Ophthalmic Genet

We report on a young female patient with the clinical features of blepharophimosis-ptosis-epicanthus inversus syndrome (BPES, OMIM 110100) and a balanced chromosome translocation 46, XX, t(2;3)(q33;q23)dn.BPES is a rare autosomal dominant congenital disorder characterized by the eponymous oculo-facial features that are, in female patients, associated either with (type 1 BPES) or without (type 2 BPES) premature ovarian failure. Both types of BPES are caused by heterozygous mutations in the FOXL2 gene, which is located in chromosome band 3q23. Chromosome aberrations such as balanced rearrangements have only rarely been observed in BPES patients but can provide valuable information about regulatory regions of FOXL2. The translocation in this patient broadens our knowledge of pathogenic mechanisms in BPES and highlights the importance of conventional cytogenetic investigations in patients with negative results of FOXL2 mutation screening as a prerequisite for optimal management and genetic counseling

A dual-antigen self-amplifying RNA SARS-CoV-2 vaccine induces potent humoral and cellular immune responses and protects against SARS-CoV-2 variants through T cell-mediated immunity

Self-amplifying RNA vaccines might induce equivalent or more potent immune responses at lower doses compared to non-replicating mRNA vaccines via amplified antigen expression. In this paper we demonstrate that 1 μg of a LNP formulated dual-antigen self-amplifying RNA vaccine (ZIP1642), encoding both the S-RBD and N antigen, elicits considerably higher neutralizing antibody titers against Wuhan-like, beta B.1.351 and delta B.1.617.2 SARS-CoV-2 variants compared to those of convalescent patients. Additionally, ZIP1642 vaccination in mice expanded both S- and N-specific CD3(+)CD4(+) and CD3(+)CD8(+) T cells and caused a Th1 shifted cytokine response. We demonstrate that induction of such dual-antigen-targeted cell-mediated immune response might provide better protection against variants displaying highly mutated Spike proteins, as infectious viral loads of both Wuhan-like and beta variants were decreased after challenge of ZIP1642 vaccinated hamsters. Supported by these results, we encourage redirecting focus towards the induction of multiple-antigen-targeted cell-mediated immunity in addition to neutralizing antibody responses, to bypass waning antibody responses and attenuate infectious breakthrough and disease severity of future SARS-CoV-2 variants

Chemically modified hCFTR mRNAs recuperate lung function in a mouse model of cystic fibrosis

Abstract Gene therapy has always been a promising therapeutic approach for Cystic Fibrosis (CF). However, numerous trials using DNA or viral vectors encoding the correct protein resulted in a general low efficacy. In the last years, chemically modified messenger RNA (cmRNA) has been proven to be a highly potent, pulmonary drug. Consequently, we first explored the expression, function and immunogenicity of human (h)CFTR encoded by cmRNAhCFTR in vitro and ex vivo, quantified the expression by flow cytometry, determined its function using a YFP based assay and checked the immune response in human whole blood. Similarly, we examined the function of cmRNAhCFTR in vivo after intratracheal (i.t.) or intravenous (i.v.) injection of the assembled cmRNAhCFTR together with Chitosan-coated PLGA (poly-D, L-lactide-co-glycolide 75:25 (Resomer RG 752 H)) nanoparticles (NPs) by FlexiVent. The amount of expression of human hCFTR encoded by cmRNAhCFTR was quantified by hCFTR ELISA, and cmRNAhCFTR values were assessed by RT-qPCR. Thereby, we observed a significant improvement of lung function, especially in regards to FEV0.1, suggesting NP-cmRNAhCFTR as promising therapeutic option for CF patients independent of their CFTR genotype

Evaluation of predictive tests for screening for dihydropyrimidine dehydrogenase deficiency

5-Fluorouracil (5-FU) is rapidly degraded by dihyropyrimidine dehydrogenase (DPD). Therefore, DPD deficiency can lead to severe toxicity or even death following treatment with 5-FU or capecitabine. Different tests based on assessing DPD enzyme activity, genetic variants in DPYD and mRNA variants have been studied for screening for DPD deficiency, but none of these are implemented broadly into clinical practice. We give an overview of the tests that can be used to detect DPD deficiency and discuss the advantages and disadvantages of these test