Selected Grantee Publications
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- nhlbi
- Cancer
- Rare Diseases
Establishing the Hybrid Rat Diversity Program: A Resource for Dissecting Complex Traits
Dwinell et al., Mammalian Genome. 2025.
https://pubmed.ncbi.nlm.nih.gov/39907792
Rat models have been extensively used for studying human complex disease mechanisms, behavioral phenotypes, and environmental factors and for discovering and developing drugs. Systems genetics approaches have been used to study the effects of both genetic variation and environmental factors. This approach recognizes the complexity of common disorders and uses intermediate phenotypes to find relationships between genetic variation and clinical traits. This article describes the Hybrid Rat Diversity Program (HDRP) at the Medical College of Wisconsin, which involves 96 inbred rat strains and aims to provide a renewable and reusable resource in terms of the HRDP panel of inbred rat strains, the genomic data derived from the HRDP strains, and banked resources available for additional studies. Supported by ORIP (R24OD024617) and NHLBI.
Plural Molecular and Cellular Mechanisms of Pore Domain KCNQ2 Encephalopathy
Abreo et al., eLife. 2025.
https://pmc.ncbi.nlm.nih.gov/articles/PMC11703504
This study investigates the cellular and molecular mechanisms underlying KCNQ2 encephalopathy, a severe type of early-onset epilepsy caused by mutations in the KCNQ2 gene. Researchers describe a case study of a child with a specific KCNQ2 gene mutation, G256W, and found that it disrupts normal brain activity, leading to seizures and developmental impairments. Male and female Kcnq2G256W/+ mice have reduced KCNQ2 protein levels, epilepsy, brain hyperactivity, and premature deaths. As seen in the patient study, ezogabine treatment rescued seizures in mice, suggesting a potential treatment avenue. These findings provide important insights into KCNQ2-related epilepsy and highlight possible therapeutic strategies. Supported by ORIP (U54OD020351, S10OD026804, U54OD030187), NCI, NHLBI, NICHD, NIGMS, NIMH, and NINDS.
SREBP-Dependent Regulation of Lipid Homeostasis Is Required for Progression and Growth of Pancreatic Ductal Adenocarcinoma
Ishida et al., Cancer Research Communications. 2024.
https://pmc.ncbi.nlm.nih.gov/articles/PMC11444119
Lipids are crucial for tumor cell proliferation, and sterol regulatory element-binding protein (SREBP) activation drives lipid synthesis and uptake to maintain cancer growth. This study investigated the role of the SREBP pathway and its regulator, SREBP cleavage–activating protein (SCAP), in lipid metabolism during the development and progression of pancreatic ductal adenocarcinoma (PDAC). Using female mouse xenograft models and male and female pancreas-specific Scap knockout transgenic mice, researchers demonstrated that SCAP is essential for PDAC progression in low-nutrient conditions, linking lipid metabolism to tumor growth. These findings highlight SREBP as a key therapeutic target for PDAC, offering potential strategies for improving treatment by disrupting cancer-associated metabolic reprogramming. Supported by ORIP (T32OD011089), NCI, NHLBI, and NIGMS.
Amphiphilic Shuttle Peptide Delivers Base Editor Ribonucleoprotein to Correct the CFTR R553X Mutation in Well-Differentiated Airway Epithelial Cells
Kulhankova et al., Nucleic Acids Research. 2024.
https://academic.oup.com/nar/article/52/19/11911/7771564?login=true
Effective translational delivery strategies for base editing applications in pulmonary diseases remain a challenge because of epithelial cells lining the intrapulmonary airways. The researchers demonstrated that the endosomal leakage domain (ELD) plays a crucial role in gene editing ribonucleoprotein (RNP) delivery activity. A novel shuttle peptide, S237, was created by flanking the ELD with poly glycine-serine stretches. Primary airway epithelia with the cystic fibrosis transmembrane conductance regulator (CFTR) R533X mutation demonstrated restored CFTR function when treated with S237-dependent ABE8e-Cas9-NG RNP. S237 outperformed the S10 shuttle peptide at Cas9 RNP delivery in vitro and in vivo using primary human bronchial epithelial cells and transgenic green fluorescent protein neonatal pigs. This study highlights the efficacy of S237 peptide–mediated RNP delivery and its potential as a therapeutic tool for the treatment of cystic fibrosis. Supported by ORIP (U42OD027090, U42OD026635), NCATS, NHGRI, NHLBI, NIAID, NIDDK, and NIGMS.
Evolution of the Clinical-Stage Hyperactive TcBuster Transposase as a Platform for Robust Non-Viral Production of Adoptive Cellular Therapies
Skeate et al., Molecular Therapy. 2024.
https://pubmed.ncbi.nlm.nih.gov/38627969/
In this study, the authors report the development of a novel hyperactive TcBuster (TcB-M) transposase engineered through structure-guided and in vitro evolution approaches that achieve high-efficiency integration of large, multicistronic CAR-expression cassettes in primary human cells. This proof-of-principle TcB-M engineering of CAR-NK and CAR-T cells shows low integrated vector copy number, a safe insertion site profile, robust in vitro function, and improved survival in a Burkitt lymphoma xenograft model in vivo. Their work suggests that TcB-M is a versatile, safe, efficient, and open-source option for the rapid manufacture and preclinical testing of primary human immune cell therapies through delivery of multicistronic large cargo via transposition. Supported by ORIP (F30OD030021), NCI, NHLBI, and NIAID.
AAV5 Delivery of CRISPR/Cas9 Mediates Genome Editing in the Lungs of Young Rhesus Monkeys
Liang et al., Human Gene Therapy. 2024.
https://pubmed.ncbi.nlm.nih.gov/38767512/
Genome editing in somatic cells and tissues has the potential to provide long-term expression of therapeutic proteins to treat a variety of genetic lung disorders. However, delivering genome-editing machinery to disease-relevant cell types in the lungs of primates has remained a challenge. Investigators of this article are participating in the NIH Somatic Cell Genome Editing Consortium. Herein, they demonstrate that intratracheal administration of a dual adeno-associated virus type 5 vector encoding CRISPR/Cas9 can mediate genome editing in rhesus (male and female) airways. Up to 8% editing was observed in lung lobes, including a housekeeping gene, GAPDH, and a disease-related gene, angiotensin-converting enzyme 2. Using single-nucleus RNA-sequencing, investigators systematically characterized cell types transduced by the vector. Supported by ORIP (P51OD01110, U42OD027094, S10OD028713), NCATS, NCI, and NHLBI.
De Novo Variants in FRYL Are Associated With Developmental Delay, Intellectual Disability, and Dysmorphic Features
Pan et al., The American Journal of Human Genetics. 2024.
https://www.cell.com/ajhg/fulltext/S0002-9297(24)00039-9
FRY-like transcription coactivator (FRYL) belongs to a Furry protein family that is evolutionarily conserved from yeast to humans, and its functions in mammals are largely unknown. Investigators report 13 individuals who have de novo heterozygous variants in FRYL and one individual with a heterozygous FRYL variant that is not confirmed to be de novo. The individuals present with developmental delay; intellectual disability; dysmorphic features; and other congenital anomalies in cardiovascular, skeletal, gastrointestinal, renal, and urogenital systems. Using fruit flies, investigators provide evidence that haploinsufficiency in FRYL likely underlies a disorder in humans with developmental and neurological symptoms. Supported by ORIP (U54OD030165), NHLBI, NICHD, and NCATS.
Pancreatic Cancer Cells Upregulate LPAR4 in Response to Isolation Stress to Promote an ECM-Enriched Niche and Support Tumour Initiation
Wu et al., Nature Cell Biology. 2023.
https://pubmed.ncbi.nlm.nih.gov/36646789/
Understanding drivers of tumor initiation is critical for cancer therapy. Investigators found transient increase of lysophosphatidic acid receptor 4 (LPAR4) in pancreatic cancer cells exposed to environmental stress or chemotherapy. LPAR4 induced tumor initiation, stress tolerance, and drug resistance by downregulating miR-139-5p, a tumor suppressor, and upregulating fibronectin. These results indicate that LPAR4 enhances cell-autonomous production of a fibronectin-rich extracellular matrix (ECM), allowing cells to survive isolation stress and compensate for the absence of stromal-derived factors by creating their own tumor-initiating niche. Supported by ORIP (K01OD030513, T32OD017863), NCI, and NHLBI.