A5016094931- CAR-T cell therapy research
- Hematopoietic Stem Cell Transplantation
- Virus-based gene therapy research
- Immune Cell Function and Interaction
- Viral Infectious Diseases and Gene Expression in Insects
- Acute Myeloid Leukemia Research
- T-cell and B-cell Immunology
- Single-cell and spatial transcriptomics
- CRISPR and Genetic Engineering
- DNA Repair Mechanisms
- MicroRNA in disease regulation
- RNA Interference and Gene Delivery
- Cytokine Signaling Pathways and Interactions
- Nanowire Synthesis and Applications
- Zebrafish Biomedical Research Applications
- Protein Degradation and Inhibitors
- Immune cells in cancer
- Cancer Cells and Metastasis
- RNA regulation and disease
- Blood disorders and treatments
- Phagocytosis and Immune Regulation
- Hippo pathway signaling and YAP/TAZ
- RNA Research and Splicing
- Cell death mechanisms and regulation
- Carcinogens and Genotoxicity Assessment
Paul Ehrlich Institut
2018-2025
Frankfurt Cancer Institute
2022-2025
Goethe University Frankfurt
2013-2025
University Hospital Frankfurt
2013-2016
Georg Speyer Haus
2010-2016
Goethe Institut
2016
LOEWE Centre for Translational Biodiversity Genomics
2013-2014
Chimeric antigen receptor (CAR) T cells brought substantial benefit to patients with B-cell malignancies. Notwithstanding, CAR T-cell manufacturing requires complex procedures impeding the broad supply chain. Here, we provide evidence that human CD19-CAR can be generated directly
T cells modified with CD19-specific chimeric antigen receptors (CARs) result in significant clinical benefit for leukemia patients but constitute a challenge manufacturing. We have recently demonstrated the vivo generation of CD19-CAR using CD8-targeted lentiviral vector (CD8-LV). In this study, we investigated CD4+ CAR CD4-targeted LV (CD4-LV). Administration CD4-LV into NSG mice transplanted human peripheral blood mononuclear (PBMCs) led to 40%–60% lymphocytes being positive while CD8+...
Chimeric antigen receptor (CAR) T cells are in prime focus of current research cancer immunotherapy. Facilitating CAR cell generation is among the top goals. We have recently demonstrated direct vivo human CD19-CAR by targeting CD8+ using lentiviral vectors (LVs). The anti-tumor potency generated was assessed PBMC-transplanted NSG mice carrying i.v. injected CD19+ Nalm-6 tumor cells. A single injection CD8-targeted LV delivering sufficient to completely eliminate from bone marrow and spleen,...
Significance Multinucleated giant tumor cells are frequently observed in tissue sections of patients with cancer. In classical Hodgkin lymphoma (HL), these so-called Reed–Sternberg (RS) pathognomonic for the disease. Despite well-described disease-promoting functions multinucleated RS cells, their development remains obscure. Long-term time-lapse microscopy and single-cell tracking HL cell lines demonstrated that generated by re-fusion small mononuclear progenitors. Importantly, fusing share...
Natural killer (NK) cells are a noteworthy lymphocyte subset in cancer adoptive cell therapy. NK initiate innate immune responses against infections and malignancies with natural cytotoxicity which is independent of foreign antigen recognition. Based on these substantive features, genetically modifying among the prime goals immunotherapy but currently difficult to achieve. Recently we reported fully human CAR19 construct (huCAR19) remarkable function gene-modified T cells. Here show...
Abstract Haematopoietic stem cells (HSCs) require the right composition of microRNAs (miR) for proper life-long balanced blood regeneration. Here we show a regulatory circuit that prevents excessive HSC self-renewal by upregulation miR-193b upon promoting thrombopoietin (TPO)-MPL-STAT5 signalling. In turn, restricts cytokine signalling, targeting receptor tyrosine kinase c-KIT. We generated knockout mouse model to unravel physiological function in haematopoiesis. MiR-193b −/− mice selective...
Hematopoietic stem cells (HSCs) maintain blood cell production life-long by their unique abilities of self-renewal and differentiation into all lineages. Growth arrest DNA-damage-inducible 45 alpha (GADD45A) is induced genotoxic stress in HSCs. GADD45A has been implicated cycle control, death senescence, as well DNA-damage repair. In general, provides cellular stability either arresting the progression until DNA damage repaired or, cases fatal damage, inducing apoptosis. However, function...
The balance of self-renewal and differentiation in long-term repopulating hematopoietic stem cells (LT-HSC) must be strictly controlled to maintain blood homeostasis prevent leukemogenesis. Hematopoietic cytokines can induce LT-HSCs; however, the molecular mechanism orchestrating this delicate requires further elucidation. We identified tumor suppressor GADD45G as an instructor LT-HSC under control differentiation-promoting cytokine receptor signaling. immediately induces accelerates LT-HSCs...
Immune checkpoint inhibitors (ICIs) can block distinct receptors on T cells or tumor thus preventing cell inactivation and immune escape. While the clinical response to treatment with ICIs in cancer patients is impressive, this therapy often associated a number of immune-related adverse events. There therefore need explore innovative strategies tumor-specific delivery ICIs. Delivery therapeutic proteins genetic level be accomplished viral vectors including those derived from...
One of the biggest challenges for in vivo gene therapy are vectors mediating highly selective transfer into a defined population therapy-relevant cells. Here we present DARPin-targeted AAVs (DART-AAVs) displaying DARPins specific human and murine CD8. Insertion GH2/GH3 loop capsid protein 1 (VP1) AAV2 AAV6 resulted high selectivity CD8-positive T cells with unimpaired delivery activity. Remarkably, core structure was unaltered protruding detectable. In complex primary cell mixtures,...
Pre-clinical humanized mouse models are a powerful tool to evaluate immunotherapies. NSG-SGM3 mice reconstituted with human stem cells (huSGM3) develop pronounced myeloid due transgenic expression of cell factor, granulocyte-macrophage colony-stimulating and interleukin-3 (IL-3) compared the widely used NSG (huNSG) model. We assessed in vivo generation CD19-CAR T huSGM3 upon single intravenous injection cell-specific lentiviral vectors (LVs) CD4-LV CD8-LV. While CAR was clearly detectable...
Precise delivery of genes to therapy-relevant cells is crucial for in vivo gene therapy. Receptor-targeting as prime strategy this purpose limited cell types defined by a single cell-surface marker. Many target are characterized combinations more than one marker, such the HIV reservoir cells. Here, we explored tropism adeno-associated viral vectors (AAV2) displaying designed ankyrin repeat proteins (DARPins) mono- and bispecific CD4 CD32a. Cryo-electron tomography revealed an unaltered...
Highlights•Bar-coded antibodies distinguish transduced and untransduced T cells by sc-multi-omics•Transduction-resistant upregulate interferon-stimulated genes•Differentially expressed genes are consistent between healthy donors patients•Inhibitors of the ERK signaling pathway increase transduction CAR cell generationSummaryDelivery chimeric antigen receptors (CARs) to is usually mediated lentiviral vectors (LVs), which can have broad tropism or be targeted. To better understand molecular...
Selective gene delivery into subtypes of interneurons remains an important challenge in vector development. Adeno-associated virus (AAV) particles are especially promising for intracerebral injections. For cell entry, AAV2 supposed to attach heparan-sulfate proteoglycans (HSPGs) followed by endocytosis via the AAV receptor (AAVR). Here, we assessed engineered deficient HSPG attachment but competent recognizing glutamate 4 (GluA4, also known as GluRD or GRIA4) through a displayed...
Abstract Lentiviral vectors (LV) have become the dominant tool for stable gene transfer into lymphocytes including chimeric antigen receptor (CAR) delivery to T cells, a major breakthrough in cancer therapy. Yet, room improvement remains, especially latest LV generations delivering genes selectively cell subtypes, key requirement vivo CAR generation. Toward improving rates with these vectors, whole transcriptome analyses on human are conducted after exposure CAR‐encoding conventional...
Chimeric antigen receptor (CAR)-expressing T cells are a complex and heterogeneous gene therapy product with variable phenotype compositions. A higher proportion of less differentiated CAR is usually associated improved antitumoral function persistence. We describe in this study novel receptor-targeted lentiviral vector (LV) named 62L-LV that preferentially transduces marked by the L-selectin CD62L, transduction rates up to 70% CD4+ 50% CD8+ primary cells. Remarkably, amounts transduced...
Quantifying gene expression in individual cells can substantially improve our understanding about complex genetically engineered cell products such as chimeric antigen receptor (CAR) T cells. Here we designed a single-cell RNA sequencing (scRNA-seq) approach to monitor the delivery of CD19-CAR via lentiviral vectors (LVs), i.e., conventional vesicular stomatitis virus (VSV)-LV and CD8-targeted CD8-LV. LV-exposed human donor peripheral blood mononuclear (PBMCs) were evaluated for panel 400...
The hallmark of Philadelphia chromosome positive (Ph+) leukemia is the BCR/ABL kinase, which successfully targeted by selective ATP competitors. However, inhibition alone unable to eradicate Ph+ leukemia. t(9;22) a reciprocal translocation encodes not only for der22 (Philadelphia chromosome) related BCR/ABL, but also der9 ABL/BCR fusion proteins, can be detected in 65% patients with chronic myeloid (CML) and 100% acute lymphatic (ALL). ABL/BCRs are oncogenes able influence lineage commitment...
Adeno-associated viral vectors (AAVs) are a widely used gene transfer platform in neuroscience. Although naturally AAV serotypes can have preferences for certain tissues, selectivity particular cell types the CNS does not exist. Towards interneuron targeting, capsid engineering of AAV2 including display designed ankyrin repeat protein (DARPin) 2K19 specific glutamate receptor subunit 4 (GluA4) at N-terminus VP2 has been established. The resulting AAV-VP2N is highly interneurons, but exhibits...