Selected Grantee Publications
Blastocyst Development After Fertilization with In Vitro Spermatids Derived From Nonhuman Primate Embryonic Stem Cells
Khampang et al., F & Science. 2021.
https://www.sciencedirect.com/science/article/pii/S2666335X21000665?via%3Dihub%C2%A0=
Rhesus macaque pluripotent stem cells were differentiated into spermatogenic germ cell linages and matured in vitro to form spermatids that were capable of fertilizing oocytes (female or germ cells involved in reproduction) by intracytoplasmic spermatid injection (i.e., the egg is fertilized outside the body and the sperm is injected through a needle into the egg). Successful in vitro preimplantation embryo development was observed in approximately 12% of zygotes. The data suggest potential mechanisms to address male infertility. Supported by ORIP (R21OD020182, R01OD028223, P51OD011092).
Safety, Pharmacokinetics and Antiviral Activity of PGT121, a Broadly Neutralizing Monoclonal Antibody Against HIV-1: A Randomized, Placebo-Controlled, Phase 1 Clinical Trial
Stephenson et al., Nature Medicine. 2021.
https://doi.org/10.1038/s41591-021-01509-0
Researchers carried out a double-blind trial of one administration of the HIV-1 V3-glycan-specific antibody (Ab) PGT121 in HIV-uninfected and HIV-infected adults on antiretroviral therapy (ART), as well as an open-label trial of one infusion of PGT121 in viremic HIV-infected adults not on ART. The investigators observed no treatment-related serious adverse events among the 48 participants, and neutralizing anti-drug Abs were not elicited. PGT121 reduced plasma HIV RNA by a median of 1.77 log in viremic participants. Two individuals experienced ART-free viral suppression for ≥168 days following Ab infusion. These findings motivate further investigation of Ab-based therapeutic strategies for long-term HIV suppression. Supported by ORIP (R01OD024917, R01OD011095), NIAID, and NCATS.
The Bowfin Genome Illuminates the Developmental Evolution of Ray-Finned Fishes
Thompson et al., Nature Genetics. 2021.
https://www.nature.com/articles/s41588-021-00914-y
The bowfin (Amia calva) is a ray-finned fish that possesses a unique suite of ancestral and derived phenotypes, which are key to understanding vertebrate evolution. The phylogenetic position of bowfin as a representative of neopterygian fishes, its archetypical body plan and its unduplicated and slowly evolving genome make bowfin a central species for the genomic exploration of ray-finned fishes. Here the authors present a chromosome-level genome assembly for bowfin that enables gene-order analyses, settling long-debated neopterygian phylogenetic relationships. These resources connect developmental evolution among bony fishes, further highlighting the bowfin's importance for illuminating vertebrate biology and diversity in the genomic era. Supported by ORIP (R01OD011116).
Advancing Human Disease Research with Fish Evolutionary Mutant Models
Beck et al., Trends in Genetics. 2021.
https://pubmed.ncbi.nlm.nih.gov/34334238/
Model organism research is essential to understand disease mechanisms. However, laboratory-induced genetic models can lack genetic variation and often fail to mimic disease severity. Evolutionary mutant models (EMMs) are species with evolved phenotypes that mimic human disease. They have improved our understanding of cancer, diabetes, and aging. Fish are the most diverse group of vertebrates, exhibiting a kaleidoscope of specialized phenotypes, many that would be pathogenic in humans but are adaptive in the species' specialized habitat. Evolved compensations can suggest avenues for novel disease therapies. This review summarizes current research using fish EMMs to advance our understanding of human disease. Supported by ORIP (R01OD011116), NIA, NIDA, and NIGMS.
A Participant-Derived Xenograft Model of HIV Enables Long-Term Evaluation of Autologous Immunotherapies
McCann et al., Journal of Experimental Medicine. 2021.
https://doi.org/10.1084/jem.20201908
HIV-specific CD8+ T cells partially control viral replication but rarely provide lasting protection due to immune escape. Investigators showed that engrafting NSG mice with memory CD4+ T cells from HIV+ donors enables evaluation of autologous T cell responses while avoiding graft-versus-host disease. Treating HIV-infected mice with clinically relevant T cell products reduced viremia. In vivo activity was significantly enhanced when T cells were engineered with surface-conjugated nanogels carrying an Interleukin-15 superagonist but was ultimately limited by the pervasive selection of escape mutations, recapitulating human patterns. This “participant-derived xenograft” model provides a powerful tool for developing T cell-based therapies for HIV. Supported by ORIP (R01OD011095), NIAID, NIDA, NIMH, NINDS, and NCATS.
Bilateral Visual Projections Exist in Non-Teleost Bony Fish and Predate the Emergence of Tetrapods
Vigouroux et al., Science. 2021.
https://pubmed.ncbi.nlm.nih.gov/33833117/
In most vertebrates, camera-style eyes contain retinal ganglion cell neurons that project to visual centers on both sides of the brain. However, in fish, ganglion cells were thought to innervate only the contralateral side, suggesting that bilateral visual projections appeared in tetrapods. Here, Vigouroux et al. showed that bilateral visual projections exist in non-teleost fishes and that the appearance of ipsilateral projections does not correlate with terrestrial transition or predatory behavior. However, overexpression of human ZIC2 induces ipsilateral visual projections in zebrafish. Therefore, the existence of bilateral visual projections likely preceded the emergence of binocular vision in tetrapods. Supported by ORIP (R01OD011116).
The SARS-CoV-2 Receptor and Other Key Components of the Renin-Angiotensin-Aldosterone System Related to COVID-19 are Expressed in Enterocytes in Larval Zebrafish
Postlethwait et al., Biology Open. 2021.
https://bio.biologists.org/content/10/3/bio058172.article-info
Hypertension and respiratory inflammation are exacerbated by the Renin-Angiotensin-Aldosterone System (RAAS), which normally protects from dropping blood pressure via Angiotensin II (Ang II) produced by the enzyme Ace. The Ace paralog Ace2 degrades Ang II and serves as the SARS-CoV-2 receptor. To exploit zebrafish to understand the relationship of RAAS to COVID-19, the group conducted genomic and phylogenetic analyses. Results identified a type of enterocyte as the expression site of zebrafish orthologs of key RAAS components, including the SARS-CoV-2 co-receptor. Results identified vascular cell subtypes expressing Ang II receptors and identified cell types to exploit zebrafish as a model for understanding COVID-19 mechanisms. Supported by ORIP (R24OD026591, R01OD011116), NIGMS, NICHD.
A Pulsatile Release Platform Based on Photo-Induced Imine-Crosslinking Hydrogel Promotes Scarless Wound Healing
Zhang et al., Nature Communications. 2021.
https://pubmed.ncbi.nlm.nih.gov/33723267/
Skin wound healing is a dynamic and interactive process involving the collaborative efforts of growth factors, extracellular matrix (ECM), and different tissue and cell lineages. Although accumulating studies with a range of different model systems have increased our understanding of the cellular and molecular basis underlying skin scar formation, they have not been effectively translated to therapy. Development of effective therapeutic approaches for skin scar management is urgently needed. In this study, team of investigators devise a water-oil-water double emulsion strategy to encapsulate proteins within a photo-crosslinkable poly-lactic-co-glycolic acid (PLGA) shell, which can produce microcapsules with pulsatile drug release kinetics after administration. The results show that pulsatile release of the TGF-β inhibitor can accelerate skin wound closure while suppressing scarring in murine skin wounds and large animal preclinical models, suggesting that it could be an effective approach to achieve scarless wound healing in skin. Supported by ORIP (R01OD023700).
Persistence of Viral RNA in Lymph Nodes in ART-suppressed SIV/SHIV-Infected Rhesus Macaques
Cadena et al., Nature Communications. 2021.
https://doi.org/10.1038/s41467-021-21724-0
The long-lived viral reservoir is a key obstacle to curing HIV/AIDS, yet the features of that reservoir during antiretroviral therapy (ART) remain poorly understood. Researchers undertook a comprehensive analysis of the SIV/SHIV reservoir in multiple lymphoid and non-lymphoid tissues from SIV/SHIV-infected rhesus macaques suppressed with ART for one year. Their findings support a model in which the tissue viral reservoir is rapidly and broadly seeded early during acute infection. Viral RNA persists lymphoid tissues despite a long period of suppressive ART. Therefore, viral latency does not appear to be universally transcriptionally silent; the reservoir may include a spectrum of latency depths. Supported by ORIP (R01OD024917) and NIAID.