Programs and Activities Highlights
- Precision Model Centers Introductory Meeting
ORIP organized and presented at the Precision Model Centers Introductory Meeting on September 15, 2025. This virtual meeting included principal investigators and project leads of ORIP’s renewed U54 Division of Comparative Medicine (DCM) initiative, the Precision Model Centers Consortium. Program officials of the projects (DCM) and project scientists (Division of Construction and Instruments) attended the meeting, presented the plan for the new cycle, discussed collaborations, and planned future meetings.
- International Mouse Phenotyping Consortium Network Call
An ORIP staff member presented an NIH update on new approach methodologies (NAMs) and the use of animals in research at the International Mouse Phenotyping Consortium (IMPC) network call on August 12, 2025. The IMPC monthly call includes members of the IMPC, as well as NIH staff. ORIP’s presentation was devoted to the current NIH policies regarding use of animals in research, as well as NAM initiatives. Attendees discussed implementation of the policies and their potential effect on Knockout Mouse Project/IMPC activities.
- Cryopreservation Workshop, Session V: Long-Term Preservation Methods for Nonhuman Primate Models in Biomedical Research
ORIP hosted the Cryopreservation and Other Preservation Approaches for Animal Models Workshop to address topics related to cryopreservation and other preservation methods. Session V, held on July 15, 2025, focused on long-term preservation of nonhuman primate models for biomedical research. This session brought together experts in the field to discuss current state-of-the-art techniques, as well as challenges and barriers in the field. A summary of the workshop will be posted on the ORIP website.
- Wonderous Worms: Unearthing New Insights Into Health
NIH News in Health published an article titled “Wonderous Worms: Unearthing New Insights Into Health” in July 2025. This article included quotes from Dr. Ann Rougvie, an expert in Caenorhabditis elegans biology and principal investigator of the ORIP-supported Caenorhabditis Genetics Center. The article was reviewed by three ORIP grantees: Drs. David Hall, Nathan Schroeder, and David Sherwood.
- Notice of Extension of the Expiration Date for RFA-OD-22-013, Resource-Related Research Projects for Development of Animal Models and Related Materials (R24, Clinical Trials Not Allowed)
ORIP published a notice to extend the expiration date for RFA-OD-22-013, Resource-Related Research Projects for Development of Animal Models and Related Materials (R24, Clinical Trials Not Allowed). RFA-OD-22-013 now expires on September 26, 2025. ORIP’s intent with this funding opportunity is to support resource-related research projects that are aimed at developing and characterizing new resources; improving existing resources; or acquiring deep understanding of a model system to improve the utilization, accessibility, and translational values of models to the research community.
Read more in the archive.
ORIP-Supported Research Highlights
- In Utero Rescue of Neurological Dysfunction in a Mouse Model of Wiedemann-Steiner Syndrome
Wiedemann-Steiner syndrome (WDSTS) is a rare, autosomal-dominant (only one mutated gene copy is needed for symptoms to develop) genetic disorder that causes intellectual disability, abnormal facial features, and reduced growth. WDSTS occurs when the histone lysine methyltransferase 2A (KMT2A) protein is mutated. In previous studies using mouse models, syndromes related to WDSTS, such as Rett and Kabuki, have shown promise in being treatable after birth. The researchers created a mouse model for WDSTS (both sexes included) and showed that the genetic disorder could be treated in the womb by restoring KMT2A protein function. This model could be used in future studies to identify possible therapies and the window for treatment.
- Alternating Hemiplegia of Childhood Associated Mutations in Atp1a3 Reveal Diverse Neurological Alterations in Mice
Pathogenic variants (changes in a gene that increase a person’s risk of developing a genetic disorder) in the Na+/K+ ATPase transmembrane ion transporter (ATP1A3) gene cause a spectrum of neurological disorders, including alternating hemiplegia of childhood (AHC). In patients, about 65% of AHC cases are caused by one of two specific mutations. Mouse models that mimic these mutations are limited by early death, which hinders our understanding of the molecular and cellular mechanisms that drive AHC. The researchers used a hybrid approach to create mouse models for these two most common ATP1A3 variations that did not suffer from early death. The researchers characterized the mouse models (both sexes included) and found that the two ATP1A3 variations cause different disease symptoms, including motor function impacts, behavior changes, and the inflammation of nervous system tissue. These mouse models can be used to test possible therapies for AHC.
- Long-Acting Lenacapavir Acts as an Effective Preexposure Prophylaxis in a Rectal SHIV Challenge Macaque Model
Nonhuman primate (NHP) studies were essential in advancing lenacapavir as a long-acting HIV prevention agent. In this rhesus macaque study with male animals, a single subcutaneous dose of lenacapavir produced sustained plasma concentrations and showed strong prophylactic activity against high-dose simian-human immunodeficiency virus (SHIV) rectal challenge. Animals whose lenacapavir levels exceeded the clinically relevant target experienced complete protection, establishing a clear exposure–efficacy relationship. Breakthrough infections occurred only when drug levels declined below this threshold, and no resistance emerged, further validating the model. These findings provided critical translational evidence for dosing intervals, protective concentrations, and the long-acting potential of lenacapavir, directly supporting its progression into human HIV pre-exposure prophylaxis trials.
- Long-Acting Lenacapavir Protects Macaques Against Intravenous Challenge with Simian-Tropic HIV
In this preclinical study, a single subcutaneous dose of lenacapavir conferred complete protection in a pigtail macaque (PTM) model (males only) against a high-dose intravenous challenge with a simian-tropic HIV-1 virus, which carries the HIV-1 capsid. Lenacapavir showed potent in vitro activity against the virus and displayed sustained plasma exposure in vivo after injection. All vehicle-control animals became infected, whereas the lenacapavir-treated cohort remained uninfected. The model confirmed that PTM exposure levels were relevant to human dosing and reinforced the translational rationale for moving lenacapavir into human pre-exposure prophylaxis development.
- Preclinical Macaque Studies Underpinning the Development of Long-Acting Lenacapavir
The 2024 Breakthrough of the Year named by Science was the drug lenacapavir, which is used as pre-exposure prophylaxis (PrEP) to reduce HIV infection. Nonhuman primate models played a central role in establishing lenacapavir’s potential as a long-acting HIV prevention agent. Across studies using both SHIV and simian-tropic HIV-1 (stHIV-A19), single subcutaneous doses of lenacapavir generated sustained plasma levels and consistently protected male rhesus and pigtail macaques from high-dose mucosal or intravenous viral challenge. These models defined the exposure–efficacy relationship by showing complete protection whenever lenacapavir concentrations exceeded clinically relevant thresholds, while breakthrough infections occurred only when drug levels fell below those targets. Importantly, no lenacapavir-associated resistance emerged in infected animals. The macaque data also confirmed that protective exposures were aligned with achievable human pharmacokinetics, strengthening the translational bridge to clinical dosing strategies. These two studies provided essential evidence that long-acting lenacapavir could deliver durable prophylactic protection, directly supporting its advancement into human HIV PrEP clinical trials.
Read more in the archive.
