Structural study gives insight into plaque formation

Investigators at the Sanford Burnham Prebys Medical Discovery Institute have gained new insights into how plaques form in a variety of different disorders, including dry age-related macular degeneration, which accounts for 90% of age-related macular degeneration cases and currently has no disease-modifying treatments. A major component of plaques is the blood protein vitronectin, and the researchers used biophysical techniques to show that vitronectin promoted plaque formation by simultaneously binding to a soluble and mineralized form of calcium phosphate called hydroxyapatite. The findings “provide a platform for understanding the pathogenesis of macular degeneration and other related degenerative disorders, and the normal functions of [vitronectin], especially those related to bone resorption,” the authors wrote. “The present findings… advance our understanding of the mechanisms of abnormal plaque formation, and introduce a target with potential for developing diagnostic, preventive, or therapeutic approaches.” Their work appeared in the July 20, 2020, online issue of the Proceedings of the National Academy of Sciences.

Studying labor identifies new pain mechanism

Researchers at the University of Cambridge have identified variants in a potassium channel that affected pain sensitivity during labor. The team was searching for genetic variants that affected pain sensitivity without causing extreme insensitivity that is itself a health risk. They reasoned that the ability to withstand childbirth without painkillers could be indicative of higher pain thresholds. The scientists genotyped almost 200 women who gave birth without requesting or receiving either regional or systemic analgesia, and identified a variant in the potassium channel KV6.4 as being more frequent in this group than in controls. When they compared the pain thresholds of women with and without the variant, women with the variant had higher pain thresholds in several different tests, but scored no different than controls in psychological measures of factors that affected pain perception such as mood, anxiety levels and certain personality traits. Childbirth, the authors wrote, “may be physiological and widely considered to be ‘‘natural’’ but remains among the most painful events in life that women can experience… If druggable, then KV6.4 would be a potential target for modulating labor pain without the maternal and neonatal side effects inherent in other analgesic interventions in this setting. Our data also raise the question of whether KV6.4 has roles in other painful visceral disorders within and outside the female genital tract” such as painful menstrual periods. They reported their results in the July 21, 2020, issue of Cell Reports.

AHR inhibition suppresses Zika infection

Researchers at the University of Sao Paolo, the University of Buenos Aires, and Brigham and Women’s Hospital have demonstrated that Zika virus (ZIKV) can activate the aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor, and that this activation inhibited immune responses to the virus that were driven by the promyelocytic leukemia (PML) protein. Zika virus can cause severe birth defects if infection occurs prenatally, and the flavivirus family includes major public health scourges, most notably dengue virus. In their work, the team showed that AHR inhibition suppressed ZIKV as well as dengue virus replication in cell culture, and that in mice, a nanoparticle-delivered AHR inhibitor could ameliorate microcephaly, which is the most serious possible consequence of fetal ZIKV infections. “These findings identify AHR as a candidate therapeutic target for ZIKV and, potentially, other flaviviruses,” the authors wrote. “In addition, our findings define AHR signaling as a candidate pathway by which environmental factors may influence the course of ZIKV infection and its associated pathology.” They published their results in the July 20, 2020, online issue of Nature Neuroscience.

iPSCs find best therapy for Best disease

Scientists at the University of Wisconsin have demonstrated that the response to gene replacement therapy differed widely in iPSC models of Best disease, a dominantly inherited form of macular degeneration that leads to blindness due to the degeneration of retinal pigment epithelium (RPE) cells. Dominantly inherited disorders are less amenable to gene therapy than recessive ones, since the problem is often that the mutated protein has toxic activity. However, when the authors tested iPSC models of Best disease, they found that two mutations that affected a specific part of the gene could be corrected via gene therapy. Several other mutations were correctable with gene editing. “These results suggest that gene augmentation is a viable first-line approach for some individuals with dominant Best disease and that non-responders are candidates for alternate approaches such as genome editing,” the authors wrote. “In summary, personalized iPSC-RPE models can be used to select among a growing list of gene therapy options to maximize safety and efficacy while minimizing time and cost. Similar scenarios likely exist for other genotypically diverse channelopathies, expanding the therapeutic landscape for affected individuals.” They reported their findings in the July 23, 2020, online issue of the American Journal of Human Genetics.

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