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Mol Ther Nucleic Acids. 2025 Jul 1;36(3):102618. doi: 10.1016/j.omtn.2025.102618. eCollection 2025 Sep 9.

ABSTRACT

Engineered T cells equipped with a chimeric antigen receptor (CAR) have shown tremendous clinical success, but tumor-mediated stimulation of T cell inhibitory receptors leads to exhaustion, hampering durable remission in patients. Mitigation of this effect via checkpoint inhibition or genome editing to knockout the genes encoding for these receptors has shown promise. Yet, the side effects of these procedures require better alternatives. Targeted epigenome editing offers a potent strategy to alter gene expression without DNA modifications. Its hit-and-run mechanism enables durable, multiplexed modulation of gene expression with greater safety. Here, we describe multiplexed epigenome editing inactivation of two critical-exhaustion-related genes, PDCD1 and LAG3, both in primary human T cells and in prostate-cancer-specific CAR T cells. Epigenetically modified CAR T cells are indistinguishable from parental cells across a range of functional assays. Although the model does not fully mimic T cell exhaustion, limiting functional assessment, gene silencing remains durable across multiple divisions and repeated CAR stimulations. Furthermore, transcriptomic analysis revealed minimal off-target effects not directly attributable to the effectors used. We demonstrate that targeted epigenome editing is effective and safe for multiplexed gene inhibition and holds potential in engineering CAR T cells with enhanced and customizable features.

PMID:40686859 | PMC:PMC12275148 | DOI:10.1016/j.omtn.2025.102618

Br J Haematol. 2025 Jul 20. doi: 10.1111/bjh.70027. Online ahead of print.

ABSTRACT

Hypogammaglobulinaemia is a potential complication in children with acute lymphoblastic leukaemia (ALL) receiving chemotherapy. However, real-world data on its prevalence and clinical impact remain limited. This study retrospectively reviewed 85 paediatric ALL patients completing Taiwan Pediatric Oncology Group (TPOG)-ALL-2013 maintenance therapy to investigate secondary hypogammaglobulinaemia. At diagnosis, 6% (5/85) of patients had hypogammaglobulinaemia, increasing to 49.2% (32/65) during maintenance chemotherapy. Patients with very-high-risk disease, poor cytogenetics or baseline immunoglobulin G (IgG) <1000 mg/dL were more likely to develop secondary hypogammaglobulinaemia. Febrile episodes were significantly more common in the hypogammaglobulinaemia group (40.6% had >10 fever episodes) and were particularly frequent in patients with IgG <400 mg/dL. However, hypogammaglobulinaemia was not associated with white blood cell count, measurable residual disease or long-term survival outcomes. Although intravenous immunoglobulin (IVIG) replacement is well established in primary immunodeficiency and B-cell malignancies, its role in paediatric ALL remains uncertain. Given the high prevalence of hypogammaglobulinaemia and its association with febrile episodes, routine IgG monitoring may help identify at-risk patients. Further studies are needed to determine the clinical benefits of IVIG supplementation in this population.

PMID:40685714 | DOI:10.1111/bjh.70027

J Clin Periodontol. 2025 Jul 20. doi: 10.1111/jcpe.14201. Online ahead of print.

ABSTRACT

BACKGROUND AND AIM: Primary Immunodeficiencies (PIDs) arise from rare genetic defects affecting humoral and cellular immunity, which can lead to reduced dental plaque control. This study aimed to characterise the subgingival dental plaque microbiome in neutropenic PID children compared to healthy controls and assess their response to non-surgical periodontal therapy.

METHODS: Subgingival plaque was collected from three first molars and one first incisor at baseline and 6 months post therapy from children with PID (n = 24) and systematically healthy control participants (n = 24) who were recruited from Great Ormond Street Hospital and Barts Health NHS Trust, respectively. The subgingival microbiome was profiled using an Illumina metabarcoding approach on the bacterial 16S rRNA gene V1-V2 region.

RESULTS: Significant shifts in community structure were observed post therapy, as measured by alpha and beta diversities. An increase in Rothia spp., Neisseria spp. and Actinomyces spp. was noted in PID children post therapy, consistent with clinical improvements. Baseline blood absolute neutrophil counts in PID children were positively associated with Streptococcus cristatus and Gemella spp., and negatively with Saccharibacteria, Capnocytophaga and Porphyromonas spp., highlighting key host-microbial relationships.

CONCLUSION: Non-surgical periodontal therapy modulated the subgingival microbiota in neutropenic PID children, revealing novel host-microbial interactions important for the oral microbiome in health.

PMID:40685148 | DOI:10.1111/jcpe.14201

BMC Immunol. 2025 Jul 19;26(1):52. doi: 10.1186/s12865-025-00723-6.

ABSTRACT

BACKGROUND: Activated phosphoinositide 3-kinase delta (PI3Kδ) syndrome (APDS) is an ultra-rare inborn error of immunity, characterised by immunodeficiency and immune dysregulation. Having only been recognised in 2013, evidence on APDS is limited. We carried out four systematic literature reviews (SLRs) to identify and narratively synthesise evidence on the following for APDS: epidemiology (epidemiology SLR), clinical efficacy/safety of treatments (clinical SLR), cost-effectiveness and costs/healthcare (HCRU) associated with (economic SLR) and health-related quality of life (HRQoL) and utility data (HRQoL SLR) from a global perspective.

METHODS: The Cochrane Collaboration and the University of York’s Centre for Reviews and Dissemination (CRD) guidelines were followed. MEDLINE, Embase, the Cochrane Library, University of York CRD, conference proceedings and other grey literature were searched through to May 2023 for all SLRs, except the epidemiology SLR (searched to Nov 2021); economic databases were also searched for the economic and HRQoL SLRs. Eligible records were: primary epidemiology publications (epidemiology SLR), interventional/observational studies of treatments (clinical SLR), cost/HCRU studies/economic evaluations (economic SLR) and HRQoL/utility studies (HRQoL SLR) in people with APDS. Risk of bias was assessed using the Downs and Black checklist (clinical SLR) and the Drummond checklist (economic SLR).

RESULTS: The numbers of unique relevant studies identified were: 0 (epidemiology SLR), 117 (clinical SLR; 87 reported on <5 patients), 2 (economic SLR) and 1 (HRQoL SLR). The clinical SLR reported symptomatic treatments to be only partially effective at controlling APDS manifestations, with variable tolerability. Outcome reporting was heterogeneous and inconsistent, with small sample sizes and patients receiving multiple treatments, limiting interpretation of results. The economic SLR reported a high direct cost of APDS. Additional HRQoL/utility studies are required to evaluate the clinical and HRQoL burden of APDS and the impact of therapies.

CONCLUSION: Four methodologically robust SLRs identified limited evidence on epidemiology, clinical outcomes, costs and HRQoL in APDS, reflecting its ultra-rare nature and recent recognition. This suggests a need for more rigorous data evaluating the clinical and economic effectiveness of APDS treatments. Outcome reporting was highly heterogeneous and inconsistent across studies, sample sizes were small and patients often received multiple treatments, limiting interpretation of results.

PMID:40684159 | DOI:10.1186/s12865-025-00723-6

Pediatr Allergy Immunol. 2025 Jul;36(7):e70138. doi: 10.1111/pai.70138.

ABSTRACT

BACKGROUND: With the advances in genetic diagnosis in the past decade, primary immunodeficiency diseases (PIDs) have been increasingly identified as emerging causes of (DAH) among children treated in our department. The literature regarding PID-associated DAH are limited. Thus, we aim to enhance the awareness that PIDs can be underlying causes of pediatric DAH and evaluate the implications of genetic diagnosis for treatment.

METHODS: This analysis included 68 children with DAH who had undergone genetic tests in the pediatric respiratory ward during the preceding 10 years. Their clinical findings, genetic results, and treatment were retrospectively examined.

RESULTS: In total, 16 children were diagnosed with PIDs. Genetic diagnoses of PIDs yielded in 14 patients revealed involvement of 10 immunity-defective genes (TNFRSF13B, TCF3, NFKB2, PIK3CD, COPA, ADA2, PLCG2, RAG1, BCL11B, and STAT3). The remaining two children had diagnoses of CVID without associated variants. The overall prevalence of PID-associated DAH in our cohort was 23.5% (16/68). The median age at DAH symptom onset was 3.5 (interquartile range: 2.1-9.3) years. In all children, DAH is the primary or even initial clinical manifestation of the PIDs. Of the children, 37.5% (6/16) developed additional autoimmune or inflammatory complications. 50% (8/16) of patients adjusted their therapeutic management according to the genetic diagnosis. 87.5% (14/16) of patients achieved remission.

CONCLUSION: This study suggests that PID is one of the most important causes of DAH in children. The identification of the PIDs and the causal variants enables genotype-specific treatment, which may offer critical guidance for clinical management.

PMID:40682328 | DOI:10.1111/pai.70138

Allergol Immunopathol (Madr). 2025 Jul 1;53(4):51-59. doi: 10.15586/aei.v53i4.1353. eCollection 2025.

ABSTRACT

INTRODUCTION: Hereditary angioedema (HAE) is a rare but potentially life-threatening disorder characterized by recurrent swelling episodes. Adherence to clinical guidelines, such as the World Allergy Organization/European Academy of Allergy & Clinical Immunology (WAO/EAACI) guidelines, is crucial for effective management. With the increasing role of artificial intelligence in medicine, large language models (LLMs) offer potential for clinical decision support. This study evaluates the performance of ChatGPT, Gemini, Perplexity, and Copilot in providing guideline-adherent responses for HAE management.

METHODS: Twenty-eight key recommendations from the WAO/EAACI HAE guidelines were reformulated into interrogative formats and posed to the selected LLMs. Two independent clinicians assessed responses based on accuracy, adequacy, clarity, and citation reliability using a five-point Likert scale. References were categorized as guideline-based, trustworthy, or untrustworthy. A reevaluation with explicit citation instructions was conducted, with discrepancies resolved by a third reviewer.

RESULTS: ChatGPT and Gemini outperformed Perplexity and Copilot, achieving median accuracy and adequacy scores of 5.0 versus 3.0, respectively. ChatGPT had the lowest rate of unreliable references, whereas Gemini showed inconsistency in citation behavior. Significant differences in response quality were observed among models (p < 0.001). Providing explicit sourcing instructions improved performance consistency, particularly for Gemini.

CONCLUSION: ChatGPT and Gemini demonstrated superior adherence to WAO/EAACI guidelines, suggesting that LLMs can support clinical decision-making in rare diseases. However, inconsistencies in citation practices highlight the need for further validation and optimization to enhance reliability in medical applications.

PMID:40682228 | DOI:10.15586/aei.v53i4.1353

Commun Biol. 2025 Jul 18;8(1):1064. doi: 10.1038/s42003-025-08482-1.

ABSTRACT

Chediak-Higashi syndrome (CHS) is a rare, autosomal recessive disorder caused by pathogenic variants in the lysosomal trafficking regulator (LYST) gene and characterized by significant immunological and neurological impairment. Current mouse models do not replicate the early-onset neurological symptoms of patients. We develop and characterize a CHS model lacking the Lyst gene (ΔLYST-B6) using CRISPR-Cas9. The ΔLYST-B6 mouse exhibits key CHS features, including partial oculocutaneous albinism, prolonged bleeding, and enlarged intracellular granules. Molecular analyses confirm LYST deficiency, with reduced Lyst mRNA and protein levels across various tissues. Histological examination reveals progressive cerebellar Purkinje cell loss and axonal degeneration in peripheral nerves. Importantly, the ΔLYST-B6 show significant neurological impairment by 6 months of age. Lipidomic and transcriptomic analyses highlight increased proinflammatory lipid levels and immune signaling, suggesting neuroinflammation in CHS pathology. The ΔLYST-B6 mouse provides a valuable tool for studying the underlying mechanisms of CHS-associated neurodegeneration and for developing potential therapeutic strategies.

PMID:40681653 | DOI:10.1038/s42003-025-08482-1

Mol Pharmacol. 2025 Jun 13;107(8):100055. doi: 10.1016/j.molpha.2025.100055. Online ahead of print.

ABSTRACT

IT1t and clobenprobit (CB) have been shown to act as anti-inflammatory compounds in dependence of the chemokine receptor C-X-C receptor type 4 (CXCR4) in model systems. Here, the direct interaction between CB and CXCR4 is demonstrated via in silico modeling and bioluminescence resonance energy transfer binding assays at wild-type and mutant versions of CXCR4. The binding site is compared with those of IT1t and AMD3100, two well known CXCR4 ligands. In contrast to AMD3100, IT1t also displays an anti-inflammatory signaling effect. Ligands observed to have this anti-inflammatory effect seem to bind into the minor pocket of CXCR4 impacting the binding of the endogenous ligand CXCL12 only at high concentrations. Based on this observation further compounds thought to bind the minor pocket of CXCR4 were designed and screened for their anti-inflammatory potency. The best of these compounds, NP1411, was tested in its ability to inhibit CXCL12 mediated G protein activation as well as CXCL12 and CB binding. SIGNIFICANCE STATEMENT: This study presents a comprehensive investigation into the binding site of anti-inflammatory compounds at the C-X-C receptor type 4 receptor using in silico and in vitro ligand binding approaches. This opens the opportunity for the development of further therapeutic agents with higher potency and/or efficacy as presented in an initial test at the end of the publication.

PMID:40680318 | DOI:10.1016/j.molpha.2025.100055

Blood Adv. 2025 Jul 17:bloodadvances.2025016213. doi: 10.1182/bloodadvances.2025016213. Online ahead of print.

ABSTRACT

Chronic granulomatous disease (CGD) is a primary immunodeficiency characterized by recurrent life-threatening infections and hyperinflammatory complications. It is caused by mutations in the 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 show that innate immune cells of CGD patients 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 acids concentrations and profound functional metabolic defects, both at the level of glycolysis and mitochondrial respiration. Ex vivo and in vivo treatment with IFN-γ restored these metabolic defects and reduced excessive 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.

PMID:40674716 | DOI:10.1182/bloodadvances.2025016213

JAMA Ophthalmol. 2025 Jul 17. doi: 10.1001/jamaophthalmol.2025.2235. Online ahead of print.

ABSTRACT

IMPORTANCE: Reactivation of the JC polyomavirus in individuals with impaired immunity is most commonly associated with progressive multifocal leukoencephalopathy. We report a case of polyomavirus-related retinopathy, representing a potentially novel manifestation of JC polyomavirus infection.

OBJECTIVE: To describe a patient with common variable immunodeficiency who exhibited isolated unilateral retinopathy related to JC polyomavirus infection of the retinal ganglion cell layer.

DESIGN, SETTING, AND PARTICIPANTS: This case report describes a patient managed at a referral center in Toulouse, France, from June 2022 to March 2025 presenting with progressive decrease in visual acuity related to a right-sided unilateral retinopathy.

INTERVENTIONS: Anterior eye chamber paracentesis was performed for polymerase chain reaction (PCR) and shotgun metagenome sequencing, and a retinal biopsy was taken for diagnostic purposes. An intravitreal injection of cidofovir was administered as a therapeutic procedure.

MAIN OUTCOMES AND MEASURES: The primary outcome was identification of a potentially novel manifestation of JC polyomavirus infection.

RESULTS: A 52-year-old White male presented with isolated, right-sided unilateral progressive retinopathy. Shotgun metagenome sequencing and specific PCR on anterior chamber paracentesis identified JC polyomavirus DNA. A biopsy of the retina demonstrated JC polyomavirus infection of retinal ganglion cells in the ganglion cell layer. A diagnosis of late-onset common variable immunodeficiency complicated by JC polyomavirus-related retinopathy was made. The single intravitreal injection of cidofovir administered was associated with transient negativation of the JC polyomavirus DNA PCR, but resulted in severe cidofovir-related adverse events.

CONCLUSIONS AND RELEVANCE: This case report extends the spectrum of clinical phenotypes associated with polyomavirus infection and raises the possibility that retinopathy may be an underappreciated complication in this setting. Testing for JC polyomavirus should be considered in immunocompromised patients presenting with retinopathy of unexplained etiology.

PMID:40674067 | DOI:10.1001/jamaophthalmol.2025.2235