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Sunday, September 16, 2018

Largest study of ‘post-treatment controllers’ holds clues on HIV remission


Most HIV patients need to take daily anti-retroviral therapy — if they suspend treatment, HIV will rebound within 3-4 weeks. But clinical trials have revealed that a small fraction of patients can stop taking medications yet keep the virus suppressed for 24 weeks or longer, maintaining viral control without the assistance of medication.
Much remains unknown about this unique group of individuals, known as HIV post-treatment controllers, including how rare this ability is. Two new studies — including the largest study of post-treatment controllers to date — explore the characteristics of this group as well as the biological mechanisms that may help explain this unique ability.
“Post-treatment controllers represent a natural model of sustained remission,” said Jonathan Li, MD, of Brigham and Women’s Hospital’s Infectious Disease Clinic and lead author on both studies. “Understanding these individuals can lead to new insights for HIV therapies.”
The researchers defined post-treatment controllers as having viral loads of 400 or fewer copies per milliliter of blood plasma for at least 24 weeks’ post-treatment interruption. The study characterized 67 post-treatment controllers, the largest cohort to date. They found these post-treatment controllers by sifting through data collected from over 700 participants in 14 clinical studies involving treatment interruption.
The CHAMP (Control of HIV after Antiretroviral Medication Pause) study, published in The Journal of Infectious Disease, examined what post-treatment control can tell us about HIV’s progression. The researchers observed that individuals treated early were significantly more likely to become post-treatment controllers. Previously published studies have found other benefits for early treatment, notably decreased risk of transmission to partners compared to treatment starting during chronic infection.
A second study published in The Journal of Clinical Investigationilluminated the biological mechanisms underlying post-treatment control. Li’s team sequenced viral DNA, which the HIV virus had woven into the patient’s DNA.
The team observed that post-treatment controllers had lower levels of intact viral DNA prior to treatment interruption. In other words, post-treatment controllers carried smaller viral reservoirs. Li believes that reservoir size could represent a useful biomarker to help predict which patients will become post-treatment controllers.
In addition to intact viral DNA, Li and his team found that reservoirs of defective viral DNA may offer novel insights for treating HIV. They observed that defective HIV DNA seemed to give rise to proteins that could interact with the immune system. They plan to study this further.
“Each year, there are millions of new HIV infections,” said Li. “The results of these studies may help inform the design of strategies and trials aimed at achieving HIV remission, which we hope will bend the curve of this epidemic.”
Story Source:
Materials provided by Brigham and Women’s Hospital. Note: Content may be edited for style and length.
Journal References:
  1. Golnaz Namazi, Jesse M Fajnzylber, Evgenia Aga, Ron Bosch, Edward P Acosta, Radwa Sharaf, Wendy Hartogensis, Jeffrey M Jacobson, Elizabeth Connick, Paul Volberding, Daniel Skiest, David Margolis, Michael C Sneller, Susan J Little, Sara Gianella, Davey Smith, Daniel R Kuritzkes, Roy M Gulick, John W Mellors, Vikram Mehraj, Rajesh T Gandhi, Ronald Mitsuyasu, Robert T Schooley, Keith Henry, Pablo Tebas, Steve Deeks, Tae-Wook Chun, Ann C Collier, Jean-Pierre Routy, Frederick M Hecht, Bruce D Walker, Jonathan Z Li. The Control of HIV after Antiretroviral Medication Pause (CHAMP) study: post-treatment controllers identified from 14 clinical studies. The Journal of Infectious Diseases, 2018; DOI: 10.1093/infdis/jiy479
  2. Radwa Sharaf, Guinevere Q. Lee, Xiaoming Sun, Behzad Etemad, Layla M. Aboukhater, Zixin Hu, Zabrina L. Brumme, Evgenia Aga, Ronald J. Bosch, Ying Wen, Golnaz Namazi, Ce Gao, Edward P. Acosta, Rajesh T. Gandhi, Jeffrey M. Jacobson, Daniel Skiest, David M. Margolis, Ronald Mitsuyasu, Paul Volberding, Elizabeth Connick, Daniel R. Kuritzkes, Michael M. Lederman, Xu G. Yu, Mathias Lichterfeld, Jonathan Z. Li. HIV-1 proviral landscapes distinguish posttreatment controllers from noncontrollers. Journal of Clinical Investigation, 2018; 128 (9): 4074 DOI: 10.1172/JCI120549
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New method promises fewer side effects from cancer drugs


Protein research is one of the hottest areas in medical research because proteins make it possible to develop far more effective pharmaceuticals for the treatment of diabetes, cancer and other illnesses.
However, while proteins have great potential, they also present great challenges for scientists. Proteins have incredibly complex chemical structures that make them difficult to modify. As a result, researchers have been looking for a tool to modify them more precisely, without increasing a drug’s side-effects.
“We often run the risk of not being approved by health authorities because protein-based drugs lack precision and may have side-effects. Among other things, this is because of the serious limitations with the tools that have been used up until now,” according to Professor Knud J. Jensen of the University of Copenhagen’s Department of Chemistry.
Together with his research colleague, Sanne Schoffelen, he has developed a new protein-modifying method that promises fewer side-effects and could be pivotal in furthering the development of protein-based pharmaceuticals. Their work has been published in the distinguished journal, Nature Communications.
Protein structure is like an intricate ball of yarn
Researchers call the method “His-tag acylation.” Among other things, it makes it possible to add a toxic molecule to proteins that can attack sick cells in a cancer-stricken body without attacking healthy ones.
“Proteins are like a ball of yarn, a long thread of amino acids, which are turned up. This method allows us to precisely target these intricate structures, as opposed to making uncertain modifications when we don’t know what is being hit within the ball of yarn. In short, it will help produce drugs where we can be far more confident about where modifications are being made, so that side effects can be minimized in the future,” says Knud J. Jensen.
Modified proteins must target precisely
The fact that His-tag acylation can accurately target these complex yarn-like protein structures also makes it possible to produce drugs with entirely new characteristics.
For example, researchers can now attach a fluorescent molecule to proteins in such a way that a microscope can be used to track a protein’s path through cells. The primary function of these proteins is to transport cancer fighting molecules around to sick cells, so it is important to carefully follow their path throughout the body in order to safely produce medications that don’t have unintended side-effects.
Story Source:
Materials provided by Faculty of Science – University of Copenhagen. Note: Content may be edited for style and length.
Journal Reference:
  1. Manuel C. Martos-Maldonado, Christian T. Hjuler, Kasper K. Sørensen, Mikkel B. Thygesen, Jakob E. Rasmussen, Klaus Villadsen, Søren R. Midtgaard, Stefan Kol, Sanne Schoffelen, Knud J. Jensen. Selective N-terminal acylation of peptides and proteins with a Gly-His tag sequence. Nature Communications, 2018; 9 (1) DOI: 10.1038/s41467-018-05695-3
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BPA replacements in plastics cause reproductive problems in lab mice


Twenty years ago, researchers made the accidental discovery that the now infamous plastics ingredient known as bisphenol A or BPA had inadvertently leached out of plastic cages used to house female mice in the lab, causing a sudden increase in chromosomally abnormal eggs in the animals. Now, the same team is back to report in the journal Current Biology on September 13 that the array of alternative bisphenols now used to replace BPA in BPA-free bottles, cups, cages, and other items appear to come with similar problems for their mice.
“This paper reports a strange déjà vu experience in our laboratory,” says Patricia Hunt of Washington State University.
The new findings were uncovered much as before as the researchers again noticed a change in the data coming out of studies on control animals. Again, the researchers traced the problem to contamination from damaged cages, but the effects this time, Hunt says, were more subtle than before. That’s because not all of the cages were damaged and the source of contamination remained less certain.
However, she and her colleagues were able to determine that the mice were being exposed to replacement bisphenols. They also saw that the disturbance in the lab was causing problems in the production of both eggs and sperm.
Once they got the contamination under control, the researchers conducted additional controlled studies to test the effects of several replacement bisphenols, including a common replacement known as BPS. Those studies confirm that replacement bisphenols produce remarkably similar chromosomal abnormalities to those seen so many years earlier in studies of BPA.
Hunt notes that the initial inadvertent exposure of their animals was remarkably similar to what might happen in people using plastics in that the exposure was accidental and highly variable. Not all of the animals’ cages were damaged, and so the findings differed among animals in different cages.
She adds that — although determining the levels of human exposure is difficult — their controlled experiments were conducted using low doses of BPS and other replacement bisphenols thought to be relevant to exposure in people using BPA-free plastics.
These problems, if they hold true in people as has been shown in the case of BPA, will carry over to future generations through their effects on the germline. The researchers showed that, if it were possible to eliminate bisphenol contaminants completely, the effects would still persist for about three generations.
Hunt says more work is needed to determine whether some replacement bisphenols might be safer than others, noting that there are dozens of such chemicals now in use. She also suspects that other widely used and endocrine-disrupting chemicals, including parabens, phthalates, and flame retardants, may be having similarly adverse affects on fertility that warrant much more study.
“The ability to rapidly enhance the properties of a chemical has tremendous potential for treating cancer, enhancing medical and structural materials, and controlling dangerous infectious agents,” the researchers write. “Importantly, this technology has paved the way for ‘green chemistry,’ a healthier future achieved by engineering chemicals to ensure against hazardous effects. Currently, however, regulatory agencies charged with assessing chemical safety cannot keep pace with the introduction of new chemicals. Further, as replacement bisphenols illustrate, it is easier and more cost effective under current chemical regulations to replace a chemical of concern with structural analogs rather than determine the attributes that make it hazardous.”
Hunt’s advice to consumers now is simple: BPA-free or not, “plastic products that show physical signs of damage or aging cannot be considered safe.”
Support for these studies was provided from the NIH.
Story Source:
Materials provided by Cell Press. Note: Content may be edited for style and length.
Journal Reference:
  1. Tegan S. Horan, Hannah Pulcastro, Crystal Lawson, Roy Gerona, Spencer Martin, Mary C. Gieske, Caroline V. Sartain, Patricia A. Hunt. Replacement Bisphenols Adversely Affect Mouse Gametogenesis with Consequences for Subsequent Generations. Current Biology, 2018; DOI: 10.1016/j.cub.2018.06.070

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Caspase-2 enzyme inhibitor shows promise against fatty liver disease


Researchers at University of California San Diego School of Medicine have discovered using mice and human clinical specimens, that caspase-2, a protein-cleaving enzyme, is a critical driver of non-alcoholic steatohepatitis (NASH), a chronic and aggressive liver condition. By identifying caspase-2’s critical role, they believe an inhibitor of this enzyme could provide an effective way to stop the pathogenic progression that leads to NASH — and possibly even reverse early symptoms.
The findings are published in the September 13 online issue of Cell.
“Our results show that caspase-2 is a critical mediator of NASH pathogenesis, not only in mice but probably in humans as well,” said Michael Karin, PhD, Distinguished Professor of Pharmacology at UC San Diego School of Medicine. “While explaining how NASH is initiated, our findings also offer a simple and effective way to treat or prevent this devastating disease.”
NASH is the most aggressive form of non-alcoholic fatty liver disease (NAFLD), which includes a spectrum of chronic liver diseases and has become a leading cause of liver transplants. The cause of both NAFLD and NASH remains a mystery, but researchers believe one factor that accelerates the progression of benign NAFLD to aggressive NASH is elevated endoplasmic reticulum (ER) stress, induced by protein misfolding within the liver. This results in excessive buildup of cholesterol and triglycerides in liver tissue.
Applying this premise in mice, researchers first identified molecules involved in NASH pathogenesis by combining liver-specific ER stress and a high-fat diet to elicit NASH like disease, duplicating the cardinal features of human NASH, including fat accumulation in liver cells, liver damage, inflammation and scarring. Using this model, researchers found that the onset of NASH correlated with increased expression of caspase-2.
In the next phase, Karin and team examined human liver specimens collected from patients with benign NAFLD or aggressive NASH to confirm caspase-2 expression was also elevated in humans. By knocking out the caspase-2 gene in mice subjected to liver ER stress and high-fat diet or treating the mice with a specific caspase-2 inhibitor, they found that caspase-2 was responsible for all aspects of NASH, including lipid droplet accumulation, liver damage, inflammation and scarring.
“We now know that by preventing caspase-2 expression or inhibiting its activity that biomarkers of NASH are mitigated,” said Juyoun Kim, PhD, senior fellow in the Karin laboratory and lead author. “This is exciting because now, we not only understand the role of caspase-2 in the disease, but also have a new avenue to find a potential drug treatment.”
Through this study, Karin and team also discovered that caspase-2 has a critical role in activating SREBP1 and 2 — the master regulators of lipogenesis, a process that takes place in the liver where nutrients like carbohydrates are turned into fatty acids, triglycerides and cholesterol. Caspase-2 was found to control SREBP1 and 2 activation by cleaving another protein called site-1 protease.
“In NASH-free individuals, the activities of SREBP1 and SREBP2 are kept under control, which is essential for preventing excessive lipid accumulation in the liver,” said Karin. “However, in NASH patients, something goes awry and the liver continues to turn out excess amounts of triglycerides and cholesterol. This correlates with elevated SREBP1 and SREBP2 activities and increased caspase-2 expression.”
Moving forward, Karin and team would like to embark on development of more effective drug-like caspase-2 inhibitors that could be used for NASH prevention, and ultimately provide a treatment option.
“This study was a great step forward in being able to understand the causes, and explore possible new treatments for patients with NASH and NAFLD,” said co-author Rohit Loomba, MD, director of the UC San Diego NAFLD Research Center and director of hepatology at UC San Diego School of Medicine. “It is our hope to eventually translate and validate these study results using a much larger cohort of human subjects.”
“This study was a great step forward in being able to understand the causes, and explore possible new treatments for patients with NASH and NAFLD,” said co-author Rohit Loomba, MD, director of the UC San Diego NAFLD Research Center and director of hepatology at UC San Diego School of Medicine. “It is our hope to eventually translate and validate these study results using a much larger cohort of human subjects.”
Co-authors include: Ricard Garcia-Carbonell, Shinichiro Yamachika, Peng Zhao, Debanjan Dhar and Alan R. Saltiel, all UC San Diego; and Randal J. Kaufman, Sanford-Burnham-Prebys Medical Discovery Institute.
Story Source:
Materials provided by University of California – San Diego. Original written by Gabrielle Johnston, MPH. Note: Content may be edited for style and length.
Journal Reference:
  1. Ju Youn Kim, Ricard Garcia-Carbonell, Shinichiro Yamachika, Peng Zhao, Debanjan Dhar, Rohit Loomba, Randal J. Kaufman, Alan R. Saltiel, Michael Karin. ER Stress Drives Lipogenesis and Steatohepatitis via Caspase-2 Activation of S1P. Cell, 2018; DOI: 10.1016/j.cell.2018.08.020
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Working with Patients and a Fresh $80M, Fulcrum Eyes a 2019 IPO


Fulcrum Therapeutics, a Cambridge, MA, startup run by the former CEO of Epizyme, has closed an $80 million Series B round that lays the groundwork for a likely IPO next year, its CEO says.
The new funding, led by Foresite Capital, comes from a wide array of crossover investors, such as Fidelity Management and Research, that back both private and public companies. These types of rounds often precede IPOs in biotech, and CEO Robert Gould says that is Fulcrum’s plan. The company hopes to go public early next year, after filing papers with the FDA to begin human testing of its first drug, for a rare muscle wasting disease called facioscapulohumeral muscular dystrophy (FSHD), Gould says.
“We think that the strength of the preclinical data and the quality of the compound is such that it’ll be an attractive investment opportunity,” he says.
That has yet to be proven, but Gould has been here before. The one-time Merck executive helped take cancer drug developer Epizyme (NASDAQ: EPZM) public in 2013, raising about $80 million at $15 a share. He left the company two years later and resurfaced as the CEO of Fulcrum in 2016.
Fulcrum is trying to use drugs to control molecular switches that turn genes on or off, hoping to treat a variety of diseases with no effective treatments—starting with FSHD, which is marked by muscle degeneration that starts in the face, back, and upper arms. Though the disease typically progresses slowly and isn’t fatal, FSHD, which affects an estimated 870,000 people worldwide according to the nonprofit FSH Society, can leave patients in wheelchairs or on respirators. There are ways to help manage the disease’s complications, but no available therapies can halt or reverse its progress. Fulcrum’s experimental drug is meant to “at bare minimum” halt the progression of FSHD by preventing the expression of a protein, DUX4, implicated in the disease, Gould says.
Its scientific aspirations aside, however, Fulcrum is a product, of sorts, of the FDA’s increasing willingness to incorporate patient perspectives throughout the drug development process. Fulcrum reached out to patient groups to figure out which diseases to go after, even before the company was officially formed in 2016. That led it to FSHD. That approach is atypical; more often, drug developers connect with patient groups later on, Michael Tranfaglia, medical director, chief scientific officer, and co-founder of the FRAXA Research Foundation, told Xconomy in 2017.
Fulcrum has worked with the FSH Society, for instance, to obtain muscle tissue samples from people with the disease undergoing surgery as part of their treatment. The company has used those samples to grow muscle cells from the tissue and test its drug candidates against those cells. “It’s a unique relationship,” FSH Society president, CEO and co-founder Daniel Perez told Xconomy last year. (Fulcrum was a finalist for Xconomy’s patient partnership award in 2017.)
Gould says establishing relationships with the patient community has helped Fulcrum get its hands on those samples. The company has also teamed with patient advocacy groups to begin work on various studies, among them a “natural history” study in FSHD to better understand the disease’s trajectory. It’s working with patients to learn how the disease affects their quality of life and what types of benefits from a drug would be valuable. That insight, in turn, should help the company design clinical trials to answer questions that “speak directly to the patient’s needs and desires,” Gould says. And working with patient groups from the outset should help Fulcrum more quickly recruit patients for those studies.
“Just like they can educate us about what’s important for daily life, we can educate them about how vitally important tissue donation is to potentially identifying a therapy for a disease,” Gould says.
Fulcrum started up with a $55 million Series A in 2016 from Third Rock Ventures. The company is also developing drugs for sickle cell disease, Duchenne muscular dystrophy, and Fragile X syndrome.
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With OneOncology, Flatiron and Cancer Docs Aim to Boost Community Care


A number of new technologies, from immunotherapy to targeted medicines and diagnostics, have all helped change cancer care the past few years. But not all cutting-edge technologies are available to patients who seek treatment at smaller clinics.
OneOncology, an unusual new startup being launched this morning, aims to help cancer patients in community settings gain access the latest treatments and learn about clinical trials, as they would if they were at a major medical center.
OneOncology is a new healthcare company formed by three of the nation’s largest community-based cancer practices that see 158,000 patients per year: Tennessee Oncology, New York Cancer & Blood Specialists, and West Cancer Center. The company brings together doctors and patients from these three practices and connects them through the cancer-specific electronic health record (EHR) software developed by Flatiron Health.
For Flatiron, a high-flying New York startup that Roche bought for $1.9 billion in February, OneOncology represents a way to acquire more patient data and customers for its EHR system.
The company is starting up with a $200 million investment from private equity firm General Atlantic. Tracy Bahl, a former CVS Health executive, is president and CEO. Each participating practice has an equity stake.
In an e-mail to Xconomy, Robin Shah, a former Flatiron executive who runs OneOncology’s business development efforts, said the goal of the organization is to “ensure patients receive the same best-class care no matter where they live.”
Shah said OneOncology’s solution involves putting a wide array of community practices on Flatiron’s EHR system, so doctors can share data on a cloud-based system, stay up on the latest research, work through changing drug payment and reimbursement models, and learn from one another. Flatiron’s software collects data that, stripped of patient-identifying information, are sold to drug companies and others to use in either research or clinical trial recruitment. It has partnerships with 275 community cancer clinics nationwide.
According to the Community Oncology Alliance, more than half of U.S. cancer patients are treated at community oncology practices—private, physician-owned businesses that aren’t part of the country’s major cancer centers like Memorial Sloan Kettering in New York or Dana-Farber in Boston. But community doctors don’t have the same resources as those at the big medical centers. Many aren’t up to speed on the latest scientific literature, research, or clinical trials.
“No one person has the bandwidth to use this developing, expanding armamentarium [of drugs] in the best possible way for patients unless they are really focused, and are in a setting where they’re always hearing about the latest clinical trials and results,” Drew Pardoll, director of the Johns Hopkins Bloomberg-Kimmel Institute for Cancer Immunotherapy, told Xconomy earlier this year.
For instance, newer diagnostic technologies such as DNA tests that scan for a tumor’s genetic alterations may be underutilized in the community setting, says Jens Reuter, medical director of the private nonprofit Maine Cancer Center Initiative. Even when community doctors use the new diagnostics, the complex reports they generate can be difficult to interpret and act upon. What happens, for example, if a test recommends using a cancer drug that isn’t approved for the patient being tested? There’s been a “lack of comprehensive education” for community oncologists, says Rueter.
Shah said with Flatiron’s help, OneOncology will build a “collective platform” to alert participating doctors about ongoing trials.
“Overall, consortia like this make a lot of sense to me,” Reuter says, noting that with bigger scale, community practices will be better able to learn about patients, share treatment insights, and attract clinical trials.
Still, Reuter notes that OneOncology isn’t championing “a precision medicine approach,” that is, sequencing patients’ tumors for a wide range of genetic alterations and using those insights to find a drug. There is much debate within the scientific community as to the benefits of precision oncology—just a few weeks ago, for example, the Journal of the American Medical Association published a paper showing that broad DNA sequencing of the tumors of lung cancer patients in community practices didn’t lead to a survival benefit.
Shah said OneOncology’s community partners will establish guidelines for the use of all types of diagnostic testing, including broad DNA sequencing tests, and get patients access to the latest treatment options. The goal is to standardize treatment across the participating practices and to be a “driver” in “value-based payment models” that tie a drug’s price to its performance. “We believe this will be the future of oncology and healthcare,” Shah said.
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Vision Assistance Startup Aira Inking Deals With UCSD, Retail Stores


Students and shoppers will soon be using technology developed by Aira, a San Diego startup that links vision-impaired people with “visual interpreters” via smartphone and smart glasses, to help them navigate their environments.
In recent weeks Aira announced that its accessibility service would be available at no cost to those who need it while at UC San Diego, in about 5,000 AT&T stores, and at all Wegmans grocery stores. The Rochester, NY-based grocery chain has 97 stores in six East Coast states.
The Aira app links people who are blind or have impaired vision with independent contractors that Aira calls “agents.” Via the app, agents help Aira users with tasks they may otherwise have difficulty managing, from shopping for groceries to reading a restaurant menu. The agents talk to users through the speaker in their phone or smart glasses.
The service is available for individuals via paid subscription; the price of the subscription varies based on how many minutes of assistance are provided. Aira offers four tiers, starting with an $89 monthly plan, which comes with 100 minutes, and topping out at $329 per month for unlimited minutes of assistance. With a subscription comes Aira Smart Glasses.
The recently signed corporate customers, however, will be providing the service free within locations each has identified. At UCSD, that includes the Scripps Institution of Oceanography in La Jolla and its medical campus in Hillcrest. Signing on businesses is a way for the company to more rapidly expand its user base—and increase revenue—as compared to acquiring individual users. That’s the goal, anyway.
CEO Suman Kanuganti founded Aira in 2014 while he was an MBA student at the UCSD Rady School of Management. Among his advisors was the late Larry Bock, a serial entrepreneur who helped start 50 companies, most after he was diagnosed at age 29 with an eye disease that causes progressive loss of vision.
The company’s connection with AT&T is longstanding. The Dallas, TX-based telecom helped Aira develop its service through its Foundry for Connected Health initiative in Houston, which focuses on digital health technologies, and AT&T provides Aira users with dedicated wireless bandwidth.
In 2017 Aira raised a $12 million Series B round to expand its services—which had been tested with about 300 people—to thousands more users. The round was led by San Francisco-based Jazz Venture Partners and Ann Arbor, MI-based Arboretum Ventures. Lux Capital, Arch Venture Partners, and Felicis Ventures also participated, and the National Federation of the Blind joined as a strategic investor.
Aira, previously housed within the Southern California incubator EvoNexus, is based in La Jolla.
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