Breakthrough Research

A Showcase of Discoveries from NIH Intramural Labs and Clinics

BY THE NIH CATALYST STAFF

Scientific breakthrough research presentations have become an end-of-year NIH Office of Intramural Research celebration.

On December 18, 2024, the scientific directors and clinical directors from each institute and center (IC) had three minutes and one slide to present a standout intramural research accomplishment from the past year. We highlight some of our favorites.

CC—Development and preclinical validation of 2-deoxy 2-[18F]fluorocellobiose as an Aspergillus-specific PET tracer

Fungal infections cause thousands of hospitalizations and deaths in the United States each year, and existing diagnostics can be invasive or not specific enough. A novel positron-emission tomography (PET) tracer was safe and effective in assessing fungal activity in mice and could lead to human trials in 2025. (NIH researchers: S. Shah, J. Lai, F. Basuli, N. Martinez-Orengo, R. Patel, M.L. Turner, B. Wang, Z-D. Shi, S. Sourabh, M. Peiravi, A. Lyndaker, S. Liu, S Seyedmousavi, P.R. Williamson, R.E. Swenson, and D.A. Hammoud, PMID: 39141701)

NCCIH—PIEZO2 and perineal mechanosensation are essential for sexual function

The PIEZO2 ion channel, found in peripheral neurons and known to mediate touch and proprioception, is also essential for interoception and reproductive health. Using in vivo functional imaging and genetic techniques, researchers found that a loss of PIEZO2 in mice and people can lead to bladder overfilling, stalled movements of the digestive system, and impaired sexual function. Future research could explore whether PIEZO2 could be targeted to treat pain or digestive and urogenital disorders. (NIH researchers: R.M. Lam, L.J. von Buchholtz, M. Falgairolle, J. Osborne, E. Frangos, M. Nagel, M.Q. Nguyen, M. Jayabalan, D. Saade, C.G. Bönnemann, N.J.P. Ryba, and A.T. Chesler, PMID: 37616369)

NICHD—Base-editing corrects metabolic abnormalities in a humanized mouse model for glycogen storage disease type-Ia

A humanized mouse model of a glycogen storage disease was used to show how base-editing technology can correct the metabolic abnormality. A base editor called BEAM-301 was delivered by lipid nanoparticles and corrected up to 60% of the genetic variant in liver cells. The treatment restored blood glucose control in, improved metabolic abnormalities in, and conferred long-term survival on the mice. Clinical trials are planned for 2025. (NIH researchers: I. Arnaoutova, Y. Aratyn-Schaus, L. Zhang, M.S. Packer, H.-D. Chen, C. Lee, S. Gautam, F.M. Gregoire, D. Leboeuf, S. Boule, T.P. Fernandez, V. Huang, L.-I. Cheng, G. Lung, B. Bannister, J. Decker, T. Leete, L.S. Shuang, C. Bock, P. Kothiyal, P. Grayson, K.W. Mok, J.J. Quinn, L. Young, L. Barrera, G. Ciaramella, and B.C. Mansfield, PMID: 39523369)

NIDCD—Early-onset hearing loss in mouse models of Alzheimer’s disease and increased DNA damage in the cochlea

Hearing loss is the largest modifiable risk factor in midlife for later developing dementia and interventions to slow hearing loss may slow cognitive decline. NIDCD and NIA investigators developed a mouse model of Alzheimer’s disease and found that the animals exhibited early-onset hearing loss before any cognitive or behavioral changes. The study provides a model system to explore the relationship and underlying mechanisms behind hearing loss and AD. (NIH researchers: J.H. Park, B.D. Sahbaz, K. Pekhale, X. Chu, M.N. Okur, M. Grati, K. Isgrig, W. Chien, and D.L. Croteau, PMID: 38500536)

NIDCR—Structure-guided discovery of anti-CRISPR and antiphage defense proteins

NIDCR scientists combined cutting-edge screening techniques to discover new proteins involved in the defense and counter-defense measures used by bacteria and phages, including anti-CRISPR proteins. Understanding those defense systems could provide translational insights that inform CRISPR genome editing, help treat antibiotic-resistant bacteria, or could be used to develop phage therapies that modulate the microbiome. (NIH researchers: N. Duan, E. Hand, M. Pheko, S. Sharma, and A. Emiola, PMID: 38245560)

Other scientific discoveries include the following:

NCATS—NIH collaboration leads to development of MMA gene therapy

NCATS and NHGRI are leading the development of an adeno-associated virus gene-therapy candidate for methylmalonic acidemia, a rare inherited metabolic disorder. The gene-therapy product named MMA-101 was codeveloped by NHGRI’s Charles Venditti, and a clinical trial is moving forward at the NIH CC in collaboration with NICHD, NHGRI, and NINDS. Read more about that clinical trial here.

NCI-DCEG—Genetic drivers and cellular selection of female mosaic X chromosome loss

In a large genome-wide association study of over 800 thousand women, 12% were found to have detectable mosaic loss of the X chromosome (mLOX). Researchers identified genetic variants associated with mLOX that may play a role in cancer predisposition and the development of autoimmune diseases. (PMID: 38867047)

NIA—Brain responses to intermittent fasting and the healthy living diet in older adults

Both a healthy diet and intermittent fasting had positive effects on the brains of insulin-resistant older adults. Although intermittent fasting reduced weight more, both diets resulted in improved cognitive function and memory, as well as improved metabolism biomarkers. (PMID: 38901423)

NIAAA—A distinct cortical code for socially learned threat

Advanced imaging techniques revealed neural networks involved in social learning and experiences of fear in mice. The findings could have important implications in treating disorders such as post-traumatic stress disorder. (PMID: 38326610)

NIAID—Subcutaneous administration of a monoclonal antibody to prevent malaria

Nearly 600,000 people die each year from malaria, and children under age five make up most of those deaths. A monoclonal antibody blocked the ability of the malaria parasite to get from the bite site to the liver with one subcutaneous injection. The findings show that a single dose administered each malaria season was effective in preventing infection and reducing clinical symptoms. (PMID: 38669354)

NIBIB—Assembly of SARS-CoV-2 nucleocapsid protein with nucleic acid

Biophysical techniques showed how the SARS-CoV-2 virus forms, revealing its molecular architecture and potentially offering an avenue for drug targets. (PMID: 38587193)

NIDDK—Molecular connectomics reveals a glucagon-like peptide-1 (GLP-1)-sensitive neural circuit for satiety

Optogenetics and chemical methods were used to identify critical neurons involved in suppressing appetite, demonstrating how the GLP-1 agonist weight loss drugs might work. (PMID: 39627618)

NIEHS—Outdoor air pollution exposure and uterine cancer incidence in the Sister Study

Greater exposure to nitrogen dioxide, a marker of outdoor air pollution, was associated with a 20% higher incidence of uterine and ovarian cancers. (PMID: 38346713)

NINDS—A cerebellar granule cell-climbing fiber computation to learn to track long time intervals

Imaging the cerebellum in mice anticipating a reward showed how neural circuits can compute time scales relative to tasks. (PMID: 38870929)

NHLBI—R406 reduces lipopolysaccharide-induced neutrophil activation

The immune modulator R406 (fostamatinib), sometimes used to treat severe COVID-19, shows promise in treating preclinical models of sepsis. (PMID: 39084187)

Keep an eye out for the NIH Catalyst throughout 2025 to learn more about these and many other new discoveries happening every day at NIH.