- The first two patients treated at the 3e13 vg/kg dose level rapidly achieved normal, sustained Factor VIII (FVIII) levels with no reported bleeding events and no factor usage for as long as 24 weeks of follow-up
- The two patients more recently treated at the 3e13 vg/kg dose level demonstrated FVIII activity kinetics that appear consistent with the first two patients in this dose cohort at similar early time points
- SB-525 showed dose-dependent increases in FVIII activity levels across all dose cohorts evaluated
- FDA recently granted regenerative medicine advanced therapy (RMAT) designation for SB-525 gene therapy to treat severe hemophilia A
Saturday, July 6, 2019
Sangamo, Pfizer Update Phase 1/2 Results for Hemophilia A Gene Therapy
uniQure Has Follow-Up Data from Phase 2b Hemophilia B Study
~ FIX Activity Up to 54% of Normal, with Mean of 45% of Normal, at 36 WeeksAfter Administration of AMT-061 in Phase IIb Study ~
~ Clinical Benefit and Tolerability of AMT-060 Maintained in All Patients Through up to 3.5 Years of Follow-up ~
uniQure N.V. (NASDAQ: QURE), a leading gene therapy company advancing transformative therapies for patients with severe medical needs, today announced updated clinical data on the three patients treated in the Company’s ongoing Phase IIb study of AMT-061, an investigational AAV5-based gene therapy containing a patent-protected FIX-Padua variant for the treatment of patients with severe and moderately severe hemophilia B. In addition, the Company presented up to 3.5 years of follow-up data on the 10 patients in the Phase I/II trial of AMT-060, its first-generation gene therapy for the treatment of hemophilia B. These clinical data were presented on Saturday, July 6 in oral presentations at the 27th Congress of the International Society on Thrombosis and Haemostasis (ISTH), taking place in Melbourne, Australia.
Featured in an oral presentation at ISTH, the 36 weeks of follow-up data show that all three patients have sustained increases in FIX levels after the one-time administration of AMT-061, with two of the three patients maintaining FIX activity in the normal range. Mean FIX activity for the three patients at 36 weeks after administration was 45% of normal, with the first patient achieving FIX activity of 54% of normal, the second patient achieving FIX activity of 30% of normal and the third patient achieving FIX activity of 51% of normal. The second and third patients had previously screen-failed and were excluded from another gene therapy study due to pre-existing neutralizing antibodies to a different AAV vector. Reported FIX activity was measured using an activated partial thromboplastin time (aPTT) assay performed at a central laboratory.
No patient in the study has experienced a material loss of FIX activity, reported any bleeding events or required any infusions of FIX replacement therapy for bleeds. One patient underwent hip surgery due to a pre-existing condition and was treated perioperatively with short-acting factor replacement. This was reported by the investigator as a serious adverse event unrelated to AMT-061.
“These updated data continue to show that a single administration of AMT-061 is well-tolerated and has the potential to increase FIX activity into the normal range for people living with hemophilia B,” stated Matt Kapusta, chief executive officer of uniQure. “We continue to be very pleased with these results, which as of this data report show durable increases in FIX activity with no bleeds and no requirement for infusions of FIX replacement therapy or immunosuppression. We believe AMT-061 has the potential to be a first- and best-in-class gene therapy for patients with hemophilia B, and we remain focused on our goal of completing enrollment in our ongoing HOPE-B pivotal trial by the end of this year.”
Array Interim Results of Colorectal Cancer Trial at ESMO Meet
BRAFTOVI combinations showed statistically significant improvement in OS and ORR versus control – – Data supports potential to be the first chemotherapy-free, targeted regimen for BRAF-mutant mCRC patients – – Results were presented in an oral presentation today, July 6, 2019
Array BioPharma Inc. (Nasdaq: ARRY) today announced the presentation of results from the Phase 3 BEACON CRC trial evaluating the combination of BRAFTOVI® (encorafenib), a BRAF inhibitor, MEKTOVI® (binimetinib), a MEK inhibitor, and ERBITUX® (cetuximab), an anti-EGFR antibody (BRAFTOVI Triplet), in patients with advanced BRAFV600E-mutant metastatic colorectal cancer (mCRC), following one or two lines of therapy. Data presented included primary and secondary endpoints, waterfall plots describing tumor reduction, subgroup analyses, and exploratory analyses comparing overall survival (OS) of the BRAFTOVI Triplet and BRAFTOVI Doublet (BRAFTOVI and cetuximab) in a subset of patients with mature follow-up, including the first 331 randomized patients, as well as safety and tolerability.
Results showed that BRAF-mutant mCRC patients treated with the BRAFTOVI Triplet combination demonstrated a statistically significant improvement in OS (9.0 months vs. 5.4 months, [HR 0.52, (95% CI 0.39-0.70), p<0.0001]) and objective response rate (ORR) (26.1% vs. 1.9%, p<0.0001, as assessed by Blinded Independent Central Review (BICR)) compared to cetuximab plus irinotecan-containing regimens (Control). Median progression-free survival (mPFS) for patients treated with the BRAFTOVI Triplet was 4.3 months [HR 0.38, (95% CI 0.29, 0.49), p<0.0001] compared to 1.5 months observed with the Control arm.
These data were presented in an oral presentation on Saturday, July 6, at the ESMO 21st World Congress on Gastrointestinal Cancer in Barcelona, Spain.
Friday, July 5, 2019
Study finds nursing homes rarely have enough RNs on staff
RN staffing levels fall much lower than CMS standards in most nursing homes, according to a study published July 1 in Health Affairs.
“Seventy-five percent of nursing homes were almost never in compliance with what CMS expected their RN staffing level to be,” the study’s authors wrote. They also found half of skilled nursing facilities only met standard staffing benchmarks on 19 days or fewer between April 2017 and March 2018.
The study supports previous analyses that also revealed staffing problems in nursing homes, according to Skilled Nursing News. The problems came to light when CMS stopped using self-reported data in favor of the payroll-based journal system in April 2018. CMS gave almost 1,400 nursing homes one-star ratings after The New York Times and Kaiser Health News analyzed the PBJ data and found a large gap between self-reported and payroll-based staffing records.
Going forward, the study’s authors advise improved measures of staffing levels based on day-to-day variation rather than averages, among other measures.
Protein-linked sugars crucial for uptake of proteins linked to Parkinson’s
Parkinson’s disease, a neurodegenerative disorder that affects more than 6 million people worldwide, is caused by the buildup of alpha-synuclein proteins in the brain. The biological function of alpha-synuclein is still not well understood, but because of its role in neurodegenerative diseases, researchers are actively studying this protein to understand the mechanisms of the disease and to look for new treatment strategies.
A new study from Elizabeth Rhoades and postdoc Melissa Birol found that when alpha-synuclein binds to extracellular glycoproteins, proteins with added sugar molecules, it can be taken up by neurons more easily. The paper also identified a specific presynaptic protein, neurexin 1?, as a key regulator in this process and a potential therapeutic target. Their findings were published in the journal PLOS Biology.
In one possible model for the pathology of Parkinson’s disease, bundles of alpha-synuclein proteins, known as aggregates, form inside a neuron. This then leads to cell death and the release of alpha-synuclein protein clusters that are taken up by other neurons. Since neurodegenerative diseases have typical progression patterns, knowing how alpha-synuclein moves between neurons in the brain helps researchers understand disease propagation.
Previous work from the Rhoades lab implicated the presence of a glycan binding site on alpha-synuclein. This finding, combined with Birol’s experience in analyzing protein-membrane interactions, led to this study of how alpha-synuclein interacts with cell membranes.
Birol was able to enzymatically remove specific glycans from the cell surface to see how their presence or absence would change how alpha-synuclein was taken up by neurons. The study found that when glycans were removed, the amount of alpha-synuclein clusters taken up by cells was greatly reduced.
And by analyzing giant plasma membrane vesicles, synthetic membranes derived from components of real cells that have the same protein and lipid composition, Birol was also able to see the detailed physical interactions between alpha-synuclein and glycans. “There’s a structural basis for the alpha-synuclein binding to the glycan, and when the glycans are removed, it changes the nature of the interaction of alpha-synuclein with the cell membrane,” explains Rhoades.
This research focused on the acetylated form of alpha-synuclein proteins, which is present in both healthy and diseased neurons and is less frequently studied. They found that the acetylated form was more effective at forming clusters of proteins inside neurons and was required for interactions with glycans. “No one’s really stressed the importance of these acetylated versions,” Birol says. “Generally, we need take a step back in trying to understand how this protein may be propagating between cells, and I think glycans could be an aspect.”
Rhoades and Birol say that the most unexpected finding was the discovery of neurexin 1? as a potential partner in how alpha-synuclein is taken up by neurons. They hope that future research on this presynaptic protein could provide insights into new treatment strategies for Parkinson’s and other neurodegenerative diseases.
In the near term, Rhoades and her group hope to obtain higher-resolution structural information of alpha-synuclein proteins bound to glycans. They also hope that this study will inspire future research on alpha-synuclein acetylation and the role of glycans in the progression of the disease and will provide an impetus to look at previously unstudied protein modifications that might be connected to Parkinson’s disease.
“Some cells spontaneously internalize these [alpha-synuclein] proteins and some do not. It has generally been assumed that there are alpha-synuclein specific receptors on the cells that do internalize aggregates. That may or may not be true, but [our study] suggests that it’s not just the protein receptors but the glycans that are also important,” says Rhoades.
This research was supported by the Michael J. Fox Foundation for Parkinson’s Research.
Story Source:
Materials provided by University of Pennsylvania. Note: Content may be edited for style and length.
Journal Reference:
- Melissa Birol, Slawomir P. Wojcik, Andrew D. Miranker, Elizabeth Rhoades. Identification of N-linked glycans as specific mediators of neuronal uptake of acetylated α-Synuclein. PLOS Biology, 2019; 17 (6): e3000318 DOI: 10.1371/journal.pbio.3000318
Homing instinct applied to stem cells show cells ‘home’ to cardiac tissue
In a world first, scientists have found a new way to direct stem cells to heart tissue. The findings, led by researchers at the University of Bristol and published in Chemical Science, could radically improve the treatment for cardiovascular disease, which causes more than a quarter of all deaths in the UK.
To date, trials using stem cells, which are taken and grown from the patient or donor and injected into the patient’s heart to regenerate damaged tissue, have produced promising results.
However, while these next generation cell therapies are on the horizon, significant challenges associated with the distribution of the stem cells have remained. High blood flow in the heart combined with various ’tissue sinks’, that circulating cells come into contact with, means the majority of the stem cells end up in the lungs and spleen.
Now, researchers from Bristol’s School of Cellular and Molecular Medicine have found a way to overcome this by modifying stem cells with a special protein so they ‘home’ to heart tissue.
Dr Adam Perriman, the study’s lead author, Associate Professor in Biomaterials, UKRI Future Leaders Fellow and founder of the cell therapy technology company CytoSeek, explained: “With regenerative cell therapies, where you are trying to treat someone after a heart attack, the cells rarely go to where you want them to go. Our aim is to use this technology to re-engineer the membrane of cells, so that when they’re injected, they’ll home to specific tissues of our choice.
“We know that some bacterial cells contain properties that enable them to detect and ‘home’ to diseased tissue. For example, the oral bacterial found in our mouths can occasionally cause strep throat. If it enters the blood stream it can ‘home’ to damaged tissue in the heart causing infective endocarditis. Our aim was to replicate the homing ability of bacteria cells and apply it to stem cells.”
The team developed the technology by looking at how bacterial cells use a protein called an adhesin to ‘home’ to heart tissue. Using this theory, the researchers were able to produce an artificial cell membrane binding version of the adhesin that could be ‘painted’ on the outside of the stem cells. In an animal model, the team were able to demonstrate that this new cell modification technique worked by directing stem cells to the heart in a mouse.
Dr Perriman added: “Our findings demonstrate that the cardiac homing properties of infectious bacteria can be transferred to human stem cells. Significantly, we show in a mouse model that the designer adhesin protein spontaneously inserts into the plasma membrane of the stem cells with no cytotoxity, and then directs the modified cells to the heart after transplant. To our knowledge, this is the first time that the targeting properties of infectious bacteria have been transferred to mammalian cells.
“This new technique carries enormous potential for the seven million people currently living with heart disease in the UK.”
Dr Perriman’s UKRI Future Leaders fellowship is based on research funded by the Elizabeth Blackwell Institute-funded Catalyst project. He is also a member of the University’s BrisSynBio, a multi-disciplinary research centre part of the Bristol BioDesign Institute, that focuses on the biomolecular design and engineering aspects of synthetic biology.
Dr Perriman is well-known for his pioneering research on the construction and study of novel synthetic biomolecular systems for regenerative engineering.
Story Source:
Materials provided by University of Bristol. Note: Content may be edited for style and length.
Journal Reference:
- Wenjin Xiao, Thomas I. P. Green, Xiaowen Liang, Rosalia Cuahtecontzi Delint, Guillaume Perry, Michael S. Roberts, Kristian Le Vay, Catherine R. Back, Raimomdo Ascione, Haolu Wang, Paul R. Race, Adam W. Perriman. Designer artificial membrane binding proteins to direct stem cells to the myocardium. Chemical Science, 2019; DOI: 10.1039/C9SC02650A
4 surprising ways to get a sunburn, and 6 ways to treat it
When University of Alberta dermatologist Robert Gniadecki was growing up in Denmark, getting a sunburn was part of every family holiday.
“The first day at the seaside you would go out in the sunshine, and the next day you would have a bonfire, peel your skin off and throw it in the fire,” he said.
“It’s so disgusting, when you think about it today, but 40 years ago this was a normal thing.”
Gniadecki said these days most of us know that even a tan is a sign of skin cell damage, but sunburn still sneaks up on us from time to time. He shared four surprising ways people can get burned:
Foods that increase your UV sensitivity
Turns out “margarita sunburn” isn’t just a reference to what happens when snowbirds roast on Mexican beaches. There’s a naturally occurring chemical called furocoumarin in limes, some kinds of carrots, celery, dill and other plants that, when ingested, causes your skin to become more sensitive to the sun’s harmful rays.
“And of course people often fall asleep after having a couple of drinks, which doesn’t help either,” said Gniadecki. “A simple thing like sleeping in the sun is terribly dangerous.”
Unexpected weather changes
It even happens to dermatologists.
“I was on a rainy winter hike in the mountains,” Gniadecki said. “Then the clouds cleared and I was left on a snow patch with no protection.”
More UV than you realized
Most of us realize the sun’s rays are stronger at the equator than in our own backyard, and weaker at sunset than at high noon—it’s all about the angle of the sun. What we may not realize is how ultraviolet light is concentrated when we are on water, sand or even snow.
“People often think that in winter, because it’s cold and you don’t feel the warmth of the sun, you will never get a sunburn or you can tolerate more sun,” Gniadecki said. “You can actually tolerate less sun during the winter because of the reflection from the snow.”
He said that sun exposure is almost doubled in the snow, compared with being on grass, while sand reflects 15 to 20 percent more and seawater reflects 25 percent more UV than grass.
Sunscreen spread too thinly
Gniadecki said you need to apply enough sunscreen to create a sheen all over your skin. If you’re using sunscreen that contains titanium or zinc oxide, a white hue should be visible. Be sure to use a product with a sun protection factor (SPF) of at least 20, which lets through just 1/20th of the sun’s harmful rays. That means that if you would normally start to burn in 10 minutes, you can stay out in the sun for 200 minutes. But be realistic about how long your exposure will be, and reapply your sunscreen if you get wet.
“If you sweat a lot, some will wash away, and you can get a sunburn,” said Gniadecki.
He recommended avoiding sunscreens that contain oxybenzone, a common ingredient that was recently shown to be absorbed through the skin into the bloodstream. Gniadecki suggested using other products until the health effects of oxybenzone are better known.
Treating a sunburn
Gniadecki recommends staying away from household remedies—such as applying cooking oil or yogurt, or the Danish prescription of putting lemon slices on your skin—which are not only ineffective, but could also be harmful. He suggests the following steps instead:
- Cool the skin with a damp cloth.
- Apply a fragrance-free moisturizer or even an over-the-counter hydrocortisone cream.
- Take oral ibuprofen. (Don’t use topical painkillers such as those branded with “caine.”)
- Rehydrate by drinking lots of water.
- If you have small blisters, apply a topical antibiotic to prevent infection.
- See a doctor if you are vomiting or if large blisters develop a crust and are visibly infected.
“The short-term effects of sunburn are trivial and you can usually manage them at home,” said Gniadecki, who is also a member of the Cancer Research Institute of Northern Alberta. “But the long-term effects are serious.”
Sunburn, especially in childhood, causes permanent and irreparable damage to the skin that can develop into cancer 20 or 30 years later.
“The skin will remember forever,” said Gniadecki.
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