Nexavar halts NASH
A study by Wuhan University scientists has demonstrated that treatment with low doses of the kinase inhibitor Nexavar (sorafenib, Bayer AG) was a safe and effective therapeutic approach to suppressing progression of nonalcoholic steatohepatitis (NASH) in both mice and monkeys. Predicted to become the most common reason for liver transplantation by 2030, NASH is one of the leading causes of end-stage liver disease, including cirrhosis, hepatocellular carcinoma (HCC) and liver failure. Previous studies from other groups have revealed an antifibrotic function of sorafenib and its underlying mechanisms in in vivo and in vitro models of NASH, including those induced by toxin injection, bile duct ligation and chronic hepatitis B. The team was testing the effects of Nexavar on earlier stages on HCC, and unexpectedly observed a strong protective effect on major hallmarks of NASH, including hepatic lipid accumulation, inflammation and fibrosis. Nexavar’s benefit in NASH was independent of its kinase therapeutic targets in HCC, instead involving induction of mitochondrial uncoupling and activation of 5’-adenosine monophosphate (AMP) activated protein kinase (AMPK). The team reported its results in the May 5, 2020, online issue of Cell Metabolism.
New MVP against SVMP
Investigators at the Liverpool School of Tropical Medicine have identified the metal chelator 2,3-dimercapto-1-propanesulfonic acid (DMPS) as a possible snakebite antidote. The disease burden of snakebite, at more than 100,000 per year, is on par with major neglected tropical diseases. Antidotes, meanwhile, are challenging to develop because snake species have individual venoms, and venoms have multiple components, making specific countermeasures impractical for rapid use in low-resource settings. The authors focused on a group of snakes, the saw-scaled vipers, that are collectively among the major perpetrators of fatal snakebites across Africa and Asia. Because the saw-scaled viper’s major toxins, the snake venom metalloproteinase (SVMPs), depend on zinc to work, they screened metal chelators for their effects on snakebite. In animal models, DMPS considerably extended survival in a “challenge and treat” model, where drug administration was delayed after venom injection and the oral administration of this chelator provided partial protection against envenoming, the authors wrote. “The potential clinical scenario of early oral DMPS therapy combined with a delayed, intravenous dose of conventional antivenom provided prolonged protection against the lethal effects of envenoming in vivo.” Their work appeared in the May 6, 2020, issue of Science Translational Medicine.
Copper escort alleviates Menkes disease
Researchers at Texas A&M University have demonstrated that the copper chaperone elesclomol was able to reverse neurodegeneration and prolong lifespan in a mouse model of the rare disorder Menkes disease. Copper is both an essential micronutrient and a free radical-producing toxin. Its presence in cells is tightly regulated by the copper transporter ATP7A, and mutations in ATP7A lead to the rare disorder Menkes disease, which is usually fatal to children by the age of 3. Among the enzymes most strongly affected by lack of copper transport is cytochrome c oxidase, which plays a role in ATP generation. Its dysfunction leads to cardiac problems and neurodegeneration. In their work, the team tested the copper-binding and membrane-traversing small molecule elesclomol, which could deliver copper to cytochrome c oxidase to cells in vitro, in a mouse model of Menkes disease. They showed that elesclomol’s effects compared favorably to the experimental Menkes drug histidine, which requires residual copper transporter activity to be effective. The team demonstrated that treatment “at relatively low dose stopped early mortality and conferred near-normal cardiac and brain histology.” They concluded that elesclomol or a complex of elesclomol and copper “hold promise as a potential, efficacious therapeutic agent for the treatment of hereditary Cu-deficiency disorders.” Their work appeared in the May 8, 2020, issue of Science.
Liver-specific pre-eclampsia treatment is maternal-specific, as well
Scientists at Alnylam Inc. and academic co-authors have developed a small interfering RNA (siRNA) that could reduce the symptoms of pre-eclampsia in pregnant rats without affecting fetuses. Pre-eclampsia, the development of dangerously high blood pressure and kidney dysfunction during pregnancy, is one of the leading causes of maternal and fetal death in developed nations. Treatment of pre-eclampsia is a form of catch-22, as treatments that are beneficial for the symptoms of hypertension are detrimental to fetal development. The authors developed a liver-targeted siRNA that inhibited the production of angiotensinogen, the precursor of angiotensin, which is a key regulator of blood pressure. Treatment reversed high blood pressure and reduced kidney dysfunction in two separate models of pre-eclampsia without affecting fetal development. The team acknowledged that “given the differences in disease pathophysiology as well as placentation between rodents and the human condition, it is unclear how directly translatable these findings are. However… future studies may seek to extend these findings. Critically, further studies are necessary to determine whether such a correction of the disease phenotype can be obtained if treatment is begun in the symptomatic phase.” They reported their results in the April 27, 2020, issue of the Journal of Clinical Investigation.
Integrated herpesvirus-6 is pre-eclampsia risk factor
In a separate study, researchers from Cambridge University have identified integrated human herpesvirus 6 (HHV6) in fetuses as a risk factor for the development of pre-eclampsia by mothers. So far there is no way to predict who is at risk for developing pre-eclampsia, but epidemiological studies have demonstrated that pregnancies fathered by some men are more likely to lead to pre-eclampsia. In their work, the authors investigated the presence of inherited HHV6, which is present in about 1% of the population, because chronic viral infection can contribute to organ failure in other contexts. They demonstrated that pregnancies in which the fetus had integrated HHV6 had a threefold increased likelihood of resulting in pre-eclampsia. In addition to its association with pre-eclampsia, previous work has demonstrated that integrated HHV6 predisposes to the development of heart disease, and that women who develop pre-eclampsia also have an elevated risk of heart disease. The study, which appeared in the May 4, 2020, online issue of Nature Genetics, suggests that pre-eclampsia and heart disease risk may be linked via HHV6.
Prying mantis identifies disease genes
Researchers at Astrazeneca plc have developed a machine-learning model, called mantis-ml, to assess the biological relevance of genes to diseases, enabling the prioritization of genes from high-throughput genomic screens. The proteome-coding genome is finite and, at this point, well known. Disease associations of many genes, however, remain incompletely understood. The authors used multiple types of information about genes, including gene expression, human disease literature, mouse phenotypes, proteomics, interactome and evidence for selection, to search for patterns shared among known disease-associated genes, and then searched for similar patterns in genes not associated with a particular disease. They compared their predictions to published exome-wide association studies for chronic kidney disease, amyotrophic lateral sclerosis and epilepsy, and they found “a statistically significant enrichment of high mantis-ml predictions among the highest-ranked genes from hypothesis-free cohort-level statistics, indicating a substantial improvement over the performance of current state-of-the-art methods and pointing to the capture of true prioritization signals for disease-associated genes.” They reported their findings in the May 7, 2020, print issue of Molecular Therapy.
Carbohydrate metabolism implicated in neuropathy
While more than 90% of patients with the demyelinating form of the hereditary neuropathy Charcot-Marie Tooth disease, CMT1, have mutations in known genes, only 20% to 30% of patients with the axonal form, CMT2, receive a genetic diagnosis. Now some clever detective work has identified biallelic mutations in the sorbitol dehydrogenase gene as a cause of CMT2, and shown it is possible to reduce the harmful levels of intracellular sorbitol that accumulate as a result, in cell and animal models. Investigators at University College London used a large collection of more than 1,100 CMT patients for whom whole exome and/or whole genome sequencing had been performed. Taking a subset of 598 patients who did not have a genetic diagnosis of their condition, they looked for genes for which potentially pathogenic DNA variants are present in multiple families. They also searched for individual alleles that were over-represented in patients. From those results, they identified 16 individuals from 14 unrelated families carrying mutations in the SORD gene. To assess the relevance, the researchers cross-referenced those findings against two further cohorts of unresolved CMT2 cases. In total, they found 45 individuals from 38 families carrying the SORD mutations. The findings also have relevance in diabetes, where sorbitol is implicated in disease complications. The team published its findings in the May 4, 2020, online issue of Nature Genetics.
T-cell mutations contribute to GVHD
Investigators at the University of Helsinki have shown that mutations in T cells can contribute to graft-vs.-host-disease, a major complication of allogeneic bone marrow transplant. Specifically, the team identified a mutation in the mTOR kinase in three out of roughly 130 screened patients with chronic graft-vs.-host-disease (cGVHD), but not in a control group of bone marrow transplant patients that did not have cGVHD. The mutation led to gain of function of the mTOR kinase and increased activity of both mTOR complex 1 and mTOR complex 2, and T cells that were more active. In vitro, the mutation also conferred resistance to mTOR inhibitors, but it increased sensitivity to Hsp90 inhibitors. The authors concluded, “Our findings imply that somatic mutations may contribute to aberrant T-cell proliferations and persistent immune activation in cGvHD, thereby paving the way for targeted therapies.” They reported their results in the May 7, 2020, online issue of Nature Communications.