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Archive - Aug 24, 2017

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Tyrosine Kinase Inhibitor Slows Cyst Growth in Autosomal Dominant Polycystic Kidney Disease (ADPKD) in New Study

A cancer drug called bosutinib may inhibit the growth of cysts in patients with autosomal dominant polycystic kidney disease (ADPKD), according to a study published online on August 24, 2017 in the Journal of the American Society of Nephrology (JASN). The JASN article is titled “Bosutinib Versus Placebo for Autosomal Dominant Polycystic Kidney Disease." The findings point to a potential new treatment strategy for affected patients, but the long-term benefits remain to be determined. ADPKD is an inherited disorder that affects up to 1 in 1000 people and is characterized by cysts in the kidney and other organs. As patients' kidney volume increases due to cyst growth, they gradually lose their kidney function and often develop kidney failure. Current treatments are primarily supportive, such as focusing on hypertension and other secondary complications. The inherited mutations that cause ADPKD affect a protein involved in various signaling pathways that often involve enzymes called tyrosine kinases. Therefore, a team led by Vladimir Tesar, MD, PhD (Charles University and General University Hospital, in the Czech Republic) tested the potential of an investigational drug called bosutinib that inhibits a particular tyrosine kinase called Src/Bcr-Abl. (Bosutinib is approved for the treatment of certain cases of chronic myeloid leukemia). The phase 2 study included patients with ADPKD who were randomized 1:1:1 to bosutinib 200 mg/day, bosutinib 400 mg/day, or placebo. Of 172 patients enrolled, 169 received at least one treatment. The higher dose of bosutinib was not well tolerated. The annual rate of kidney enlargement was reduced by 66% for patients receiving bosutinib 200 mg/day vs. those receiving placebo (1.63% vs. 4.74%, respectively) and by 82% for all patients receiving bosutinib vs.

Scientists Develop Innovative System to Characterize Regulatory DNA Sequences Responsible for Human Diseases

Scientists from the Children’s Medical Center Research Institute at the University of Texas (UT) Southwestern (CRI) have developed an innovative system to identify and characterize the molecular components that control the activities of regulatory DNA sequences in the human genome. The genome, which is the complete complement of human DNA, including all protein-coding genes, has nearly 3 billion base pairs. Despite its vast size, only 2 percent of our genome codes for proteins. The other 98 percent is comprised of noncoding regions that regulate where and when the protein-coding genes are activated. These noncoding regions have repeatedly been identified by human genetics and cancer genomic studies as potential drivers for human diseases such as cancer. A better understanding of these regulatory regions and the underlying principles that guide when genes are turned on and off is necessary to uncover how diseases develop and to find new treatments. However, the tools to identify these noncoding regions and to understand how they work are limited. They require the prior identification of the protein factors that regulate these regions, depend on the availability of reagents such as antibodies, and often need sophisticated genetic manipulations. The new system, developed by researchers in the Dr. Jian Xu lab and published in the August 24, 2017 issue of Cell, is paving the way for an in-depth look at these regulatory genetic elements. This system, named CAPTURE (CRISPR Affinity Purification in situ of Regulatory Elements), provides an approach to simultaneously isolate genomic sequence-associated proteins, as well as their RNA and DNA interactions.