A5112414178- Blood disorders and treatments
- Neutropenia and Cancer Infections
- Immunodeficiency and Autoimmune Disorders
- Acute Myeloid Leukemia Research
- Erythrocyte Function and Pathophysiology
- CRISPR and Genetic Engineering
- CAR-T cell therapy research
- Cytokine Signaling Pathways and Interactions
- RNA Interference and Gene Delivery
- RNA modifications and cancer
- HER2/EGFR in Cancer Research
- Ubiquitin and proteasome pathways
- Flavonoids in Medical Research
- Immune Cell Function and Interaction
- Hyperglycemia and glycemic control in critically ill and hospitalized patients
- Glycosylation and Glycoproteins Research
- T-cell and Retrovirus Studies
- Caveolin-1 and cellular processes
- Nanofabrication and Lithography Techniques
- Cytomegalovirus and herpesvirus research
- RNA Research and Splicing
- Virus-based gene therapy research
- Immunotherapy and Immune Responses
- RNA and protein synthesis mechanisms
University Children's Hospital Tübingen
2019-2025
University of Tübingen
2018-2024
A Autosomal-dominant ELANE mutations are the most common cause of severe congenital neutropenia. Although majority neutropenia patients respond to daily granulocyte colony stimulating factor, approximately 15 % do not this cytokine at doses up 50 μg/kg/day and will develop myelodysplasia or acute myeloid leukemia. “Maturation arrest,” failure marrow progenitors form mature neutrophils, is a consistent feature associated As mutant neutrophil elastase abnormality, we hypothesized that could be...
Missplicing of transcripts is a frequent molecular mechanism in wide range inherited genetic conditions. Therapeutic splicing correction can be achieved through antisense oligonucleotides; however, they do not enable permanent correction. Concurrently, CRISPR-Cas9 approaches often rely on dual-guide RNA-induced larger deletions-for instance, pseudoexons removal-which raises concerns about higher genotoxicity from multiple double-strand breaks. We therefore investigated single-guide RNA to...
Safety considerations for gene therapies of inherited preleukemia syndromes, including severe congenital neutropenia (CN), are paramount. We compared several strategies CRISPR/Cas9 editing autosomal-dominant
Abstract Protein therapeutics frequently face major challenges, including complicated production, instability, poor solubility, and aggregation. De novo protein design can readily address these challenges. Here, we demonstrate the utility of a topological refactoring strategy to novel granulopoietic proteins starting from granulocyte-colony stimulating factor (G-CSF) structure. We change fold by rearranging sequence optimising it towards new fold. Testing four designs, obtain two that...
Abstract Patients with the pre-leukemia bone marrow failure syndrome called severe congenital neutropenia (CN) have an approximately 15% risk of developing acute myeloid leukemia (AML; here CN/AML). Most CN/AML patients co-acquire CSF3R and RUNX1 mutations, which play cooperative roles in development AML. To establish vitro model leukemogenesis, we utilized lin − cells from transgenic C57BL/6-d715 Csf3r mice expressing a CN patient–mimicking truncated mutation. We transduced these vectors...
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Mutations in the ELANE gene, encoding neutrophil elastase (NE) protein, are responsible for most CyN cases and approximately 25 % of CN cases. In CyN, a median 2.8 CD34+ cells were early CD49f+ hematopoietic stem (eHSC) that did not express thus escape from unfolded protein response (UPR) caused by mutated NE. respond to G-CSF with significant upregulation stem-cell-specific transcription factors, C/EBP/, MLL1, HOXA9, MEIS1, HLF during ascending arm cycle, resulting differentiation myeloid...
Topic: 24. Gene therapy, cellular immunotherapy and vaccination - Biology & Translational Research Background: Severe congenital neutropenia (CN) is an inherited bone marrow failure syndrome. Autosomal-dominant ELANE mutations are the most common cause of CN. Although patients respond to daily treatment with granulocyte colony-stimulating factor, a group does not this cytokine approximately 20 % develop myelodysplasia or acute myeloid leukemia. Hematopoietic stem cell transplantation would...
Topic: 11. Bone marrow failure syndromes incl. PNH - Biology & Translational Research Background: Severe congenital neutropenia (CN) and cyclic (CyN) are disorders of hematopoiesis that differ markedly in disease severity. Mutations the ELANE gene, encoding neutrophil elastase (NE) protein, responsible for most CyN CN cases. These mutations lead to accelerated myeloid progenitor cell apoptosis due production misfolded NE subsequently enhanced unfolded protein response (UPR). Aims: Unraveling...
Abstract Enhancing cytokine-based therapies by systematically tuning how an agonist associates its receptor is emerging as a powerful new concept in drug discovery. Here, we report the design and characterization of agonists that tune granulocyte-colony stimulating factor (G-CSFR) activity, which central for proliferation granulocytic differentiation hematopoietic stem cells. Using agonists, study impact varying receptor-binding affinity dimerization geometry on association, downstream...