Selected Grantee Publications
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- Cancer
- Women's Health
- Genetics
Multimodal Analysis of Dysregulated Heme Metabolism, Hypoxic Signaling, and Stress Erythropoiesis in Down Syndrome
Donovan et al., Cell Reports. 2024.
https://pubmed.ncbi.nlm.nih.gov/39120971
Down syndrome (DS), a genetic condition caused by the presence of an extra copy of chromosome 21, is characterized by intellectual and developmental disability. Infants with DS often suffer from low oxygen saturation, and DS is associated with obstructive sleep apnea. Investigators assessed the role that hypoxia plays in driving health conditions that are comorbid with DS. A multiomic analysis showed that people with DS exhibit elevated heme metabolism and activated stress erythropoiesis, which are indicators of chronic hypoxia; these results were recapitulated in a mouse model for DS. This study identified hypoxia as a possible mechanism underlying several conditions that co-occur with DS, including congenital heart defects, seizure disorders, autoimmune disorders, several leukemias, and Alzheimer's disease. Supported by ORIP (R24OD035579), NCATS, NCI, and NIAID.
Establishment and Characterization of Three Human Ocular Adnexal Sebaceous Carcinoma Cell Lines
Lee et al., International Journal of Molecular Sciences. 2024.
https://pmc.ncbi.nlm.nih.gov/articles/PMC11432008
Researchers established three new cell lines to model ocular adnexal sebaceous carcinoma (SebCA) and test new therapies. SebCA is a highly problematic periorbital tumor requiring aggressive surgical treatment, and its pathobiology remains poorly understood. With consent from one male and two female patients, tumor tissue was cultured under conditional reprograming, and the cells were analyzed for growth, clonogenicity, apoptosis, and differentiation using methods including western blotting, short tandem repeat profiling, and next-generation sequencing. These newly developed cell lines provide valuable preclinical models for understanding and treating SebCA. Supported by ORIP (K01OD034451).
Placental Gene Therapy in Nonhuman Primates: A Pilot Study of Maternal, Placental, and Fetal Response to Non-Viral, Polymeric Nanoparticle Delivery of IGF1
Wilson et al., Molecular Human Reproduction. 2024.
https://academic.oup.com/molehr/article/30/11/gaae038/7876288#493719584
This study investigates a novel nanoparticle-mediated gene therapy approach for addressing fetal growth restriction (FGR) in pregnant female nonhuman primates. Using polymer-based nanoparticles delivering a human insulin-like growth factor 1 (IGF1) transgene, the therapy targets the placenta via ultrasound-guided injections. Researchers evaluated maternal, placental, and fetal responses by analyzing tissues, immunomodulatory proteins, and hormones (progesterone and estradiol). Findings highlight the potential of IGF1 nanoparticles to correct placental insufficiency by enhancing fetal growth, providing a groundbreaking advancement for in utero treatments. This research supports further exploration of nonviral gene therapies for improving pregnancy outcomes and combating FGR-related complications. Supported by ORIP (P51OD011106) and NICHD.
Commentary: The International Mouse Phenotyping Consortium: High-Throughput In Vivo Functional Annotation of the Mammalian Genome
Lloyd, Mammalian Genome. 2024.
https://pubmed.ncbi.nlm.nih.gov/39254744
The International Mouse Phenotyping Consortium (IMPC), a collectively governed consortium of 21 academic research institutions across 15 countries on 5 continents, represents a groundbreaking approach in genetics and biomedical research. Its goal is to create a comprehensive catalog of mammalian gene function that is freely available and equally accessible to the global research community. So far, the IMPC has uncovered the function of thousands of genes about which little was previously known. By 2027, when the current round of funding expires, the IMPC will have produced and phenotyped nearly 12,000 knockout mouse lines representing approximately 60% of the human orthologous genome in mice. This new knowledge has produced numerous insights about the role of genes in health and disease, including informing the genetic basis of rare diseases and positing gene product influences on common diseases. However, as IMPC nears the end of the current funding cycle, its path forward remains unclear. Supported by ORIP (UM1OD023221).
The Mutant Mouse Resource and Research Center (MMRRC) Consortium: The U.S.-Based Public Mouse Repository System
Agca et al., Mammalian Genome. 2024.
https://link.springer.com/article/10.1007/s00335-024-10070-3
The MMRRC has been the nation’s preeminent public repository and distribution archive of mutant mouse models for 25 years. The Consortium, with support from NIH, facilitates biomedical research by identifying, acquiring, evaluating, characterizing, preserving, and distributing a variety of mutant mouse strains to investigators around the world. Since its inception, the MMRRC has fulfilled more than 20,000 orders from 13,651 scientists at 8,441 institutions worldwide. Today, the MMRRC maintains an archive of mice, cryopreserved embryos and sperm, embryonic stem-cell lines, and murine monoclonal antibodies for nearly 65,000 alleles. The Consortium also provides scientific consultation, technical assistance, genetic assays, microbiome analysis, analytical phenotyping, pathology, husbandry, breeding and colony management, and more. Supported by ORIP (U42OD010918, U42OD010924, U42OD010983).
Alterations in Tumor Aggression Following Androgen Receptor Signaling Restoration in Canine Prostate Cancer Cell Lines
Vasilatis et al., International Journal of Molecular Sciences. 2024.
https://pubmed.ncbi.nlm.nih.gov/39201315
Prostate cancer (PCa) ranks second worldwide in cancer-related mortality, but only a few animal models exhibit naturally occurring PCa that recapitulates the symptoms of the disease. Neutered dogs have an increased risk of PCa and often lack androgen receptor (AR) signaling, which is involved in upregulating tumorigenesis but can also suppress aggressive cell growth. In this study, researchers sought to understand more about the role of AR signaling in canine PCa initiation and progression by restoring AR in canine PCa cell lines and treating them with dihydrotestosterone. One cell line exhibited AR-mediated tumor suppression; one cell line showed altered proliferation (but not migration or invasion); and a third cell line exhibited AR-mediated alterations in migration and invasion (but not proliferation). The study highlights the heterogeneous nature of PCa in dogs and humans but suggests that AR signaling might have therapeutic potential under certain conditions. Supported by ORIP (T32OD011147).
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.
Integrin αvβ3 Upregulation in Response to Nutrient Stress Promotes Lung Cancer Cell Metabolic Plasticity
Nam, Cancer Research. 2024.
https://pubmed.ncbi.nlm.nih.gov/38588407/
Tumor-initiating cells can survive in harsh environments via stress tolerance and metabolic flexibility; studies on this topic can yield new targets for cancer therapy. Using cultured cells and live human surgical biopsies of non-small cell lung cancer, researchers demonstrated that nutrient stress drives a metabolic reprogramming cascade that allows tumor cells to thrive despite a nutrient-limiting environment. This cascade results from upregulation of integrin αvβ3, a cancer stem cell marker. In mice, pharmacological or genetic targeting prevented lung cancer cells from evading the effects of nutrient stress, thus blocking tumor initiation. This work suggests that this molecular pathway leads to cancer stem cell reprogramming and could be linked to metabolic flexibility and tumor initiation. Supported by ORIP (K01OD030513), NCI, NIGMS, and NINDS.
Transcriptome- and Proteome-Wide Effects of a Circular RNA Encompassing Four Early Exons of the Spinal Muscular Atrophy Genes
Luo, Scientific Reports. 2024.
https://pubmed.ncbi.nlm.nih.gov/38714739/
Spinal muscular atrophy (SMA) is a leading genetic cause of mortality in infants and often results from a deficiency of deletions of or mutations in the SMN1 gene. In this study, researchers report the transcriptome- and proteome-wide effects of overexpression of C2A‑2B3-4, a circular RNA produced by SMN1 and SMN2, in cells. They report that C2A-2B-3-4 is associated with expression of genes associated with chromatin remodeling, transcription, spliceosome function, ribosome biogenesis, lipid metabolism, cytoskeletal formation, cell proliferation, and neuromuscular junction formation. More work is needed to investigate the role of these genes in processes associated with SMA and other pathological conditions, including cancer and male infertility. Supported by ORIP (T35OD027967) and NINDS.