Achromatopsia is an inherited retinal degeneration characterized by the loss of cone photoreceptor function. In this issue of the JCI, Moshiri et al. characterize a naturally occurring model of the disease in the rhesus macaque caused by homozygous mutations in the phototransduction enzyme PDE6C. Using retinal imaging, and electrophysiologic and biochemical methods, the authors report a clinical phenotype nearly identical to the human condition. These findings represent the first genetic nonhuman primate model of an inherited retinal disease, and provide an ideal testing ground for the development of novel gene replacement, gene editing, and cell replacement therapies for cone dystrophies.
Katherine E. Uyhazi, Jean Bennett
Necrotizing fasciitis and myositis caused by group A streptococci (GAS) are among the most fulminating infections, with a mortality rate of 20% to 30%. Although numerous regimens have been utilized in attempts to control these devastating infections, such as combinations of various antimicrobial agents and intravenous immunoglobulin (IVIG) as well as hyperbaric oxygen therapy, none have been the complete answer. Zhu and colleagues have utilized a transposon-directed insertion-site sequencing (TraDIS) protocol to identify 126 genes of M1 and 116 genes of M28 strains of GAS required for myositis, of which 25% encode transporters, which could be used as possible targets for future therapeutic protocols.
Harry R. Hill
The adenomatous polyposis coli (APC) gene plays, among other things, a crucial role in the regulation of cell proliferation and survival through its ability to regulate canonical Wnt signaling. In this issue of the JCI, Wang et al. provide an intriguing new mechanism for APC function involving the regulation of a novel long noncoding RNA (lncRNA), leading to changes in exosome production. APC signaling via this novel pathway can regulate cell proliferation and invasion as well as angiogenesis. In addition to enhancing our understanding of APC function, this new mechanism is of particular clinical significance, as it may provide additional targets for the treatment of APC-mutated cancers.
Pat J. Morin
Neoantigen-targeted therapies have typically been based upon personalized neoantigen-specific vaccines; however, in this issue of JCI, van der Lee et al. describe the development of a potential cellular immunotherapy targeting a “public” neoantigen derived from nucleophosmin 1 (NPM1), which is mutated in approximately 30% of acute myeloid leukemias (AMLs). The authors use reverse immunology to predict, and biochemically confirm, NPM1-derived neoepitopes (ΔNPM1) and then generate high-avidity T cell clones and retrovirally transduced T cell populations that kill NPM1-mutated AML. This study provides a general approach to adoptive cellular therapy that can be applied to targeting other tumors with public neoantigens.
Paul M. Armistead
A predominant feature of intestinal inflammation is the accumulation of neutrophils, which dictates a fine balance between epithelial repair or progression to chronic inflammation. While the processes of mucosal healing are well studied, how neutrophils advance an inflammatory insult towards epithelial neoplasia is less understood. In this issue of the JCI, Butin-Israeli et al. outline a mechanism whereby neutrophils control epithelial fitness and genomic instability via delivery of miR-23a–and miR-155–containing microparticles. Localized delivery of antisense oligonucleotides targeting miR-23a and miR-155 reversed this genomic instability and accelerated mucosal healing. This mechanism of neutrophil-derived microRNA shuttling opens up new therapeutic potential to enhance epithelial healing and limit mucosal injury.
Eóin N. McNamee
Stressful situations provoke the fight-or-flight response, incurring rapid elevation of cardiac output via activation of protein kinase A (PKA). In this issue of the JCI, Yang et al. focus on the L-type calcium channel complex (LTCC), and their findings require reexamination of dogmatic principles. LTCC phosphorylation sites identified and studied to date are dispensable for PKA modulation of LTCC; however, a CaVβ2-CaV1.2 calcium channel interaction is now shown to be required. Yang et al. suggest a new hypothesis that LTCC modulation involves rearrangement of auxiliary proteins within the LTCC. However, we still do not know the targets of PKA that mediate LTCC modulation.
Brooke M. Ahern, Jonathan Satin
Hutchinson-Gilford progeria syndrome (HGPS) is a fatal disease characterized by premature aging in which young children fail to thrive and adolescents die from myocardial infarction or stroke. The pathogenesis of HGPS is studied intensively because the mechanisms of premature aging may lead to a better understanding of normal aging. In this issue of the JCI, Osmanagic-Myers and colleagues identify the cellular mechanisms that lead to vascular abnormalities and death in children with HGPS.
Charles J. Lowenstein, J. Allen Bennett
Antibody-mediated rejection (AMR) has emerged as an important cause of lung graft failure. In the current issue of the JCI, a study by Li et al. identifies a critical role of Foxp3+ T cells residing within lung allografts in the regulation of AMR. This study not only provides new insights into the nature of lung allografts as a primary site where T and B cell priming and immune regulation can occur, but also introduces the mouse orthotopic lung transplant as a model for studying the immunobiology of AMR. Because AMR can be so difficult to effectively treat in lung transplant recipients, the development of an animal model is a major advance in understanding the immunopathogenesis of AMR.
Elizabeth A. Lendermon, John F. McDyer
Hereditary angioedema (HAE) is a rare genetic disorder primarily caused by mutations in the SERPING1 gene encoding the C1 inhibitor (C1INH) that leads to plasma deficiency, resulting in recurrent attacks of severe swelling. In the current issue of the JCI, Haslund et al. show that in a subset of patients with type I HAE, mutated C1INH encoded by HAE-causing SERPING1 acts upon wildtype (WT) C1INH in a dominant-negative manner and forms intracellular C1INH aggregates. These aggregates lead to a reduction in the levels of secreted functional C1INH, thereby manifesting in the condition that allows the disease state. Interestingly, administration of WT SERPING1 gene is able to restore the levels of secreted C1INH, thereby opening up a novel mechanism justifying gene therapy for HAE.
Alvin H. Schmaier
Hepcidin is the master regulator of iron metabolism. It plays a key role in the regulation of iron transport across the duodenal epithelium, which in turn is dependent on the oxygen-regulated transcription factor hypoxia-inducible factor 2α (HIF-2α). In this issue of the JCI, Schwartz and colleagues show that duodenal HIF-2α is itself regulated by hepcidin, thereby indicating that this transcription factor is not only regulated by oxygen, but also by iron. This work indicates that the crosstalk between liver hepcidin and intestinal HIF-2α plays an important role during iron overload, systemic iron deficiency, and anemia.
Frank S. Lee
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