Publications by authors named "Joachim Kunz"

Background: Transfusion-dependent β-thalassaemia (TDT) is a severe disease, resulting in lifelong blood transfusions, iron overload, and associated complications. Betibeglogene autotemcel (beti-cel) gene therapy uses autologous haematopoietic stem and progenitor cells (HSPCs) transduced with BB305 lentiviral vector to enable transfusion independence.

Methods: HGB-212 was a non-randomised, multicentre, single-arm, open-label, phase 3 study of beti-cel in patients with TDT conducted at eight centres in France, Germany, Greece, Italy, the UK, and the USA.

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Article Synopsis
  • Gene addition and editing therapies for β-thalassemia, particularly betibeglogene autotemcel (beti-cel), show promise as potentially curative options, with real-world studies demonstrating their effectiveness and safety.* -
  • Out of 15 patients evaluated for treatment with beti-cel, 8 were treated post-busulfan conditioning, achieving transfusion independence within 8 to 59 days, while experiencing some acute toxicity typical of the conditioning regimen.* -
  • Monitoring of patients revealed several unexpected side effects, including endocrine dysfunction, posttreatment depression and anxiety in one patient, and fatigue impacting quality of life in another, underscoring the need for careful management of these complications.*
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Sickle Cell Disease.

Transfus Med Hemother

October 2024

Background: Sickle cell disease (SCD) is among the most frequent hereditary disorders globally and its prevalence in Europe is increasing due to migration movements.

Summary: The basic pathophysiological event of SCD is polymerization of deoxygenated sickle hemoglobin, resulting in hemolysis, vasoocclusion, and multiorgan damage. While the pathophysiological cascade offers numerous targets for treatment, currently only two disease-modifying drugs have been approved in Europe and transfusion remains a mainstay of both preventing and treating severe complications of SCD.

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Article Synopsis
  • Patients with sickle cell disease (SCD) in Germany have different types of genetic traits, especially in a part of their blood called β-globin.
  • In a study of 90 patients, those with a specific type called HbS/β-thal showed better health markers like higher blood levels and fewer blood transfusions compared to patients with another type called HbSS.
  • The amount of a blood component called HbA affects how sick someone with HbS/β-thal might be, with little or no HbA causing a higher risk for a serious issue called splenic sequestration.
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Objectives: Sickle cell disease (SCD) is an inherited disorder that causes lifelong complications, substantially impacting the physical and emotional well-being of patients and their caregivers. Studies investigating the effects of SCD on quality of life (QOL) are often limited to individual countries, lack SCD-specific QOL questionnaires, and exclude the caregiver experience. The SHAPE survey aimed to broaden the understanding of the global burden of SCD on patients and their caregivers and to capture the viewpoint of healthcare providers (HCPs).

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Background: Third-generation chimeric antigen receptor (CAR)-engineered T cells (CARTs) might improve clinical outcome of patients with B cell malignancies. This is the first report on a third-generation CART dose-escalating, phase-1/2 investigator-initiated trial treating adult patients with refractory and/or relapsed (r/r) acute lymphoblastic leukemia (ALL).

Methods: Thirteen patients were treated with escalating doses of CD19-directed CARTs between 1 × 10 and 50 × 10 CARTs/m.

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Article Synopsis
  • Sickle cell disease is a rare hereditary illness affecting multiple organs, and it's mostly found in the EU, where a plan for rare diseases was started in 2017.
  • This plan created 24 networks in Europe to help manage rare diseases, including a special network for blood-related illnesses named ERN-EuroBloodNet.
  • The goal of these networks is to improve care for people with sickle cell disease by sharing knowledge, creating training programs, and collecting important health data for research.
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Early diagnosis of severe combined immunodeficiency (SCID), spinal muscular atrophy (SMA), and sickle cell disease (SCD) improves health outcomes by providing a specific treatment before the onset of symptoms. A high-throughput nucleic acid-based method in newborn screening (NBS) has been shown to be fast and cost-effective in the early detection of these diseases. Screening for SCD has been included in Germany's NBS Program since Fall 2021 and typically requires high-throughput NBS laboratories to adopt analytical platforms that are demanding in terms of instrumentation and personnel.

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The mechanisms underlying T-ALL relapse remain essentially unknown. Multilevel-omics in 38 matched pairs of initial and relapsed T-ALL revealed 18 (47%) type-1 (defined by being derived from the major ancestral clone) and 20 (53%) type-2 relapses (derived from a minor ancestral clone). In both types of relapse, we observed known and novel drivers of multidrug resistance including MDR1 and MVP, NT5C2 and JAK-STAT activators.

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  • The study investigates how genetic variations that increase fetal hemoglobin (HbF) levels impact sickle cell disease (SCD) patients treated with hydroxyurea, using data from over 400 patients.
  • Researchers found that some genetic polymorphisms (specifically in the γ-globin promoter, BCL11A, and HMIP) were associated with higher HbF levels but did not decrease the frequency of painful crises or vaso-occlusive events.
  • Notably, patients with the γ-globin polymorphism had significantly higher hemoglobin levels but also experienced more painful crises and hospitalizations, suggesting a complex relationship between HbF levels and disease symptoms.
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Sickle Cell Disease (SCD) is the most common monogenic disorder globally but qualifies as a rare disease in Germany. In 2012, the German Society for Paediatric Oncology and Haematology (GPOH) mandated a consortium of five university hospitals to develop a disease management program for patients with SCD. Besides other activities, this consortium issued treatment guidelines for SCD that strongly favour the use of hydroxyurea and propagated these guidelines in physician and patient education events.

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Sickle cell disease and the ß-thalassemias are caused by mutations of the ß-globin gene and represent the most frequent single gene disorders worldwide. Even in European countries with a previous low frequency of these conditions the prevalence has substantially increased following large scale migration from Africa and the Middle East to Europe. The hemoglobin diseases severely limit both, life expectancy and quality of life and require either life-long supportive therapy if cure cannot be achieved by allogeneic stem cell transplantation.

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We aimed at identifying the developmental stage at which leukemic cells of pediatric T-ALLs are arrested and at defining leukemogenic mechanisms based on ATAC-Seq. Chromatin accessibility maps of seven developmental stages of human healthy T cells revealed progressive chromatin condensation during T-cell maturation. Developmental stages were distinguished by 2,823 signature chromatin regions with 95% accuracy.

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Pyruvate kinase (PK) deficiency is a rare recessive congenital hemolytic anemia caused by mutations in the PKLR gene. This study reports the molecular features of 257 patients enrolled in the PKD Natural History Study. Of the 127 different pathogenic variants detected, 84 were missense and 43 non-missense, including 20 stop-gain, 11 affecting splicing, five large deletions, four in-frame indels, and three promoter variants.

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Structural variation (SV), involving deletions, duplications, inversions and translocations of DNA segments, is a major source of genetic variability in somatic cells and can dysregulate cancer-related pathways. However, discovering somatic SVs in single cells has been challenging, with copy-number-neutral and complex variants typically escaping detection. Here we describe single-cell tri-channel processing (scTRIP), a computational framework that integrates read depth, template strand and haplotype phase to comprehensively discover SVs in individual cells.

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Background: Limited data on the prevalence and medical care of sickle cell disease (SCD) in Germany are available. Here, we make use of a patient registry to characterize the burden of disease and the treatment modalities for patients with SCD in Germany.

Procedure: A nationwide German registry for patients with SCD documents basic data on diagnosis and patient history retrospectively at the time of registration.

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Introduction: Chimeric antigen receptor (CAR) T cells spark hope for patients with CD19+ B cell neoplasia, including relapsed or refractory (r/r) acute lymphoblastic leukaemia (ALL) or r/r non-Hodgkin's lymphoma (NHL). Published studies have mostly used second-generation CARs with 4-1BB or CD28 as costimulatory domains. Preclinical results of third-generation CARs incorporating both elements have shown superiority concerning longevity and proliferation.

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We compared 24 primary pediatric T-cell acute lymphoblastic leukemias (T-ALL) collected at the time of initial diagnosis and relapse from 12 patients and 24 matched patient-derived xenografts (PDXs). DNA methylation profile was preserved in PDX mice in 97.5% of the promoters (ρ = 0.

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