Publications by authors named "J Skokowa"
Severe congenital neutropenia (CN) patients require life-long treatment with recombinant human granulocyte colony-stimulating factor (rhG-CSF), but some show no response. We sought to establish a therapy for CN that targets signaling pathways causing maturation arrest of granulocytic progenitors. We developed an isogenic induced pluripotent stem cell (iPSC) in vitro model of CN associated with ELANE mutations (ELANE-CN) and performed an in silico drug repurposing analysis of the transcriptomics of iPSC-generated hematopoietic stem and progenitor cells.
View Article and Find Full Text PDFWe have identified a new inherited bone marrow (BM) failure syndrome with severe congenital neutropenia (CN) caused by autosomal recessive mutations in the coatomer protein complex I (COPI) subunit zeta 1 (COPZ1) gene. A stop-codon COPZ1 mutation and a missense mutation were found in three patients from two unrelated families. While two affected siblings with a stop-codon COPZ1 mutation suffered from congenital neutropenia (CN) that involves other hematological lineages, and non-hematological tissues, the patient with a missense COPZ1 mutation had isolated neutropenia.
View Article and Find Full Text PDFArticle Synopsis
- Dysregulation of cytokines and their receptors can lead to serious health issues like cancer and autoimmune disorders, prompting the need for effective treatments.
- Researchers designed specific blockers for the granulocyte-colony stimulating factor receptor (G-CSFR), which plays a role in leukemia and inflammatory diseases.
- The engineered proteins were highly stable and effective at inhibiting G-CSFR in cancer cells, suggesting that this method could also be applied to develop treatments for other related cytokine receptors.
Article Synopsis
- Safety is crucial in gene therapies for inherited preleukemia syndromes like severe congenital neutropenia (CN), and various CRISPR/Cas9 strategies were tested on CD34 cells from CN patients.
- All gene editing methods, including universal knockout and allele-specific mutation correction, showed at least 30% editing success without toxicity and helped restore blood cell production.
- Personalized assessments of off-target effects were conducted using patient-derived stem cells, revealing that allele-specific methods had the best safety profiles, highlighting the need for careful strategy selection in gene therapies for these diseases.