Selected Grantee Publications
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- New Approach Methodologies
Monitoring Biological Effects of Somatic Cell Genome Editing
Freedman et al., Nature Reviews Genetics. 2026.
https://pubmed.ncbi.nlm.nih.gov/41530266
CRISPR-based genome editing is an innovative technique for treating a variety of diseases. This therapy is entering the clinic, and preclinical-to-clinical tools are needed to ensure the therapy is safe and effective. Researchers affiliated with the Somatic Cell Genome Editing (SCGE) Consortium provided a review of these efforts. The review outlines key technologies—including microphysiological systems and noninvasive in vivo (within an organism) imaging—to examine the on-target and off-target biological effects of genome editing in different organ systems and disease settings. Microphysiological systems, such as organoids and organ-on-a-chip, are useful for modeling physical characteristics of human physiology and disease. Examples of these models for a broad range of diseases and their use for gene editing applications were discussed. Challenges related to these methods were noted. The review also explained how microphysiological systems complement traditional preclinical models—including mouse models—because of species differences when compared with humans. The researchers highlighted lessons learned from the NIH-funded SCGE Biological Effects Initiative and outlined a proposed framework for the integration of these technologies into the development of genome-editing therapies. Supported by ORIP (P51OD011107, S10OD016261, S10OD018102, S10OD028713, and U42OD027094), NCATS, NHGRI, NHLBI, NIA, NIAID, NIBIB, NIDDK, NIEHS, NIGMS, and NINDS.
Therapeutic Remodeling of the Ceramide Backbone Prevents Kidney Injury
Nicholson et al., Cell Metabolism. 2026.
https://pubmed.ncbi.nlm.nih.gov/41232539
Acute kidney injury (AKI) can be caused by a broad range of conditions, including drug toxicity, sepsis, preexisting kidney disorders, and heart failure. AKI increases a person’s chance for chronic kidney disease, morbidity, and mortality, but an effective therapy for AKI is not currently available. Proximal tubules (PTs) within the kidney secrete nonfiltered substances while reabsorbing filtered molecules. Abnormal lipid metabolism and lipid imbalances are linked to AKI, but the underlying mechanisms remain unknown. Using previously published data, urine samples from patients, and 8- to 11-week-old male mouse models, researchers showed that AKI triggers the production of toxic ceramides in PTs and that urine ceramide levels correlate with disease severity. Ceramides disrupt mitochondrial structure and function by altering critical protein complexes, and damage requires a specific molecular feature of ceramides created by the DES1 enzyme. Genetic deletion of DES1 protected mice from kidney injury following bilateral ischemia reperfusion. A novel DES1 inhibitor provided a protective effect, offering a promising therapeutic strategy. This work reveals ceramide remodeling as a promising target for treating AKI. Supported by ORIP (S10OD016232, S10OD018210, and S10OD021505), NCI, NHLBI, NIA, NIDDK, and NIGMS.
Gastrointestinal MAIT Cells in Chronic HIV-1 Infection
Ferre et al., Journal of Immunology. 2026.
https://pubmed.ncbi.nlm.nih.gov/41024436
Mucosa-associated invariant T (MAIT) cells are innate-like T cells abundant in blood and the gastrointestinal tract. They help control infections by producing immunoproteins, killing infected cells, and hindering microbial growth. Chronic HIV infection reduces MAIT cells and increases vulnerability to secondary infections. In this work, researchers studied immunological responses of blood and mucosal MAIT cells to microbes between people (both sexes) with chronic HIV who are on long-term antiretroviral therapy and people without HIV. While MAIT cells were depleted in the blood of HIV-infected individuals, mucosal MAIT cell levels remained comparable between the two groups. Blood MAIT cells responded robustly to general immune stimulation. However, mucosal MAIT cells responded poorly to Escherichia coli bacterial stimulation, suggesting selective unresponsiveness to normal microbes while maintaining immune functions to other stimuli. HIV-infected individuals showed an impaired MAIT cell antimicrobial defense, providing novel insights worth studying. Supported by ORIP (S10OD018223), NCI, and NIDDK.
Targeting FSP1 Triggers Ferroptosis in Lung Cancer
Wu et al., Nature. 2026.
https://pubmed.ncbi.nlm.nih.gov/41193800
Growing evidence shows that cancer cells are highly sensitive to lipid peroxidation (a chemical process that degrades lipids in cell membranes). Ferroptosis is a form of cell death that relies on iron and lipid peroxidation, and two proteins known to suppress ferroptosis are GPX4 and FSP1. In this study, researchers used 8- to 12-week-old genetically engineered mouse models for lung cancer (both sexes used) and selectively deleted these two proteins. Results showed that deleting GPX4 and FSP1 triggered lipid peroxidation and significantly inhibited lung adenocarcinoma tumor development. FSP1 was essential for protecting tumors from ferroptosis in vivo (within an organism) but not in vitro (outside of an organism), highlighting the utility of the mouse models to mimic the physiological conditions of patients. FSP1 expression correlated with disease progression and reduced survival in lung adenocarcinoma patients (sex not stated), unlike GPX4. Drug inhibition of FSP1 showed substantial therapeutic efficacy in preclinical models. These findings establish ferroptosis as a barrier to tumor development and identify FSP1 inhibition as a promising novel therapy for lung cancer patients. Supported by ORIP (S10OD021747, S10OD032292), NCI, and NIGMS.
NSD2 Targeting Reverses Plasticity and Drug Resistance in Prostate Cancer
Li et al., Nature. 2026.
https://pubmed.ncbi.nlm.nih.gov/41299174
Most prostate cancer tumors develop resistance to therapies. In castration-resistant prostate cancer (CRPC), lineage plasticity—a cancer cell’s ability to change physical characteristics and behavior—drives disease progression and promotes drug resistance. NSD2 is a protein involved in modifying histones to change gene expression. NSD2 upregulation in neuroendocrine prostate cancer correlates with poor survival and regulates the genes that drive neuroendocrine differentiation. Using both mouse and human patient–derived organoids and 3- to 5-month-old NPp53 mice (sex not stated), researchers successfully reversed treatment resistance in neuroendocrine CRPC by inhibiting NSD2. Notably, combining NSD2 inhibition with enzalutamide (a current drug used to treat prostate cancer) effectively suppressed tumor growth and promoted cell death in multiple CRPC subtypes. These findings establish combination therapy as a promising therapeutic strategy for lethal forms of CRPC that are currently treatment resistant. Supported by ORIP (S10OD021764, S10OD012351), NCI, NIDCR, NIDDK, and NIGMS.
Lung Cancer Cells Secrete Glutamine to Accumulate Tumor-Associated Macrophages
Reddy et al., Molecular Carcinogenesis. 2026.
https://pubmed.ncbi.nlm.nih.gov/41498201
Macrophages are a type of immune cell that are highly plastic—meaning environmental cues change their phenotype (physical characteristics) and behavior. Cancer cells take advantage of this plasticity to recruit and create tumor-associated macrophages (TAMs) that benefit the tumor microenvironment and promote tumor development. However, the underlying mechanism that cancer cells use to recruit TAMs remains unknown. In this study, researchers used murine and human non-small cell lung cancer cell models to show that integrin αvβ3 expression is needed to drive TAM accumulation. This research highlights a novel mechanism—αvβ3-mediated glutamine secretion—to promote TAM accumulation and begin tumor development. Developing therapies that target this signaling axis could help treat αvβ3-expressing cancers. Supported by ORIP (K01OD030513) and NINDS.
Inducing Ferroptosis to Impede Metastasis by Inhibiting the Calcium Channel TRPC6
Dimitrov et al., Cell Reports. 2025.
https://pubmed.ncbi.nlm.nih.gov/41206865
Aggressive cancers such as triple negative breast cancer (TNBC) are able to resist standard chemotherapy and metastasize (spread to other parts of the body) quickly. Previous research shows that the calcium channel TRPC6 helps a subset of cancer cells remain quiescent (a reversable, inactive cell state), which promotes chemotherapy and ferroptosis resistance. Researchers noted that circulating tumor cells isolated from breast cancer patients displayed a higher level of TRPC6 than the primary tumor. Using in vitro (outside of an organism) experiments and 6- and 12-week-old female mice, researchers studied whether the quiescent subset of TNBC cells was sensitive to ferroptosis when targeting TRPC6. Results showed that TRPC6 can cause ferroptosis resistance. The underlying mechanism for ferroptosis resistance was that TRPC6 limits c-Myc to sustain high levels of glutathione. TNBC metastasis was significantly reduced when a TRPC6 inhibitor was used. This study supports a possible opportunity to mitigate TNBC metastasis by targeting TRPC6. Supported by ORIP (K01OD034451) and NCI.
Apparent Expansion of Virulent Vibrio Parahaemolyticus in Humans and Sea Otters
Sebastian et al., Virulence. 2025.
https://pubmed.ncbi.nlm.nih.gov/41399136
Vibriosis, caused by Vibrio species, causes about 80,000 human cases of illness in the United States each year. It is considered the most important public health threat from seafood consumption and marine recreational activities. In addition, pathogenic (disease-causing) Vibrio species infect marine animals, including otters. Although sea otters could be used as a marine bioindicator, virulence (ability of the bacteria to cause disease) factor data on Vibrio species that infect northern and southern sea otters are limited. Researchers used genomic epidemiology data to identify virulence factors of Vibrio species collected from different sources in the United States. Virulence factor prevalence varied depending on whether the isolate was environmental or derived from an organism. Specific virulence factors in V. parahaemolyticus were most prevalent in humans and northern sea otters. Co-occurrence of T3SS2 and T6SS1, two virulence factors, was linked to disease findings. This study highlights that V. parahaemolyticus undergoes selection pressures that result in the expansion of virulent strains that infect humans and sea otters. Supported by ORIP (T32OD011147).
A Thymus-Independent Artificial Organoid System Supports Complete Thymopoiesis from Rhesus Macaque-Derived Hematopoietic Stem and Progenitor Cells
Wilde et al., Biomedicines. 2025.
https://pubmed.ncbi.nlm.nih.gov/41301785
The creation of T cells within the body involves many steps that begin with T cell progenitor cells (cells that become T cells) in the bone marrow. T cells finish developing and multiply in the thymus. Although nonhuman primates (NHPs) serve as key models for studying T cell development and output under normal and disease conditions, no non-animal technology for T cell development and output currently exists. To address this gap, researchers developed an NHP-specific organoid (3D cell cultures that contain several cell types and mimic specific functions of an organ). This NHP organoid mimics thymopoiesis (a series of events leading to the creation of T cells) in a thymus-tissue-free environment. This study is the first to demonstrate an NHP-specific artificial thymic organoid that models thymopoiesis and can be used in future research studies to understand T cell development and output in different diseases. Supported by ORIP (R21OD035572, P51OD011132) and NIAID.
Functional Analysis of Pathogenic Variants in LAMB1-Related Leukoencephalopathy Reveals Genotype–Phenotype Correlations and Suggests Its Role in Glial Cells
Yasuda et al., Human Molecular Genetics. 2025.
https://pubmed.ncbi.nlm.nih.gov/40237576
Cells are surrounded by a matrix, known as the basement membrane, that provides structural support and enhances signaling. Laminin B1 (LAMB1) is a matrix protein in the basement membrane that helps form this supportive structure around cells. Mutations (mistakes in the DNA sequence) in the LAMB1 gene can cause rare neurological disorders. Researchers studied the fruit fly version of the LAMB1 gene, which is LanB1. Using fruit flies, the researchers were able to gain insight into the link between LAMB1 gene mutations and disease symptoms. The LanB1 protein is found in a subset of brain cells, called glia cells, and in the blood–brain barrier. Reducing the amount of LanB1 protein in the blood–brain barrier caused shorter lifespans and movement defects in the fruit flies. Human LAMB1 was not functional in flies, but fly experiments showed that some LanB1 mutations cause severe defects, while others were milder. Tests in human cells suggested some LAMB1 mutations might cause disorders, even in the presence of a normal copy of LAMB1. This study reveals the role of LanB1 in keeping the healthy structure of the fly blood–brain barrier and understanding the consequences of different LAMB1 mutations in humans. Supported by ORIP (R24OD022005, R24OD031447).