillus lentulus infection in children with CGD have been reported in the literature. This case underscores the critical importance of identifying the causative microorganism. It also highlights the value of emerging detection methods, such as mNGS. At present, there is no consensus for the optimal antifungal regimen against pediatric Aspergillus lentulus infections. Clinical improvement was achieved in this patient following combination therapy with voriconazole and micafungin, offering a practical therapeutic reference for managing this refractory fungal infection.
cell therapies
2026-07-09 | Clinical analysis and follow up study of chronic granulomatous disease with neonatal onset
Objective To address the existing gap in knowledge regarding the small subset of chronic granulomatous disease (CGD) patients who present during the neonatal period, this study aimed to characterize their clinical features, genetic profiles, and long-term prognosis. Methods This study retrospectively selected CGD patients with neonatal onset who were diagnosed using neutrophil respiratory burst tests and genetic analysis at the Guangzhou Women and Children's Medical Center, Guangzhou Medical University, between January 2018 and September 2024. Results This study included nine male patients diagnosed with CGD presenting with neonatal onset. The median age at onset was 20 days (7–23 days). Pneumonia was observed in eight patients (88.9%), with Aspergillus species detected in five of these cases (62.5%). The stimulation index (SI) in the neutrophil oxidative burst assay was significantly reduced. All nine patients exhibited hemizygous variants in the CYBB gene. The median hospital stay was 42 days (15.5–48 days). Three patients died due to disease progression during their initial hospitalization. Regarding long-term prognosis, one patient was lost to follow-up at six months of age, and three patients died from severe infections during infancy. The remaining two patients underwent hematopoietic stem cell transplantation (HSCT) and achieved complete clinical remission. Conclusion Patients with CGD presenting in the neonatal period predominantly harbor mutations in the CYBB gene, which are associated with severe clinical manifestations. Aspergillus species are the most common pathogens in these patients. Although the prognosis is generally poor, it may be improved by hematopoietic stem cell transplantation (HSCT).
2026-06-20 | Expansion and CAR engineering of granulocyte-monocyte progenitors for cellular immunotherapy.
Engineered macrophages are promising for tumor immunotherapy but are limited by poor ex vivo expansion, genetic tractability, and biodistribution after transfer. Here, we develop defined culture conditions that enable long-term expansion of mouse and human granulocyte-monocyte progenitors (GMPs) while preserving progenitor identity and myeloid potential, establishing GMPs as a renewable engineering platform. Mechanistically, we identify myeloperoxidase as a regulator of GMP proliferation. Expanded GMPs are readily engineered and, after transfer, seed hematopoietic niches and generate donor-derived myelopoiesis that restores antibacterial defense in chronic granulomatous disease mice and yields abundant tumor-infiltrating macrophages. GMPs engineered with chimeric antigen receptors (CARs) suppress CD19-positive leukemia and human epidermal growth factor receptor 2 (HER2)-positive solid tumors. We further introduce a CAR incorporating an immunoglobulin G (IgG) Fc domain that recruits host Fc receptor-expressing phagocytes, enables T cell priming across major histocompatibility complex (MHC) mismatch, and enhances efficacy in immunocompetent allogeneic cancer models. Together, these findings establish expandable GMPs as a scalable platform for engineered immunotherapy.
2026-05-22 | Non-cryopreserved Kx negative packed red cell concentrates to support hematopoietic stem cell transplantation in McLeod contiguous gene deletion syndrome.
Transfusion management of Kx- individuals with McLeod phenotype (MLP) is highly challenging, particularly as cryopreservation affects red blood cell (RBC) concentrate quality. We developed a concept to provide non-cryopreserved Kx- RBCs over the complete period of hematopoietic stem cell transplantation (HSCT) for treatment of X-linked chronic granulomatous disease (X-CGD) with MLP. An infant with a large deletion affecting 12 protein-coding genes, including DMD, PRRG1, LANCL3, XK, CYBB, and DYNLT3, leading to CGD, Duchenne muscular dystrophy, and MLP, was scheduled for HSCT with the need of Kx- blood supply. No Kx- and RhD compatible donors were identified by rare donor programs, and autologous blood collection was not possible. In an interdisciplinary multicenter effort pre- and post-HSCT blood management, including procurement of non-cryopreserved allogeneic Kx- RBCs from an individual with MLP, was orchestrated, balancing donations, storage, pediatric RBC preparation, and irradiation with the clinical schedule. Our concept ensured compatible blood supply from 100 days prior HSCT to the peritransplant phase. The patient received 5 non-cryopreserved Kx- pediatric RBCs and was discharged with complete chimerism at day +68. The screen was repeatedly negative for antibodies to high frequency RBC antigens. After 2.8 years, the patient remained independent of transfusions and was without signs of graft-versus-host disease. Close coordination between institutions and disciplines and process optimization allow readily available provision of non-cryopreserved Kx- RBCs to support HSCT to a patient with unique contiguous gene deletion syndrome of X chromosome.
2026-05-22 | Hematopoietic stem cell transplantation following invasive mold infection in chronic granulomatous disease: Insights from a case series and literature review.
Chronic granulomatous disease (CGD) is an inborn error of immunity leading to severe invasive mold infections (IMIs). Questions remain regarding the safety of hematopoietic stem cell transplantation (HSCT) in patients following IMI. We retrospectively collected data from CGD patients undergoing HSCT within 2 years after a diagnosis of probable or proven IMI in France. The primary endpoint was to describe 1-year overall survival (OS). 14 patients were included, with aspergillosis (n = 10), mucormycosis (N = 2), scedosporiosis, or lomentosporiosis (n = 1 each). IMI status at time of HCST included four in complete response, four in partial response (PR), one in stable response (SR), and five with disease progression (DP). 1-year OS was 86 % (12/14). Two patients with scedosporiosis and lomentosporiosis died before engraftment. The remaining patients all achieved engraftment followed by prolonged clinical response of IMI. HSCT appears safe in patients with complete response or PR of IMI and could be a promising curative option for progressive IMI, specifically in those with invasive aspergillosis.
2026-05-22 | How I Treat: Chronic granulomatous disease.
Chronic granulomatous disease (CGD) is a rare inborn error of immunity with both high risk of invasive bacterial and fungal infections as well as inflammatory complications. Though diagnostic testing via the dihydrorhodamine assay is widely available, disease recognition can be challenging due to the broad range of initial clinical presentations. Preventative antimicrobial therapy is the backbone of management, while treatment of inflammatory disease remains a challenge. Definitive therapy via hematopoietic stem cell transplantation is increasingly favored for resolution of long-term disease risks, while gene therapy remains a promising but investigational treatment. Here, we present our consensus approach to diagnosis and management of CGD.
proteins
2025-12-01 | Mitigating chronic granulomatous disease (CGD) through mutational analysis and de novo drug design targeting the CYBA gene through different approaches
Chronic Granulomatous Disease (CGD) is a rare genetic immunodeficiency disorder that arises from mutations in genes responsible for encoding the NADPH oxidase complex, including the CYBA. Such genetic alterations impair the production of reactive oxygen species (ROS), which culminates in impaired microbial eradication, recurrent infections, and the formation of granulomas. This study aimed to conduct an in silico mutational analysis of the CYBA gene and design a novel therapeutic candidate to mitigate Chronic Granulomatous disease. The FASTA sequence of the protein Cytochrome b-245 light chain was retrieved from the UniProt. Mutational analysis was performed using BLASTp and UniProt to identify and confirm the possible mutations. AlphaFold server 3 was utilized to generate the mutated 3D structure of the CYBA protein. The pharmacokinetics and toxicity profiles performed using ADMET AI and ProToxII indicated that the drug compound is nontoxic with medium solubility. Finally, the molecular dynamics simulation studies were carried out using the OpenMM engine with the AMBER force field. The mutated protein structure was validated and assessed for quality using Ramachandran and ERRAT analysis which showed a quality factor of 98.5 according to ERRAT and 98.6 % of residues within favorable regions. For drug design, the ELEA-3D tool was utilized to synthesize the 20 ligands against the targeted protein from which the best one was selected based on a confidence score of 81.23 %. The molecular docking and interaction analysis was carried out utilizing HDock yielding a docking score of −165.5 and Ligplot+ and Discovery studio. The quality, validity, interaction analysis, and non-toxicity nature of the designed drug compound suggest it is a promising candidate for Chronic Granulomatous disease.
2025-07-17 | Interferon gamma rebalances immunopathological signatures in chronic granulomatous disease through metabolic rewiring.
Chronic granulomatous disease (CGD) is a primary immunodeficiency characterized by recurrent life-threatening infections and hyperinflammatory complications. It is caused by mutations in the reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex and the consequent loss of reactive oxygen species (ROS) production. Recombinant human interferon gamma (rIFN-γ) prophylaxis reduces the risk of severe infections, but the mechanisms behind its efficacy in CGD are still an open question, as it does not restore NADPH oxidase-dependent ROS production. Here, we demonstrate that the innate immune cells of patients with CGD are transcriptionally and functionally reprogrammed to a hyperactive inflammatory status, displaying an impaired in vitro induction of trained immunity. CGD monocytes have reduced intracellular amino acid concentrations and profound functional metabolic defects, both at the level of glycolysis and mitochondrial respiration. Ex vivo and in vivo treatments with IFN-γ restored these metabolic defects and reduced excessive interleukin 1β (IL-1β) and IL-6 production in response to fungal stimuli in CGD monocytes. These data suggest that prophylactic rIFN-γ modulates the metabolic status of innate immune cells in CGD. These data shed light on the effects of NADPH oxidase-derived ROS deficiency to the metabolic programs of immune cells and pose the basis for targeting this immunometabolic axis, potentially beyond CGD, with IFN-γ immunotherapy.
2024-07-07 | Self-extinguishing relay waves enable homeostatic control of human neutrophil swarming.
Neutrophils collectively migrate to sites of injury and infection. How these swarms are coordinated to ensure the proper level of recruitment is unknown. Using an ex vivo model of infection, we show that human neutrophil swarming is organized by multiple pulsatile chemoattractant waves. These waves propagate through active relay in which stimulated neutrophils trigger their neighbors to release additional swarming cues. Unlike canonical active relays, we find these waves to be self-terminating, limiting the spatial range of cell recruitment. We identify an NADPH-oxidase-based negative feedback loop that is needed for this self-terminating behavior. We observe near-constant levels of neutrophil recruitment over a wide range of starting conditions, revealing surprising robustness in the swarming process. This homeostatic control is achieved by larger and more numerous swarming waves at lower cell densities. We link defective wave termination to a broken recruitment homeostat in the context of human chronic granulomatous disease.
2023-02-24 | Recent topics and advanced therapies in chronic granulomatous disease.
Chronic granulomatous disease (CGD) is a primary immunodeficiency characterized by the inability of phagocytes to produce reactive oxygen species (ROS) owing to a defect in any of the five components (CYBB/gp91phox, CYBA/p22phox, NCF1/p47phox, NCF2/p67phox, and NCF4/p40phox) and a concomitant regulatory component of Rac1/2 and CYBC1/Eros of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex. Patients with CGD are at an increased risk of life-threatening infections caused by catalase-positive bacteria and fungi and of inflammatory complications such as CGD colitis. Antimicrobial and azole antifungal prophylaxes have considerably reduced the incidence and severity of bacterial and improved fungal infections and overall survival. CGD studies have revealed the precise epidemiology and role of NADPH oxidase in innate immunity which has led to a new understanding of the importance of phagocyte oxygen metabolism in various host-defense systems and the fields leading to cell death processes. Moreover, ROS plays central roles in the determination of cell fate as secondary messengers and by modifying of various signaling molecules. According to this increasing knowledge about the effects of ROS on the inflammasomal system, immunomodulatory treatments, such as IFN-γ and anti-IL-1 antibodies, have been established. This review covers the current topics in CGD and the relationship between ROS and ROS-mediated pathophysiological phenomena. In addition to the shirt summary of hematopoietic stem cell transplantation and gene therapy, we introduce a novel ROS-producing enzyme replacement therapy using PEG-fDAO to compensate for NADPH oxidase deficiency.
2022-06-16 | Treatment with Polyethylene Glycol-Conjugated Fungal D-Amino Acid Oxidase Reduces Lung Inflammation in a Mouse Model of Chronic Granulomatous Disease.
Chronic granulomatous disease (CGD) is a primary immunodeficiency wherein phagocytes are unable to produce reactive oxygen species (ROS) owing to a defect in the nicotinamide adenine dinucleotide phosphate oxidase (NADPH) complex. Patients with CGD experience bacterial and fungal infections and excessive inflammatory disorders. Bone marrow transplantation and gene therapy are theoretically curative; however, residual pathogenic components cause inflammation and/or organic damage in patients. Moreover, antibiotic treatments may not help in preventing excessive inflammation due to the residual presence of fungal cell wall β-glucan. Thus, better treatment strategies against CGD are urgently required. Polyethylene glycol-conjugated recombinant porcine D-amino acid oxidase (PEG-pDAO) supplies ROS to defective NADPH oxidase in neutrophils of patients with CGD, following which the neutrophils regain bactericidal activity in vitro. In this study, we employed an in vivo nonviable Candida albicans (nCA)-induced lung inflammation model of gp91-phox knockout CGD mice and supplied novel PEG conjugates of Fusarium spp. D-amino acid oxidase (PEG-fDAO), as it exhibits higher enzyme activity than PEG-pDAO. The body weight, lung weight, and lung pathology were evaluated using three experimental strategies with the in vivo lung inflammation model to test the efficacy of the ROS-generating enzyme replacement therapy with PEG-fDAO. The lung weight and pathological findings suggest the condition was ameliorated by administration PEG-fDAO, followed by intraperitoneal injection of D-phenylalanine or D-proline. Although a more precise protocol is essential, these data reveal the targeted delivery of PEG-fDAO to the nCA-induced inflammation site and show that PEG-fDAO can be used to treat inflammation in CGD in vivo.
gene therapies
2026-09-25 | Prime Editing and Its Delivery: Recent Advances in Gene Correction for Genetic Diseases.
Prime editing (PE), as a transformative genome-editing technology, overcomes many of the limitations of CRISPR-Cas9, particularly by enabling high-fidelity base conversions independent of double-strand breaks (DSBs). This unique mechanism significantly reduces unintended insertions, deletions, and chromosomal rearrangements, positioning PE as a safer and more precise tool for therapeutic gene correction. Recently, the world's first FDA-approved PE clinical trial (PM359 for chronic granulomatous disease) was officially launched, representing a major milestone in the field and highlighting the growing clinical translational potential of PE for treating human genetic disorders. Since the introduction of PE technology, extensive research efforts have been devoted to improving its gene correction efficiency, expanding the editing window, broadening target-site compatibility, reducing the size of the editing protein, and optimizing in vivo delivery vector systems. This review systematically summarizes the key improvements and evolutionary progress in the prime editor design and its updated delivery systems, with a particular focus on innovative modifications that have successfully overcome technical barriers. This study also highlights recent advances in engineered PE variants and their derivative systems, which have collectively expanded the scope and precision of PE-mediated gene correction. Additionally, this study critically discusses the remaining limitations and challenges associated with its application.
2026-07-25 | Gene therapy approaches for inborn errors of immunity: from bench to bedside.
Inborn errors of immunity (IEI) are rare genetic defects that disrupt immune function, often resulting in life-threatening infections, malignancies, and immune dysregulation. Allogeneic hematopoietic stem cell transplantation (HSCT), a curative option for some diagnoses, is limited by donor availability and the risks of graft-versus-host disease. This review explores the 30-year evolution of autologous gene therapy as a vital alternative to allogeneic HSCT for IEIs. Literature search using PubMed for gene therapy for IEI in the last 20 years. We trace the transition from early gamma-retroviral gene addition, which successfully restored immunity in severe combined immunodeficiency (SCID) but carried high risks of insertional mutagenesis and leukemogenesis, to the adoption of safer self-inactivating lentiviral vectors. The field is rapidly advancing beyond viral gene addition toward highly precise gene‑editing technologies, including CRISPR/Cas9 and base/prime editing, which offer targeted correction with minimized genotoxicity. Recent milestones in diseases such as Wiskott -Aldrich syndrome (WAS) and chronic granulomatous disease (CGD) highlight enormous scientific success, yet significant barriers to accessibility, manufacturing, and affordability remain. Overcoming this requires innovative regulatory frameworks and collaborative funding models. Streamlining development and ensuring equitable access are essential next steps to establishing gene therapy as a safe alternative.
2026-07-08 | Chronic granulomatous disease: A multicenter study from the MENA region.
To study chronic granulomatous disease (CGD) in the Middle East and North Africa (MENA) region, we conducted a retrospective multicenter study to investigate the clinical features, infections, microorganisms, management, mortality, and survival of patients with CGDs. A total of 322 patients were included; the M:F ratio was 1.8, and the median ages at disease onset and diagnosis were 6.0 and 20.0 mo, respectively. The most common infections included pneumonia (58.0%), lymphadenitis (49.1%), skin abscesses/cellulitis (40.7%), and invasive pulmonary aspergillosis (17.7%). The most commonly isolated microorganisms were Staphylococcus spp. (22%), Aspergillus spp. (19.3%), and Pseudomonas spp. (11.2%). The genetic diagnosis was established in 108 (30.4%) patients: AR inheritance in 84.3% and X-linked in 15.7%. The median survival age is 8.5 years, and the estimated 10-year survival rate is 77.3%. CGD represents a significant disease burden in the MENA region, necessitating early intervention with molecular/genetic testing and HSCT availability.
2026-03-14 | The New Wave of Gene and Cell Therapies Across Diseases.
Recent years have seen rapid progress in biological treatments for genetic diseases, as well as conditions like type 1 diabetes that lack an obvious genetic component. The authors sought to explain why this progress has emerged at this particular moment. The best way to illustrate this is by showcasing a wide range of therapies targeting diverse diseases. This progress has been driven by technological advances in genetically modified CAR-T and CAR-NK cells (e.g., using CRISPR or transgenes), which have led to significant improvements in cancer therapy. A key trend now is the emergence of "off-the-shelf" approaches aimed at generating cellular therapies compatible with a range of recipients by mitigating alloreactivity and immune rejection. Different diseases impose distinct biological and logistical limitations; thus, treatment of each patient requires an appropriate strategy. Emerging advances include the modification of therapeutic cells, either ex vivo or in vivo. Current options for transgene delivery mainly comprise lipid nanoparticles (LNPs), adeno-associated virus (AAV) vectors, and lentiviral vectors. Researchers also focus on selecting suitable promoters for specific expression in selected cell types. Altogether, these advances have led to remarkable progress in treating various diseases in recent years. This publication discusses the development of biological therapies, with particular emphasis on cell and gene therapies, illustrated by viable examples across various disorders. It covers implemented solutions for several types of cancer, as well as selected hereditary diseases and syndromes, including Huntington's disease, carbamoyl phosphate synthetase 1 (CPS1) deficiency, hemiplegia, epidermolysis bullosa, chronic granulomatous disease, and congenital deafness. Emerging applications in heart diseases and diabetes are also summarized, along with therapeutic strategies involving tRNA gene editing. Although numerous strategies exist, only the most representative, practical, and up-to-date examples are emphasized.
2026-02-22 | Human infections caused by pathogenic Burkholderia: current clinical challenges and future perspectives.
The genus Burkholderia comprises diverse environmental bacteria, although only a limited number of species are clinically significant. Among these, Burkholderia mallei, Burkholderia pseudomallei, and the Burkholderia cepacia complex (Bcc) are the primary human pathogens associated with severe infections. This review aims to synthesize current knowledge on these species, focusing on their epidemiology, pathogenicity, diagnostic approaches, and treatment challenges, while identifying key gaps and future research directions. A narrative synthesis of the literature was conducted, integrating findings from microbiological, clinical, and genomic studies addressing major pathogenic Burkholderia species and their management. B. mallei causes glanders, a zoonotic infection transmitted through contact with infected animals. B. pseudomallei, an environmental organism endemic to tropical and subtropical regions, causes melioidosis, particularly in individuals with risk factors such as diabetes. The Bcc, comprising over 20 species, poses significant risks in patients with cystic fibrosis and chronic granulomatous disease, where it may lead to severe outcomes including "cepacia syndrome" and nosocomial outbreaks linked to contaminated medical products. Pathogenic Burkholderia species exhibit highly dynamic genomes shaped by horizontal gene transfer, contributing to virulence and intrinsic resistance to multiple antimicrobials, including polymyxins and many β-lactams. Advances in laboratory diagnosis include the use of molecular techniques, mass spectrometry, and whole-genome sequencing alongside conventional methods. Treatment remains challenging due to multidrug resistance, often requiring prolonged and intensive therapeutic regimens. Clinically significant Burkholderia species present substantial diagnostic and therapeutic challenges due to their virulence and intrinsic antimicrobial resistance. Improved diagnostic strategies, optimized treatment protocols, and further research into prevention and control measures are essential to mitigate their clinical impact.
other
2026-06-04 | Severe Colitis in X-Linked Chronic Granulomatous Disease Bridged to Hematopoietic Cell Transplantation with Tacrolimus and Biologic Agents
Case A 22-month-old boy presented with hematochezia beginning in infancy. He had a history of lymphadenitis after Bacille Calmette-Guérin vaccination. Based on absent neutrophil oxidative burst activity, absent gp91phox expression (0%), and a CYBB variant (c.252G>A), he was diagnosed with X-linked chronic granulomatous disease (X-CGD). Colonoscopy revealed ulcerative colitis-like pancolitis characterized by diffuse loss of the vascular pattern, fine mucosal granularity, and friability, without perianal fistula. Histopathology showed neither foamy histiocytes nor granulomas. Treatment with 5-aminosalicylic acid (5-ASA) was discontinued because of intolerance. Vedolizumab (VED) was insufficiently effective, and prednisolone (PSL) and tacrolimus (Tac) were added. Although Tac induced remission at higher trough concentrations, relapse recurred as the trough concentration was lowered. After mirikizumab (MRK) was introduced, clinical remission could be maintained at lower Tac trough concentrations. However, colitis remained difficult to fully control, and prolonged Tac use led to renal dysfunction and septic shock secondary to a catheter-related infection. He therefore underwent unrelated donor bone marrow transplantation at 32 months of age. Conditioning consisted of fludarabine, dose-adjusted busulfan, antithymocyte globulin, and 3-Gy total body irradiation. For graft-versus-host disease (GVHD) prophylaxis, Tac and short-course methotrexate were used. At the start of conditioning, MRK was replaced with VED. Neutrophil engraftment was achieved on day 17 after transplantation, and hematochezia resolved. Although skin GVHD and vomiting developed, endoscopy showed improvement of colitis. Erythema in the stomach and duodenum prompted the addition of PSL while VED was continued, resulting in prompt symptom improvement. VED was discontinued 4 months after transplantation, Tac 9 months after transplantation. He remains alive without recurrence of colitis 1 year after transplantation. Discussion Anti-tumor necrosis factor-alpha agents are generally avoided in chronic granulomatous disease-associated colitis because fatal cases have been reported. The efficacy of VED and ustekinumab, an anti–interleukin-12/23 antibody, has been described in case series, but an optimal treatment strategy for refractory cases has not been established. In this case, MRK reduced the Tac requirement, and VED was safely continued before and after transplantation as bridging therapy. Careful selection of biologic agents with attention to infection risk may facilitate bridging to transplantation in refractory X-CGD–associated colitis. Further accumulation of cases is needed to establish an optimal treatment strategy.
2025-12-29 | Incidence, risk factors and outcomes of BCGosis following BCG vaccination in infants: a systematic review and meta-analyses.
The Bacille Calmette-Guerin (BCG) vaccine is widely administered in countries with high tuberculosis (TB) prevalence to protect against severe forms of childhood TB. Despite its efficacy, the vaccine can lead to adverse effects like BCGosis, a severe but rare condition marked by systemic granulomatous inflammation. This is because the vaccine is comprised of attenuated BCG bacteria which has the potential to cause uncontrolled dissemination beyond the injection site. Immunocompromised children are particularly vulnerable to this side effect. Through a systematic review of the current literature, this analysis seeks to determine the global incidence of BCGosis and identify critical risk factors associated with its onset. The review was conducted in accordance with the PRISMA-2020 guidelines (Preferred Reporting Items for Systematic Reviews and Meta-Analyses). The review's objectives and scope were framed using the PICOS (Population, Intervention, Comparison, Outcomes and Study Design) framework. Not surprisingly, BCGosis is most prevalent in infants with underlying genetic immunodeficiencies such as severe combined immunodeficiency (SCID) and chronic granulomatous disease (CGD). We found a high correlation between the development of BCGosis and genetic mutations affecting certain immune processes, notably those involved in NADPH oxidase function and interferon-gamma signalling. The risks of developing these mutations also correlated with the prevalence of consanguinity, a common practice in certain populations. Factors like early neonatal vaccination (often within the first week of life) and variations in BCG strains may also influence BCGosis risk. There is an urgent need for enhanced pre-vaccination screening for genetic and immunologic vulnerabilities in infants at hight risk for BCGosis, particularly in populations with high consanguinity rates. Alternatively, considerations should be made as to modifying existing vaccination schedules or postponing BCG immunization until immune competency can be confirmed in these high risk groups.
2025-10-09 | Antisense phosphorodiamidate morpholino oligomers retain activity in Burkholderia cepacia complex biofilm.
Members of the Burkholderia cepacia complex (Bcc) are known to cause severe pulmonary infections in immunocompromised hosts, namely individuals with cystic fibrosis (CF) and chronic granulomatous disease (CGD). Due to innate antibiotic-resistant phenotypes and the formation of protective biofilms, Bcc bacteria are difficult to eradicate from colonized lungs using traditional antibiotics. An alternative therapeutic approach involves the use of antisense molecules, specifically peptide-conjugated phosphorodiamidate morpholino oligomers (PPMOs). Previously, we found that PPMOs targeting the acyl carrier protein (AcpP) can reduce the burden of planktonic Bcc bacteria. Antimicrobial activities of AcpP PPMOs were assessed against established biofilms produced by Bcc clinical isolates, in which viable cells, biomass, and metabolic activity were enumerated. Bactericidal effects were further evaluated by microscopy. Cytotoxicity of these molecules was tested in human pulmonary cell lines. AcpP PPMO treatment resulted in over three-log reductions (p < 0.0001) in biofilm burden across five clinical isolates of Bcc that were tested. A dose-dependent effect was observed (5-40 μΜ). This effect was visualized using confocal and scanning electron microscopy. We further demonstrated that PPMOs associate with bacterial cells in a time-dependent fashion using a fluorescently labeled AcpP PPMO with B. cenocepacia K56-2 DsRed. Finally, alveolar cells retained viability with AcpP PPMOs at bactericidal dosages. The Bcc biofilm setting is not a deterrent against PPMO delivery or antimicrobial activity. This is supported by the colocalization of AcpP PPMOs with cells, membrane destruction, loss of cell viability, and biomass reduction. Collectively, these data provide evidence that AcpP PPMOs are a promising therapeutic strategy in the treatment of Bcc infections.
2025-09-23 | A 10-year-old Girl with an 8-Month History of Progressive Photophobia and Hemeralopia.
To report a case of nonparaneoplastic autoimmune retinopathy in a 10-year-old female with chronic granulomatous disease (CGD) due to compound heterozygous mutations in NCF1. The patient was evaluated at Columbia University Irving Medical Center using a comprehensive multimodal imaging protocol that included color fundus photography, short-wave autofluorescence (SW-AF), and spectral-domain optical coherence tomography (SD-OCT). Functional assessments were conducted using Goldmann visual fields and full-field electroretinography (ERG) were completed on-site and followed the ISCEV standard protocols to ensure consistent and reproducible measurements of photoreceptor activity. A 10-year-old female presented with decreased visual acuity, light sensitivity, and decreased color vision over the past 8 months with no improvement upon refraction. Upon detection of anti-retinal antibodies, treatment was initiated with stabilization and improvement of visual acuity and ERG responses with rituximab treatment. Whole genome sequencing revealed two mutations in NCF1 causing chronic granulomatous disease. We present a case of autoimmune retinopathy in a CGD patient with compound heterozygous mutations in the NCF1 gene. This novel association may suggest that autoimmunity may be involved the development of the chorioretinal lesions seen in CGD patients. It also supports the use of rituximab in the management of autoimmune retinopathy.
2025-09-04 | Importance of BCG Vaccination at birth in Pediatric Patients with Chronic Granulomatous Disease after Hematopoietic Stem Cell Transplantation in Developing Countries.
Recent advances in hematopoietic stem cell transplantation (HSCT) have improved clinical outcomes; however, various factors continue to influence HSCT success, especially vaccination in immunocompromised patients who receive vaccination at birth. While several studies have investigated the efficacy of vaccines in Chronic Granulomatous Disease (CGD) patients, the specific impact of vaccination on HSCT outcomes in these patients has not yet been studied. This study aimed to address an important gap in the current literature by investigating the effects of BCG vaccination on HSCT outcomes in patients with CGD. In this prospective study, 24 pediatric patients with CGD were enrolled from 2016 to 2022, all of whom received the same reduced-intensity conditioning (RIC) regimen before HSCT. Of these, 12 patients received the Bacillus Calmette-Guérin (BCG) vaccine, while 14 patients were not vaccinated. Contrary to other studies, our results showed that CGD patients who received the BCG vaccine before HSCT experienced varying degrees of BCGosis and BCGitis. Specifically, 8 patients showed symptoms of BCGosis, while 4 patients showed symptoms of BCGitis. In addition, our findings revealed no significant differences in graft-versus-host disease (GvHD) and other complications of HSCT between BCG-vaccinated and non-BCG-vaccinated CGD patients, although the overall survival (OS) rate was lower in the vaccinated group. This may be attributed to the reduced-intensity conditioning regimen applied to all patients which can balance HSCT outcome in CGD patients. Our study emphasizes the importance of screening and diagnosing immunodeficient patients at birth, especially in developing countries where BCG vaccine is administered at birth, as post- vaccination complications can significantly affect HSCT outcomes and subsequent treatments. BCG vaccination can significantly affect HSCT outcomes and subsequent treatments.
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Drug Discovery Landscape
10 orphan drug designations for Chronic granulomatous disease, including 1 approved therapy.
10 orphan drug designations for Chronic granulomatous disease, including 1 approved therapy.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
two independent HDAd vectors, in which one vector contains the integration transgenes and the other vector the CYBB therapeutic transgene | gene therapies | FDA | Ensoma | |
PE CD34+ cell-based drug product targeting the delGT mutation in the NCF1 gene | cell therapies | FDA | Prime Medicine | |
Autologous CD34+ cells transduced a lentiviral vector that encodes for the human NCF1 cDNA sequence | cell therapies | FDA | Somagenetix AG | |
Autologous CD34+ cells transduced with a lentiviral vector encoding the human NCF1 gene | gene therapies | EMA | — | 3R Pharma Consulting GmbH |
autologous CD34+ hematopoietic stem and progenitor cells modified ex-vivo with a lentiviral vector that restores expression of Gp91phox | cell therapies | FDA | — | ImmunoVec |
Autologous CD34+ enriched cell population that contains hematopoietic stem and progenitor cells transduced ex vivo using a lentiviral vector encoding the human gp91phox gene | gene therapies | FDA | — | Orchard Therapeutics (Europe) Limited |
Autologous haematopoietic cells genetically modified with a lentiviral vector containing the human gp91(phox) gene | gene therapies | EMA | Genethon | |
Autologous haematopoietic cells genetically modified with a lentiviral vector containing the human gp91(phox) gene [Oxisin] | gene therapies | EMA | — | [INACTIVE] Vision 7 GmbH |
T-cell depleted stem cell enriched cellular product from peripheal b lood stem cells | cell therapies | FDA | — | Nexell Therapeutics Inc. |
Interferon gamma 1-b [Actimmune] | proteins | FDA | Approved | Horizon Therapeutic Ireland DAC |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
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