A5085703649- Virus-based gene therapy research
- RNA Interference and Gene Delivery
- Heparin-Induced Thrombocytopenia and Thrombosis
- Viral Infectious Diseases and Gene Expression in Insects
- CAR-T cell therapy research
- Platelet Disorders and Treatments
- SARS-CoV-2 and COVID-19 Research
- vaccines and immunoinformatics approaches
- Viral gastroenteritis research and epidemiology
- Advanced biosensing and bioanalysis techniques
- Immunotherapy and Immune Responses
- Mesenchymal stem cell research
- Venous Thromboembolism Diagnosis and Management
- Retinal and Optic Conditions
- Cell Adhesion Molecules Research
- Cancer Research and Treatments
- Blood disorders and treatments
- Viral Infections and Immunology Research
- Monoclonal and Polyclonal Antibodies Research
- Animal Virus Infections Studies
Universität Ulm
2015-2024
University Hospital Ulm
2023
Helmholtz-Institute Ulm
2020-2022
ORCID
2022
Abstract During the last months many countries have started immunization of millions people by using vector-based vaccines. Unfortunately, severe side effects became overt during these vaccination campaigns: cerebral venous sinus thromboses (CVST), absolutely rare under normal life conditions, were found as a effect that occured 4-14 days after first vaccinations. Besides CVST, Splanchnic Vein Thrombosis (SVT) was also observed. This type adverse event has not been observed in clinical...
To fight the COVID-19 pandemic caused by RNA virus SARS-CoV-2, a global vaccination campaign is in progress to achieve immunization of billions people mainly with adenoviral vector- or mRNA-based vaccines, all which encode SARS-CoV-2 Spike protein. In some rare cases, cerebral venous sinus thromboses (CVST) have been reported as severe side effect occurring 4-14 days after first and were often accompanied thrombocytopenia. Besides CVST, splanchnic vein (SVT) other thromboembolic events...
ChAdOx1 nCov-19 and Ad26.COV2.S are approved vaccines inducing protective immunity against SARS-CoV-2 infection in humans by expressing the Spike protein of SARS-CoV-2. We analyzed content composition biochemical methods mass spectrometry. Four out four tested lots nCoV-19 contained significantly higher than expected levels host cell proteins (HCPs) free viral proteins. The most abundant contaminating HCPs belonged to heat-shock cytoskeletal families. HCP exceeded 400 ng specification limit...
Abstract Background SARS-CoV-2 vaccine ChAdOx1 nCov-19 rarely causes vaccine-induced immune thrombotic thrombocytopenia (VITT) that—like autoimmune heparin-induced thrombocytopenia—is mediated by platelet-activating anti-platelet factor 4 (PF4) antibodies. Methods We investigated vaccine, PF4, and VITT patient-derived anti-PF4 antibody interactions using dynamic light scattering, 3D-super-resolution microscopy, electron microscopy. Mass spectrometry was used to analyze composition. the...
The biodistribution of adenovirus type 5 (Ad5) vector particles is heavily influenced by interaction the with plasma proteins, including coagulation factor X (FX), which binds specifically to major Ad5 capsid protein hexon. FX mediates hepatocyte transduction intravenously-injected vectors and shields from neutralization natural antibodies complement. In mice, mutant that are ablated for FX-binding become detargeted hepatocytes, desirable certain applications, but unfortunately such...
Amphiphilic surface groups play an important role in many biological processes. The synthesis of amphiphilic polyphenylene dendrimer branches (dendrons), providing alternating hydrophilic and lipophilic one reactive ethynyl group at the core is reported. serve as biorecognition units that bind to adenovirus 5 (Ad5), which a common vector gene therapy. Ad5/dendron complexes showed high transduction efficiencies coxsackie-adenovirus receptor (CAR)-negative cells. Moreover, dendrons offer...
Oncolytic viruses (OVs) are promising therapeutics for tumors with a poor prognosis. An OV based on herpes simplex virus type 1 (oHSV-1), talimogene laherparepvec (T-VEC), has been recently approved by the Food and Drug Administration (FDA) European Medicines Agency (EMA) treatment of unresectable melanoma. T-VEC, like most OVs, is administered via intratumoral injection, underlining unresolved problem systemic delivery oncolytic agent metastases deep-seated tumors. To address this drawback,...
Oncolytic viruses are promising anticancer agents; however, regarding their clinical efficacy, there is still significant scope for improvement. Preclinical
The epidermal growth factor receptor (EGFR) plays a central role in the progression of many solid tumors. We used this validated target to analyze de novo design EGFR-binding peptides and their application for delivery complex payloads via rational viral vector. Peptides were computationally designed interact with EGFR dimerization interface. Two new reference (EDA peptide) chemically synthesized, binding ability characterized. Presentation these each 60 capsid proteins recombinant...
Abstract Sinus venous thrombosis has been linked to immunization with the ChAdOx1 nCov-19 vaccine. The initial trigger for this serious adverse event not determined. We analyzed vaccine by biochemical and proteomic methods. found that vaccine, in addition adenovirus vector, contains substantial amounts of both human non-structural viral proteins. Among proteins, heat-shock proteins cytoskeletal were particularly abundant. often-observed strong clinical reaction one or two days after...
Human multipotent mesenchymal stromal cells (hMSCs) are of significant therapeutic interest due to their ability deliver oncolytic adenoviruses tumors. This approach is also investigated for targeting head and neck squamous cell carcinomas (HNSCCs). HAdV-5-HexPos3, a recently reported capsid-modified vector based on human adenovirus type 5 (HAdV-5), showed strongly improved infection both hMSCs the HNSCC line UM-SCC-11B. Given that, we generated life cycle-unmodified -modified...
A multitude of alterations in the old immune system impair its functional integrity. Closely related, older individuals show, for example, a reduced responsiveness to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) vaccines. However, systematic strategies specifically improve efficacy vaccines are missing or limited simple approaches like increasing antigen concentration injection frequencies. We here asked whether intrinsic, trimeric structure SARS-CoV-2 spike (S) and/or DNA-...
Treatment of head and neck squamous cell carcinomas (HNSCC) by oncolytic adenoviral vectors holds promise as an efficient anti-cancer therapy. The epidermal growth factor receptor (EGFR) represents attractive target since it is frequently overexpressed in many types HNSCC.To achieve EGFR-specific targeting human adenovirus type 5 (HAdV-5) based vectors, the EGFR affinity ligand Affilin was covalently attached a position specific manner either to fiber or hexon protein vector capsid. In vitro...
In adenovirus type 5 (HAdV-5)-derived viral vectors, the fiber protein has been preferred locale for modifications to alter natural tropism. Hexon, most abundant capsid protein, rarely used retargeting purposes, likely because insertion of larger targeting peptides into Hexon often interferes with assembly capsid. We previously observed that positively charged molecules enhance transduction human multipotent mesenchymal stromal cells (hMSCs)-a cell significant interest clinical development...
Human multipotent mesenchymal stromal cells (hMSCs) are currently developed as cell therapeutics for different applications, including regenerative medicine, immune modulation, and cancer treatment. The biological properties of hMSCs can be further modulated by genetic engineering. Viral vectors based on human adenovirus type 5 (HAdV-5) belong to the most frequently used vector types modification in vitro vivo. However, due a lack primary attachment receptor coxsackievirus (CAR) hMSCs,...
Human adenovirus type 5 (HAdV-5)-based oncolytic viruses hold significant promise for anti-cancer therapy. However, poor tumor-targeting and off-target organ transduction after systemic administration limit their therapeutic efficacy. In addition, the strong liver tropism of HAdV-5-based vectors poses risk hepatotoxicity. By genetic modification major capsid protein hexon we generated a vector (HAdV-5-HexPos3) with reduced negative surface charge. Coxsackie receptor (CAR) binding-ablated...
Abstract Amphiphilic surface groups play an important role in many biological processes. The synthesis of amphiphilic polyphenylene dendrimer branches (dendrons), providing alternating hydrophilic and lipophilic one reactive ethynyl group at the core is reported. serve as biorecognition units that bind to adenovirus 5 (Ad5), which a common vector gene therapy. Ad5/dendron complexes showed high transduction efficiencies coxsackie‐adenovirus receptor (CAR)‐negative cells. Moreover, dendrons...
The clinical efficacy of adenovirus serotype 5-based vectors is limited by complex interactions the vector with host blood components. These trigger sequestration systemically administered particles mainly reticuloendothelial system. In order to generate retargeted Ad suitable for i.v. delivery it mandatory understand and manipulate these non-target interactions. mice, was shown that coagulation factor X bound hexon reduces shielding virus from natural antibodies macrophage uptake, but also...