A5035110445- CRISPR and Genetic Engineering
- Virus-based gene therapy research
- RNA Interference and Gene Delivery
- CAR-T cell therapy research
- Pluripotent Stem Cells Research
- Immunotherapy and Immune Responses
- RNA regulation and disease
- MicroRNA in disease regulation
- Mosquito-borne diseases and control
- Advanced biosensing and bioanalysis techniques
- Immune Cell Function and Interaction
- interferon and immune responses
- Cytomegalovirus and herpesvirus research
- Hemoglobinopathies and Related Disorders
- Cytokine Signaling Pathways and Interactions
- Viral Infections and Vectors
- Circular RNAs in diseases
- HIV Research and Treatment
- RNA modifications and cancer
- Cancer Immunotherapy and Biomarkers
- Animal Genetics and Reproduction
- RNA Research and Splicing
- Congenital heart defects research
- Prostate Cancer Treatment and Research
- Cancer-related molecular mechanisms research
Aarhus University
2016-2025
Stanford University
2015-2024
ORCID
2018
Palo Alto University
2016
Institute for Biomedicine
2013
International AIDS Vaccine Initiative
2013
Scripps Research Institute
2013
Oncogenes are activated through well-known chromosomal alterations such as gene fusion, translocation, and focal amplification. In light of recent evidence that the control key genes depends on chromosome structures called insulated neighborhoods, we investigated whether proto-oncogenes occur within these oncogene activation can via disruption neighborhood boundaries in cancer cells. We mapped neighborhoods T cell acute lymphoblastic leukemia (T-ALL) found tumor genomes contain recurrent...
Significance HIV-1 is a lentivirus and replicates through replication cycle involving several DNA forms including ssDNA. Here we report that synthetic oligos corresponding to of the as well viral are detected by immunological sensor IFN-inducible protein 16 (IFI16) stimulate innate immune responses pathway dependent on stimulator IFN genes (STING). Moreover, show elevated in cells with decreased expression IFI16 or STING. We suggest for macrophages stimulating responses, which contribute...
Abstract Stimulator of interferon genes (STING) is known be involved in control DNA viruses but has an unexplored role RNA viruses. During infection with STING activated downstream cGAMP synthase (cGAS) to induce type I interferon. Here we identify a STING-dependent, cGAS-independent pathway important for full production and antiviral enveloped viruses, including influenza A virus (IAV). Further, IAV interacts through its conserved hemagglutinin fusion peptide (FP). Interestingly, FP...
Preclinical efficacy and safety data in mice provide support for ex vivo β-globin gene correction to treat patients with sickle cell disease.
Understanding the molecular pathways driving acute antiviral and inflammatory response to SARS-CoV-2 infection is critical for developing treatments severe COVID-19. Here, we find decreasing number of circulating plasmacytoid dendritic cells (pDCs) in COVID-19 patients early after symptom onset, correlating with disease severity. pDC depletion transient coincides decreased expression type I IFNα systemic cytokines CXCL10 IL-6. Using an vitro stem cell-based human model, further demonstrate...
The induction of proinflammatory T cells by dendritic cell (DC) subtypes is critical for antitumor responses and effective immune checkpoint blockade (ICB) therapy. Here, we show that human CD1c + CD5 DCs are reduced in melanoma-affected lymph nodes, with expression on correlating patient survival. Activating enhanced priming improved survival after ICB DC numbers increased during therapy, low interleukin-6 (IL-6) concentrations promoted their de novo differentiation. Mechanistically, was...
The CRISPR/Cas9 system has recently been shown to facilitate high levels of precise genome editing using adeno-associated viral (AAV) vectors serve as donor template DNA during homologous recombination (HR). However, the maximum AAV packaging capacity ∼4.5 kb limits size. Here, we overcome this constraint by showing that two co-transduced can donors consecutive HR events for integration large transgenes. Importantly, method involves a single-step procedure applicable primary cells with...
Precise and efficient manipulation of genes is crucial for understanding the molecular mechanisms that govern human hematopoiesis developing novel therapies diseases blood immune system. Current methods do not enable precise engineering complex genotypes can be easily tracked in a mixed population cells. We describe method to multiplex homologous recombination (HR) hematopoietic stem progenitor cells primary T by combining rAAV6 donor delivery CRISPR/Cas9 system delivered as...
Genome-editing technologies are currently being translated to the clinic. However, cellular effects of editing machinery have yet be fully elucidated. Here, we performed global microarray-based gene expression measurements on human CD34+ hematopoietic stem and progenitor cells that underwent editing. We probed entire process as well each component individually, including electroporation, Cas9 (mRNA or protein) with chemically modified sgRNA, AAV6 transduction. identified differentially...
Abstract Lysosomal enzyme deficiencies comprise a large group of genetic disorders that generally lack effective treatments. A potential treatment approach is to engineer the patient’s own hematopoietic system express high levels deficient enzyme, thereby correcting biochemical defect and halting disease progression. Here, we present an efficient ex vivo genome editing using CRISPR-Cas9 targets lysosomal iduronidase CCR5 safe harbor locus in human CD34+ stem progenitor cells. The modified...
Engineered nuclease-mediated gene targeting through homologous recombination (HR) in hematopoietic stem and progenitor cells (HSPCs) has the potential to treat a variety of genetic hematologic immunologic disorders. Here, we identify critical parameters reproducibly achieve high frequencies RNA-guided (single-guide RNA [sgRNA]; CRISPR)-Cas9 nuclease (Cas9/sgRNA) rAAV6-mediated HR at β-globin (HBB) locus HSPCs. We identified that by transducing HSPCs with rAAV6 post-electroporation, there was...
Future therapeutic use of engineered site-directed nucleases, like zinc-finger nucleases (ZFNs) and transcription activator-like effector (TALENs), relies on safe effective means delivering to cells. In this study, we adapt lentiviral vectors as carriers designer nuclease proteins, providing efficient targeted gene disruption in vector-treated cell lines primary By co-packaging pairs ZFN proteins with donor RNA ‘all-in-one’ particles, co-deliver the template for homology-directed repair...
Prime editing is a new CRISPR-based, genome-editing technology that relies on the prime editor (PE), fusion protein of Cas9-nickase and M-MLV reverse transcriptase (RT), guide RNA (pegRNA) serves both to target PE desired genomic locus carry edit be introduced. Here, we make advancements RT moiety improve efficiencies truncations mitigate issues with adeno-associated virus (AAV) viral vector size limitations, which currently do not support efficient delivery large components. These efforts...
During mammalian development, the left and right ventricles arise from early populations of cardiac progenitors known as first second heart fields, respectively. While these have been extensively studied in non-human model systems, their identification study vivo human tissues limited due to ethical technical limitations accessing gastrulation-stage embryos. Human-induced pluripotent stem cells (hiPSCs) present an exciting alternative for modeling embryogenesis well-established ability...
Abstract A comprehensive investigation of ovarian cancer (OC) progression at the single-cell level is crucial for enhancing our understanding disease, as well development better diagnoses and treatments. Here, over half a million transcriptome data were collected from 84 OC patients across all clinical stages. Through integrative analysis, we identified heterogeneous epithelial-immune-stromal cellular compartments their interactions in microenvironment. The epithelial cells displayed subtype...