A5040568538- CRISPR and Genetic Engineering
- Pluripotent Stem Cells Research
- Lipid metabolism and disorders
- Genetic Associations and Epidemiology
- RNA and protein synthesis mechanisms
- RNA Research and Splicing
- RNA regulation and disease
- RNA modifications and cancer
- Innovation and Socioeconomic Development
- Misinformation and Its Impacts
- Virus-based gene therapy research
- Lipoproteins and Cardiovascular Health
- Viral Infections and Immunology Research
- Cardiomyopathy and Myosin Studies
- Diabetes, Cardiovascular Risks, and Lipoproteins
- Congenital heart defects research
- Biomedical Ethics and Regulation
- Media Influence and Politics
- Genetics, Aging, and Longevity in Model Organisms
- Endoplasmic Reticulum Stress and Disease
- Vaccine Coverage and Hesitancy
- Cancer-related molecular mechanisms research
- Cancer, Lipids, and Metabolism
- Viral Infectious Diseases and Gene Expression in Insects
- Cardiovascular Function and Risk Factors
California University of Pennsylvania
2024-2025
University of Pennsylvania
2014-2024
Cardiovascular Institute of the South
2016-2024
Cardiovascular Institute Hospital
2022
Twitter (United States)
2021
GTx (United States)
2018-2021
Regeneron (United States)
2019
AstraZeneca (France)
2019
The University of Texas Southwestern Medical Center
2019
Creative Commons
2019
Abstract Circular RNAs (circRNAs) are broadly expressed in eukaryotic cells, but their molecular mechanism human disease remains obscure. Here we show that circular antisense non-coding RNA the INK4 locus ( circANRIL ), which is transcribed at a of atherosclerotic cardiovascular on chromosome 9p21, confers atheroprotection by controlling ribosomal (rRNA) maturation and modulating pathways atherogenesis. CircANRIL binds to pescadillo homologue 1 (PES1), an essential 60S-preribosomal assembly...
We sequenced all protein-coding regions of the genome (the "exome") in two family members with combined hypolipidemia, marked by extremely low plasma levels low-density lipoprotein (LDL) cholesterol, high-density (HDL) and triglycerides. These participants were compound heterozygotes for distinct nonsense mutations ANGPTL3 (encoding angiopoietin-like 3 protein). has been reported to inhibit lipase endothelial lipase, thereby increasing triglyceride HDL cholesterol rodents. Our finding...
Individuals with naturally occurring loss-of-function proprotein convertase subtilisin/kexin type 9 (PCSK9) mutations experience reduced low-density lipoprotein cholesterol levels and protection against cardiovascular disease.
Methods to deliver gene editing agents in vivo as ribonucleoproteins could offer safety advantages over nucleic acid delivery approaches. We report the development and application of engineered DNA-free virus-like particles (eVLPs) that efficiently package base editor or Cas9 ribonucleoproteins. By engineering VLPs overcome cargo packaging, release, localization bottlenecks, we developed fourth-generation eVLPs mediate efficient several primary mouse human cell types. Using different...
High-efficiency genome editing to disrupt therapeutic target genes, such as PCSK9 (proprotein convertase subtilisin/kexin type 9), has been demonstrated in preclinical animal models, but there are safety concerns because of the unpredictable nature cellular repair double-strand breaks, well off-target mutagenesis. Moreover, precise knock-in specific nucleotide changes-whether introduce or correct gene mutations-has proven be inefficient nonproliferating cells vivo. Base editors comprising...
The viral delivery of base editors has been complicated by their size and the limited packaging capacity adeno-associated viruses (AAVs). Typically, dual-AAV approaches based on trans-splicing inteins have used. Here we show that, compared with systems, AAVs size-optimized genomes incorporating compact adenine (ABEs) enable efficient editing in mice at similar or lower doses. Single-AAV-encoded ABEs retro-orbitally injected led to efficiencies liver (66%), heart (33%) muscle (22%) tissues...
Abstract Realizing the promise of prime editing for study and treatment genetic disorders requires efficient methods delivering editors (PEs) in vivo. Here we describe identification bottlenecks limiting adeno-associated virus (AAV)-mediated vivo development AAV-PE vectors with increased PE expression, guide RNA stability modulation DNA repair. The resulting dual-AAV systems, v1em v3em PE-AAV, enable therapeutically relevant mouse brain (up to 42% efficiency cortex), liver 46%) heart 11%)....
Lipid nanoparticles have demonstrated utility in hepatic delivery of a range therapeutic modalities and typically deliver their cargo via low-density lipoprotein receptor-mediated endocytosis. For patients lacking sufficient receptor activity, such as those with homozygous familial hypercholesterolemia, an alternate strategy is needed. Here we show the use structure-guided rational design series mouse non-human primate studies to optimize GalNAc-Lipid nanoparticle that allows for independent...
Chicken embryo fibroblasts (CEFs) localize β-actin mRNA to their lamellae, a process important for the maintenance of cell polarity and motility. The localization requires cis element (zipcode) involves zipcode binding protein 1 (ZBP1), that specifically binds zipcode. Both lamellipodia polarized CEFs. ZBP1 its homologues contain two NH2-terminal RNA recognition motifs (RRMs) four COOH-terminal hnRNP K homology (KH) domains. By using truncations fused GFP in conjunction with situ...