Programs and Activities Highlights
- PAR-24-258: Research Resource for Human Organs and Tissues (U42 Clinical Trial Not Allowed)
The purpose of this funding opportunity is to support a Human Tissue and Organ Research Resource program to enable the continued availability of human tissues and organs to biomedical researchers. The overall goal of the research resource is to provide a wide variety of human tissues and organs, both diseased and non-diseased, to investigators. The research resource is expected to facilitate the procurement and preservation of human tissues and organs, as well as the distribution of these materials to qualified biomedical researchers.
- 22nd Annual Meeting of the Mutant Mouse Resource and Research Center Consortium
ORIP participated in organizing and presented at the annual Mutant Mouse Resource and Research Center (MMRRC) Consortium meeting, which was held on August 7–8, 2024. This hybrid meeting took place in Bethesda, Maryland, and was attended by the MMRRC principal investigators and co-investigators, invited speakers, members of the advisory board, and ORIP staff and leadership. Sessions were organized on the following topics: data management and precision model systems, topic discussions, center updates, and external advisory committee discussion.
- Nonhuman Primate Evaluation and Analysis
On August 15, 2024, NIH released a report prepared by ORIP and the Office of AIDS Research on the evaluation and analysis of nonhuman primate (NHP) supply and demand in U.S. biomedical research, spanning research fields, species, services, and future needs. The purpose of the report is to improve our understanding of the demand for and supply of NHPs within the United States, with particular emphasis on the resources supported by NIH. The report identifies a trend of increasing demand for NHPs in several critical areas of NIH-funded research and highlights challenges, such as balancing demands with breeding efforts that could be met through collaborative efforts across NIH and between NIH and other federal agencies. NIH previously conducted a similar analysis, prepared by ORIP and released in September 2018, on which this report builds. The findings from the report will inform NIH strategies to benefit the greater biomedical research community.
- Cryopreservation Workshop Session I: Cryopreservation and Other Preservation of Invertebrate Models in Biomedical Research
The opening session of the Cryopreservation and Other Preservation Approaches for Animal Models Workshop was held on September 6, 2024. This session focused on cryopreservation and other alternative long-term preservation methods for invertebrate models widely used in biomedical research. Presentations covered current techniques, limitations in preserving these organisms, and key insights gained from preserving other invertebrate species. Participants highlighted critical gaps and challenges in the field, fostering discussion on advancing preservation strategies.
- Invertebrate Models Fact Sheet
ORIP revised its fact sheet on invertebrate models. ORIP reviewed the existing section for accuracy and added a link to “MAGIC tools,” a genetic tool for genome-wide mosaic analysis of Drosophila resources. This fact sheet is one of several fact sheets that serve as valuable resources for potential investigators to learn about ORIP resources and programs.
Read more in the archive.
ORIP-Supported Research Highlights
- Immunization With Germ Line–Targeting SOSIP Trimers Elicits Broadly Neutralizing Antibody Precursors in Infant Macaques
Broadly neutralizing antibodies (bnAbs) offer a promising approach for preventing and treating HIV infection, but the ability to induce bnAbs at protective levels has been a challenge. Previous studies have shown that children living with HIV develop bnAbs more efficiently than adults living with HIV. This study evaluated the ability of a stabilized form of Env (envelope glycoprotein)—SOSIP (protein stabilized by a disulfide bond between gp120-gp41-named “SOS” and an isoleucine-to-proline point mutation-named “IP” at residue 559)—to elicit an immune response in young rhesus macaques. The SOSIP protein was engineered to activate naïve B cells expressing germline antibody precursors. Male and female infant macaques were immunized with wild-type SOSIP (SOSIP) or germline-targeting SOSIP (GT1.1), followed by a SOSIP booster. Both SOSIP and GT1.1 induced a protective immune response, but only GT1.1 induced VRC01-like bnAb precursors—antibodies that bind Env’s CD4-binding site and provide the broadest possible protection. These results represent a possible childhood HIV immunization strategy that would elicit protective immunity before sexual debut.
- Intrinsic Link Between PGRN and GBA1 D409V Mutation Dosage in Potentiating Gaucher Disease
Gaucher disease (GD) is an autosomal recessive disorder and one of the most common lysosomal storage diseases. GD is caused by mutations in the GBA1 gene that encodes glucocerebrosidase (GCase), a lysosomal protein involved in glyocolipid metabolism. Progranulin (PGRN, encoded by GRN) is a modifier of GCase, and GRN mutant mice exhibit a GD-like phenotype. The researchers in this study aimed to understand the relationship between GCase and PGRN. They generated a panel of male and female mice with various doses of the GBA1 D409V mutation in the GRN-/- background and characterized the animals’ disease progression using biochemical, pathological, transcriptomic, and neurobehavioral analyses. Homozygous (GRN-/-, GBA1 D409V/D409V) and hemizygous (GRN-/-, GBA1 D409V/null) animals exhibited profound inflammation and neurodegeneration compared to PG96 wild-type mice. Compared to homozygous mice, hemizygous mice showed more profound phenotypes (e.g., earlier onset, increased tissue fibrosis, shorter life span). These findings offer insights into GD pathogenesis and indicate that GD severity is affected by GBA1 D409V dosage and the presence of PGRN.
- Systematic Multi-trait AAV Capsid Engineering for Efficient Gene Delivery
Engineering novel functions into proteins while retaining desired traits is a key challenge for developers of viral vectors, antibodies, and inhibitors of medical and industrial value. In this study, investigators developed Fit4Function, a generalizable machine learning (ML) approach for systematically engineering multi-trait adeno-associated virus (AAV) capsids. Fit4Function was used to generate reproducible screening data from a capsid library that samples the entire manufacturable sequence space. The Fit4Function data were used to train accurate sequence-to-function models, which were combined to develop a library of capsid candidates. Compared to AAV9, top candidates from the Fit4Function capsid library exhibited comparable production yields; more efficient murine liver transduction; up to 1,000-fold greater human hepatocyte transduction; and increased enrichment in a screen for liver transduction in macaques. The Fit4Function strategy enables prediction of peptide-modified AAV capsid traits across species and is a critical step toward assembling an ML atlas that predicts AAV capsid performance across dozens of traits.
- The Mutant Mouse Resource and Research Center (MMRRC) Consortium: The U.S.-Based Public Mouse Repository System
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.
- Disruption of Myelin Structure and Oligodendrocyte Maturation in a Macaque Model of Congenital Zika Infection
Using a pigtail macaque model for Zika virus infection, researchers show that in utero exposure of a fetus to Zika virus due to maternal infection results in significantly decreased myelin formation around neurons. Myelin is a protective sheath that forms around neurons and is required for brain processing speed. Damaged myelin resulting from Zika infection in utero is likely a contributing factor to the severe deficits in brain development and microcephaly that result from maternal Zika virus infection.
Read more in the archive.
