A5044222617- Cystic Fibrosis Research Advances
- CRISPR and Genetic Engineering
- Neonatal Respiratory Health Research
- Genomics and Rare Diseases
- RNA regulation and disease
- Tracheal and airway disorders
- Cytomegalovirus and herpesvirus research
- Inhalation and Respiratory Drug Delivery
- Autism Spectrum Disorder Research
- Genomic variations and chromosomal abnormalities
- Nasal Surgery and Airway Studies
- Genetics and Neurodevelopmental Disorders
- Immunodeficiency and Autoimmune Disorders
- Sinusitis and nasal conditions
- Neurogenetic and Muscular Disorders Research
- RNA Research and Splicing
- Child Nutrition and Feeding Issues
- Congenital heart defects research
- RNA Interference and Gene Delivery
- RNA and protein synthesis mechanisms
- Advanced biosensing and bioanalysis techniques
- HIV Research and Treatment
- Respiratory viral infections research
- Bacterial Genetics and Biotechnology
- Peptidase Inhibition and Analysis
Johns Hopkins Medicine
2018-2024
Johns Hopkins University
2018-2024
University of Massachusetts Chan Medical School
2023-2024
Treatment of individuals with cystic fibrosis (CF) has been transformed by small molecule therapies that target select pathogenic variants in the CF transmembrane conductance regulator (CFTR). To expand treatment eligibility, we stably expressed 43 rare missense CFTR associated moderate from a single site genome human bronchial epithelial (CFBE41o–) cells. The magnitude drug response was highly correlated residual function for potentiator ivacaftor, corrector lumacaftor, and...
Rationale: The advent of precision treatment for cystic fibrosis using small-molecule therapeutics has created a need to estimate potential clinical improvements attributable increases in transmembrane conductance regulator (CFTR) function. Objectives: To derive CFTR function variety genotypes and correlate with key features (sweat chloride concentration, pancreatic exocrine status, lung function) develop benchmarks assessing response modulators. Methods: assigned 226 unique was correlated...
CFTR modulators have revolutionized the treatment of individuals with cystic fibrosis (CF) by improving function existing protein. Unfortunately, almost half disease-causing variants in are predicted to introduce premature termination codons (PTC) thereby causing absence full-length We hypothesized that a subset nonsense and frameshift allow expression truncated protein might respond FDA-approved modulators. To address this concept, we selected 26 PTC-generating from four regions determined...
Elucidating the functional consequence of molecular defects underlying genetic diseases enables appropriate design therapeutic options. Treatment cystic fibrosis (CF) is an exemplar this paradigm as development CFTR modulator therapies has allowed for targeted and effective treatment individuals harboring specific variants. However, mechanism these drugs limits effectiveness to particular classes variants that allow production protein. Thus, assessment individual imperative proper assignment...
Gene editing holds great promise for muscular dystrophy treatment, but the rapid evaluation of different modalities in skeletal muscle vivo remains challenging due to lack simple, effective delivery tools. Here we demonstrate that selective organ targeting (SORT) lipid nanoparticles (LNP) encapsulating optimized Cas9 cargo can facilitate efficient, local muscles achieving rates ≥35% and restore protein expression a proof-of-concept target. Interestingly, efficient was observed despite strong...
Small molecule drugs known as modulators can treat ~90% of people with cystic fibrosis (CF), but do not work for premature termination codon variants such W1282X (c.3846G>A). Here we evaluated two gene editing strategies, Adenine Base Editing (ABE) to correct W1282X, and Homology-Independent Targeted Integration (HITI) a CFTR superexon comprising exons 23-27 (SE23-27) enable expression mRNA without W1282X. In Flp-In-293 cells stably expressing minigene bearing ABE corrected 24% alleles,...
Abstract Prime editing efficiency is modest in cells that are quiescent or slowly proliferating where intracellular dNTP levels tightly regulated. MMLV-reverse transcriptase - the prime editor polymerase subunit requires high dNTPs for efficient polymerization. We report primary and vivo increased by mutations enhance enzymatic properties of can be further complemented targeting SAMHD1 degradation.
We broaden the clinical versatility of human nasal epithelial (HNE) cells. HNEs were isolated from 10 participants harboring
Chromosomal structural variation can cause severe neurodevelopmental and neuropsychiatric phenotypes. Here we present a nonverbal female adolescent with stereotypic movement disorder problem behavior (e.g., self-injurious behavior, aggression, disruptive destructive behaviors), autism spectrum disorder, intellectual disability, attention deficit hyperactivity global developmental delay. Previous cytogenetic analysis revealed balanced translocations in the patient's apparently normal mother....