Quarterly picks from the editors

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Science Translational Medicine  30 Sep 2020:
Vol. 12, Issue 563, eabe7354
DOI: 10.1126/scitranslmed.abe7354


Four times a year, the Science Translational Medicine editors select recently published articles across the Science family of journals and highlight interesting translational ties. These short write-ups identify common links between disparate diseases; technologies and research approaches that could prove complementary; and biomedical insights that may inform therapies or treatments. This quarter’s articles cover approaches to improve early cancer detection, treatments using polymer particles, fibrosis and graft-versus-host disease, gene therapy, and insight into SARS-CoV-2 infections.


Treating GVHD with a goblet of microbes

Graft-versus-host disease remains a major impediment to the success of allogeneic hematopoietic cell transplant, in part by damaging the gastrointestinal tract. In two recent papers, Ara et al. and van Lier et al. investigated the connection between gastrointestinal epithelial cells, the gut microbiome, and graft-versus-host disease. Ara et al. found that pretransplant treatment of mice with interleukin-25 ameliorated graft-versus-host disease severity by preventing loss of antimicrobial mucus-producing goblet cells, whereas van Lier et al. demonstrated that donor fecal microbiota transplantation reduced symptoms in a cohort of patients with gastrointestinal graft-versus-host disease. These papers demonstrate that strategies to modulate the complex relationship between the intestinal microbiota, gut epithelial cells, and immune cells may ameliorate graft-versus-host disease severity. —CM


The pervasiveness of a pandemic

The true burden of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is difficult to pinpoint given the prevalence of asymptomatic cases and insufficient or inaccurate clinical testing for the virus itself. Silverman et al. used a statistical model to infer the number of SARS-CoV-2 infections in the United States from the excess of reported influenza-like illness compared to years prior, estimating that up to 80% of infected individuals in the country went undetected early in the pandemic. Salje et al. fit a transmission model to hospital admissions data in France and estimated that 4.4% of the population would have contracted SARS-CoV-2 by May 2020, which would be insufficient for herd immunity. Both studies present methods to infer large-scale yet geographically situated trends in SARS-CoV-2 prevalence by modelling available data from illness-reporting infrastructures and could have ramifications for public health policy. —CAC


More accurate, better, faster

Early detection is a major goal in the field of oncology, but both technological and societal obstacles can interfere with the prompt diagnosis of cancer. In two recent studies, Min et al. and Lennon et al. demonstrated promising approaches for addressing diagnostic difficulties in cancer in different types of clinical care settings. Min et al. focused on improving breast cancer evaluation in low-resource environments by designing a machine that permits rapid and accurate molecular diagnosis at low cost and without extensive training. Lennon et al. devised a method for improving early cancer detection that combines blood testing and imaging. The findings in these studies have the potential to improve the accuracy and speed of cancer diagnosis in a variety of settings, helping patients to receive appropriate treatment while their tumors are still small and potentially curable. —YN


Going after gene therapy

Gene therapies have not been as successful as predicted from preclinical studies, and Cabanes-Creus et al. may have discovered one underlying cause. They found that the liver-tropic adeno-associated virus 2 (AAV2) may have adapted to culture by mutating to bind heparan sulfate proteoglycans more tightly, reducing its ability to infect the liver. Use of naturally occurring AAVs may improve the success of liver-directed gene therapy. The inability to transcriptionally activate a functionally equivalent gene to the diseased gene is another problem facing gene therapy. Using inactive Cas9 fused to transcriptional activators split into two AAV vectors, Böhm et al. overcame this hurdle to activate cone photoreceptor-specific M-opsin in rod photoreceptors in the retinas of rhodopsin-deficient mice. These findings can significantly improve gene therapy targeting both the liver and the retina. —MN


Powerful polymer particles

Tiny polymer particles can have big therapeutic effects. Lu and colleagues showed that polylactic-co-glycolic acid (PLGA) microparticles could be used to deliver an agonist of stimulator of interferon gene in a pulsatile fashion, inhibiting tumor growth and extending survival in mice with cancer. As a treatment for atherosclerosis, Tao et al. used hybrid lipid-polymer nanoparticles to deliver siRNA to silence calcium/calmodulin-dependent protein kinase II γ in plaque-destabilizing macrophages in mice. Taking a third therapeutic approach, Ganugula et al. encapsulated curcumin in PLGA nanoparticles and demonstrated reduction in ocular inflammation upon oral administration to dogs with lens-induced uveitis. These three studies highlight the versatility of polymer particle therapies. —CC


Elucidating host immune responses to SARS-CoV-2

Many questions remain about how severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the pathogen that causes coronavirus disease 2019 (COVID-19), interacts with the immune system of its human host and why the disease in children is milder than in adults. Pierce et al. report in Science Translational Medicine their detailed analysis of cytokine, antibody, and lymphocyte responses in 65 children and 60 adults hospitalized with COVID-19 in New York City. Pediatric patients had a shorter hospital stay, lower mortality, higher interleukin-17A (IL-17A) and interferon-γ (IFN-γ) serum concentrations, and lower serum neutralizing antibody titers than did adult patients. The authors propose an important role for the innate immune response during early infection. Delving even deeper, Arunachalam et al., reporting in Science, used mass cytometry and single-cell transcriptomics to probe immune cell responses and cytokine production in 76 adult patients with COVID-19 and 69 healthy controls in the United States and Hong Kong. They observed impaired type I interferon production, reduced human leukocyte antigen class-DR (HLA-DR) expression by myeloid cells and increased inflammatory mediators in plasma of patients with severe disease. Together these two studies start to paint a portrait of immune responses to infection with SARS-CoV-2 in patients of different ages and with mild to severe disease. —OS


Understanding fibrogenesis: A tale of two organs

Fibrosis is a pathological process characterized by the deposition of extracellular matrix by myofibroblasts and consequent disruption of tissue function. The mechanisms mediating the fibrotic process are still unclear. Alsamman et al. studied liver fibrosis and discovered that inhibiting acid ceramidase had antifibrotic effects in vivo in mice and in human and rodent liver explants. Matera et al. were interested in pulmonary fibrosis and developed a three-dimensional model of pulmonary interstitial tissue. They showed that matrix metalloproteinases are critical for myofibroblast differentiation during pulmonary fibrosis. Better preclinical models and a more detailed understanding of fibrogenesis will aid the development of more effective therapies. —MM

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