Hsp47

Bristol Myers Squibb disclosed Thursday at its R&D Day that it cut six programs, including mid-stage drug candidates for NASH and solid tumors. The New Jersey pharma company axed an siRNA for NASH, known as HSP47, which it licensed from Nitto Denko for $100 million upfront in 2016. Bristol Myers completed a Phase II study in 2019 investigating the therapy in patients with advanced liver fibrosis, or scar tissue buildup, after they were cured of hepatitis C. It had tested two different doses versus placebo in 61 patients, but both doses failed to make a difference in liver scarring compared to placebo, according to results in the federal clinical trials database .

FRIDAY, April 14, 2023 -- Long periods of immobility can put people at risk of dangerous blood clots — yet hibernating bears lie around for months without any problem. Now scientists think they've figured out why. The researchers hope the insight can eventually lead to new drugs for preventing life-threatening blood clots — the kind that begin in the legs but can travel to the brain and cause a stroke, or to the lungs and cause a pulmonary embolism. In their new study , the researchers found that in hibernating bears, a particular protein — called heat shock protein 47 (HSP47) — is substantially dialed down from its normal activity level. And that appears to prevent blood clots from forming while the animals are in months-long slumber. Even more importantly, the investigators found, that phenomenon also occurs in other species, including humans. Specifically, HSP47 activity is low in people paralyzed by spinal cord injuries. That may sound counterintuitive, since temporary immobility — recovering from an injury or surgery, or taking a long-haul flight — can promote blood clots in some people. But it's known that people with paralysis have no higher blood clot risk than mobile people do. And the new findings suggest that HSP47 may be the key, the study authors said. The hope is that the finding will lead to new ways to prevent blood clots in vulnerable people, according to Dr. Tobias Petzold , one of the researchers on the study. "We would like to further study the mechanism by which HSP47 works in preventing (blood clots) in more detail," said Petzold, of Ludwig-Maximilians-University in Munich, Germany. Some long-used medications are already used for preventing blood clots in at-risk people, including old-fashioned aspirin. But, Petzold said, they have side effects, such as an increased risk of bleeding. So there is still a need to keep hunting for medications that are highly effective but safer. "We think that a ‘natural’ blood thinner that the body is capable of mobilizing spontaneously could help tackle that unmet clinical need," Petzold said. Why turn to bears in that quest? "We believe that the bear is a walking library of solutions to our sedentary lifestyle," Petzold said. After all, he pointed out, hibernating bears spend a large portion of their waking lives feasting and packing on huge amounts of weight, only to then spend half the year lying around doing nothing. For humans, that's a virtual recipe for obesity, muscle loss, thinning bones, type 2 diabetes and many other health problems — including blood clots. Yet bears emerge from their hibernation unscathed. Understanding what, exactly, protects them could theoretically point to completely new treatments for various human diseases related to "modern lifestyles," Petzold said. Other researchers are studying bears for that very reason. A study published last year by a Washington State University team identified specific proteins that seem to help shield hibernating grizzlies from diabetes. Humans, it turns out, have counterparts to those protective proteins. For the new study, Petzold and his colleagues studied not only brown bears, but also pigs that were either cooped-up or free-roaming, and people who were mobile or paralyzed by spinal cord injuries. The researchers found that, on average, HSP47 from hibernating bears' blood cells was reduced by 55 times, versus active-season bears. A similar pattern was seen in both pigs and people. It all suggests that HSP47 could be a good target for new medications for people at high risk of blood clots during shorter periods of immobility, according to an editorial published with the study. At the moment, researchers know a lot more about the things that trigger clots than what protects against them, wrote Mirta Schattner , who studies blood clotting mechanisms at the National Academy of Medicine in Buenos Aires, Argentina. According to Schattner, the new study "shows that looking at nature can be a good way to learn about human biology." Blood clots, however, do not only form when people are immobilized, Schattner pointed out. Chronic health conditions like diabetes and various cancers can raise the risk, too. So, she added, one question going forward is whether this heat shock protein is important to blood clotting in those cases, too. The findings were published online April 13 in the journal Science . Sources Tobias Petzold, MD, department of cardiology, Ludwig-Maximilians-University, Munich, Germany Science , April 13, 2023, online Posted April 2023

'Don't poke the bear', they said. But that's exactly what a team of scientists have been doing, to discover the secrets of blood clotting. Hibernating bears, paralysed humans, and pigs kept in small enclosures all avoid dangerous blood clots, despite being immobile for extremely long periods. “Don’t poke the bear”, they said. But that’s exactly what a team of scientists have been doing, to discover the secrets of blood clotting. Hibernating bears, paralysed humans, and pigs kept in small enclosures all avoid dangerous blood clots, despite being immobile for extremely long periods. Research from the University of Reading, with partners in Denmark, Germany, Norway and Sweden, shows that reduction of a key protein prevents the formation of blood clots in all three mammal species when they are still for days, weeks, months, or even years at a time. The study is published today (13 April 2023), in Science. If you’ve ever taken a long haul flight, you might have taken advice to prevent a dangerous blood clot – deep vein thrombosis – from forming in one or both of your legs, while you sit still for multiple hours, dreaming of your destination. Perhaps you set a reminder to get up and walk around, and you wore compression socks to keep the blood from pooling in your legs. Most people won’t experience a clot if they take care on a flight, but there is a serious risk for some people who are pre-disposed to blood clots, due to genetic factors. The discovery that a protein known as Hsp47 is dramatically reduced, by 55 times, when someone is immobilised for a much longer period than a flight, could lead to new medicines to help those who have inherited blood clotting disorders that put them at risk for pulmonary embolism, heart attack, and stroke. Professor Jon Gibbins led the work at the University of Reading. He said: “It seems counterintuitive that people who have severe paralysis don’t appear to be at higher risk of blood clots. This tells us that something interesting is happening. And it turns out that reducing levels of Hsp47 plays a key role in preventing clots, not just in humans, but in other mammals, including bears and pigs. “When we see something like this in multiple species, that reinforces its importance. Having Hsp47 must have been an evolutionary advantage.” Hsp47 is released by platelets – the sticky blood cells that trigger blood clotting.  Usually clotting is an important response to an injury, to prevent blood loss, and Hsp47 is one of the necessary ingredients to enable platelets to do their job. Examining the role of Hsp47 in clotting function the team found that when released into the blood of bears, mice and humans that it promoted conditions that may give rise to deep vein thrombosis. Professor Gibbins said “We aren’t totally sure how, but it appears that there is something about movement that keeps Hsp47 at an appropriate level. It could be that the mechanical forces involved in moving around actually have an impact on gene expression, dramatically increasing the amount of Hsp47 that circulates in the blood.” The team took blood samples from bears in winter, while hibernating, and in summer, while awake and moving around. They also compared people who were immobilised with those who can move and walk. And finally, pigs kept in small pens were compared with others that were free to move around in barns. In all three cases, proteomics experiments showed that the absence of movement was associated with having far less Hsp47. Professor Gibbins said: “Now we know that Hsp47 is so important, we can begin to look for new or existing medicines that might be able to inhibit the function of this protein in blood clotting and protect mobile people who are prone to clots.”