SPOKANE, Wash. – Scientists used human white blood cell membranes to carry two drugs, an antibiotic and an anti-inflammatory, directly to infected lungs in mice.
The nano-sized drug delivery method developed at Washington State University successfully treated both the bacterial growth and inflammation in the mice’s lungs. The study, recently published in Communications Biology, shows a potential new strategy for treating infectious diseases, including COVID-19.
“If a doctor simply gives two drugs to a patient, they don’t go directly to the lungs. They circulate in the whole body, so potentially there’s a lot of toxicity,” said Zhenjia Wang, the study’s corresponding author and an associate professor in WSU’s College of Pharmacy and Pharmaceutical Sciences. “Instead, we can load the two types of drugs into these vesicles that specifically target the lung inflammation.”
Wang and his research team have developed a method to essentially peel the membrane from neutrophils, the most common type of white blood cells that lead the body’s immune system response. Once emptied, these membranes can be used as nanovesicles, tiny empty sacks only 100 to 200 nanometers wide, which scientists can then fill with medicine.
These nanovesicles retain some of the properties of the original white blood cells, so when they are injected into a patient, they travel directly to the inflamed area just as the cells would normally, but these nanovesicles carry the medicines that the scientists implanted to attack the infection.
In this study, first author Jin Gao, a WSU research associate, loaded the nanovesicles with an antibiotic and resolvinD1, an anti-inflammatory derived from Omega 3 fatty acids, to treat lungs infected by P. aeruginosa, a common potentially fatal pathogen patients can catch in hospital settings. The researchers used two drugs because lung infections often create two problems, the infection itself and inflammation created by a strong immune system response.
Toxicity studies and clinical trials would have to be conducted before this method could be used in human patients, but this study provides evidence that the innovation works for lung inflammation. If the method is ultimately proven safe and effective for humans, Wang said the nanovesicles could be loaded with any type of drug to treat a range of infectious diseases, including COVID-19.
“I think it’s possible to translate this technology to help treat COVID-19,” said Wang. “COVID-19 is a virus, not a bacterial pathogen, but it also causes an inflammation response in the lung, so we could load an antiviral drug like remdesivir into the nanovesicle, and it would target that inflammation.”
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Strong emotions such as fear and anxiety tend to be accompanied and reinforced by measurable bodily changes including increased blood pressure, heart rate and respiration, and dilation of the eyes’ pupils. These so-called “physiological arousal responses” are often abnormally high or low in psychiatric illnesses such as anxiety disorders and depression. Now scientists at the UNC School of Medicine have identified a population of brain cells whose activity appears to drive such arousal responses.
The scientists, whose study is published in Cell Reports, found that artificially forcing the activity of these brain cells in mice produced an arousal response in the form of dilated pupils and faster heart rate, and worsened anxiety-like behaviors.
The finding helps illuminate the neural roots of emotions, and point to the possibility that the human-brain counterpart of the newly identified population of arousal-related neurons might be a target of future treatments for anxiety disorders and other illnesses involving abnormal arousal responses.
“Focusing on arousal responses might offer a new way to intervene in psychiatric disorders,” said first author Jose Rodríguez-Romaguera, PhD, assistant professor in the UNC Department of Psychiatry and member of the UNC Neuroscience Center, and co-director of the Carolina Stress Initiative at the UNC School of Medicine.
Rodríguez-Romaguera and co-first author Randall Ung, PhD, an MD-PhD student and adjunct assistant professor in the Department of Psychiatry, led this study when they were members of the UNC laboratory of Garret Stuber, PhD, who is now at the University of Washington.
“This work not only identifies a new population of neurons implicated in arousal and anxiety, but also opens the door for future experiments to systematically examine how molecularly defined cell types contribute to complex emotional and physiological states,” Stuber said. “This will be critical going forward for developing new treatments for neuropsychiatric disorders.”
Anxiety disorders, depression, and other disorders featuring abnormally high or low arousal responses affect a large fraction of the human population, including tens of millions of adults in the United States alone. Treatments may alleviate symptoms, but many have adverse side effects, and the root causes of these disorders generally remain obscure.
Untangling these roots amid the complexity of the brain has been an enormous challenge, one that laboratory technology has only recently begun to surmount.
Rodríguez-Romaguera, Ung, Stuber and colleagues examined a brain region within the amygdala called the BNST (bed nucleus of the stria terminalis), which has been linked in prior research to fear and anxiety-like behaviors in mice.
Increasingly, scientists view this region as a promising target for future psychiatric drugs. In this case, the researchers zeroed in on a set of BNST neurons that express a neurotransmitter gene, Pnoc, known to be linked to pain sensitivity and more recently to motivation.
The team used a relatively new technique called two-photon microscopy to directly image BNST Pnoc neurons in the brains of mice while the mice were presented with noxious or appealing odors — stimuli that reliably induce fear/anxiety and reward behaviors, respectively, along with the appropriate
Researchers have discovered an imbalance in the amounts of fatty molecules called lipids inside the brain cells of people with Parkinson’s disease. A buildup of lipids in nerve cells may cause inflammation.
Parkinson’s disease is a movement disorder that gets progressively worse over time.
The death of dopamine-producing nerve cells in the substantia nigra region of the brain causes the illness. Dopamine is a neurotransmitter that plays several vital roles, including regulating motivation, reward, and movement.
However, the exact train of events leading to the death of dopamine-producing cells remains unclear.
Researchers have focused much of their attention on a misfolded form of a protein called alpha-synuclein as the trigger for Parkinson’s. Studies have found toxic clumps or aggregates of the misfolded protein in the brains of people with the disease.
However, an alternative theory proposes that lipid dysregulation and inflammation play a more important role, similar to the part played by fatty plaques and inflammation in the walls of arteries in cardiovascular disease.
Researchers at the Neuroregeneration Institute at McLean Hospital in Belmont, MA, have now discovered an accumulation of lipids in dopamine-producing neurons in the postmortem brains of people who had Parkinson’s.
The excess amounts of lipid in these nerve cells correlate with changes in lipid levels in neighboring cells called microglia and astrocytes. They also found evidence of inflammation.
When the researchers simulated a breakdown of lipid metabolism in an animal model of the disease, they saw remarkably similar changes.
“These results support our lipid-inflammation hypothesis in the causation of Parkinson’s disease initiation and progression,” says senior author Dr. Ole Isacson, who is the founding director of the Neuroregeneration Institute and a professor of neurology at Harvard Medical School in Boston, MA.
“[The results] may help us discover and develop new therapies by leaving behind conventional thinking about [Parkinson’s disease] pathology, which to some extent has been limited to neurons and protein aggregates,” he adds.
The study appears in the journal Proceedings of the National Academy of Sciences.
The scientists compared postmortem brain tissue from 26 individuals with Parkinson’s with 23 age-matched controls without the disease.
They used fluorescent lipid-binding molecules to determine lipid levels in different brain cells in the substantia nigra.
In brain tissue from people with Parkinson’s, there was an accumulation of lipids inside dopamine nerve cells, which was matched by a deficiency of lipids within astrocytes in the same samples.
Astrocytes are star-shaped cells that support nerve cells, both structurally and through the exchange of nutrients and their byproducts.
In their paper, the researchers note that nerve cells have a limited capacity to use lipids for energy, with excess amounts being transported to neighboring astrocytes to avoid the buildup of toxic byproducts.
This did not seem to be happening correctly in the brains of individuals with Parkinson’s.
Compared with healthy brain tissue, the scientists also found excess amounts of lipid inside microglia, which are the brain’s immune cells.
They also discovered high levels of a signaling molecule called GPNMB. Scientists know that
— Creating new category of cellular medicines —
Be Biopharma (“Be Bio”), a leader in developing B cells as medicines, founded by Longwood Fund, David Rawlings, MD, and Richard James, PhD, today announced a $52 million Series A financing led by Atlas Venture and RA Capital Management and joined by Alta Partners, Longwood Fund and Takeda Ventures, Inc. The company plans to use this funding to precisely engineer B cells to treat a range of diseases, building on the pioneering work of Drs. Rawlings and James at Seattle Children’s Research Institute. B cells are prolific protein producers that can be collected from peripheral blood, have a programmable lifetime that could last decades, can target specific tissues, and have broad, customizable functionality.
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David Steinberg, CEO, co-founder & director, Be Bio; general partner, Longwood Fund (Photo: Business Wire)
“Be Bio is capitalizing on the unique attributes of B cells to create a new category of medicine that is distinct from traditional cell or gene therapy,” said David Steinberg, Chief Executive Officer, co-founder and Director, Be Biopharma and General Partner, Longwood Fund. “B cells can be engineered to express a wide variety of proteins, have the potential to generate durable responses, and can be dose-titrated and administered multiple times without the need for toxic preconditioning. Moreover, the varied functions of B cells suggest that B cell medicines can address a range of conditions including autoimmune diseases, cancer, and monogenic disorders, as well as enhance the immune response to infectious pathogens. We believe Be Bio is at the forefront of a new approach to fighting disease.”
“B cells play a key role in combatting diseases by catalyzing humoral immunity – the arm of the immune system that manufactures large quantities of proteins to neutralize disease-causing pathogens and manipulate immune cell behavior,” said Be Biopharma co-founder David Rawlings, MD, Director, Center for Immunity and Immunotherapies, Seattle Children’s Research Institute and Professor of Pediatrics, University of Washington School of Medicine. “Today, this powerful part of the immune system is only passively and/or indirectly addressed therapeutically. Our ambition is to advance the field by building a new class of engineered B cell medicines that will provide direct control over the power of humoral immunity and help transform the prognosis for patients who currently have limited treatment options.”
In addition to Rawlings, James and Steinberg, Be Bio’s co-founders are Aleks Radovic-Moreno, PhD, President and Director, and Lea Hachigian, PhD, with Longwood Fund. The Board of Directors also includes Josh Resnick, MD, MBA, Managing Director, RA Capital Management; Jason Rhodes, Partner, Atlas Venture; and Dan Janney, MBA, Managing Partner, Alta Partners.
Be Biopharma’s Scientific Advisory Board consists of David Rawlings MD; Richard James, PhD, Principal Investigator, Seattle Children’s Research Institute and Associate Professor, Department of Pediatrics, University of Washington, as well as Frances Eun-Hyung Lee, MD, an Asthma, Allergy, and Immunology physician and researcher in Atlanta, GA; Shiv Pillai, MD, PhD, Professor, Harvard Medical School, Investigator
It is no secret that thousands of laboratories around the world use cells derived from a fetus that was aborted decades ago to develop vital medicines.
But it is a contentious topic in the US, where conservatives and anti-abortion activists have long deemed the practice unethical.
The matter is once more under the spotlight after President Donald Trump was treated for Covid-19 using Regeneron’s antibody treatment. The company used aborted fetal cells as part of its testing process.
“It’s becoming annoying,” Andrea Gambotto, a professor at the University of Pittsburgh, said of the controversy.
Gambotto has used a cell line called HEK 293, the same used by Regeneron, as part of his research for 25 years.
“It’d be a crime to ban the use of these cells,” he added. “It never harmed anybody — it was a dead embryo so the cells back then (were used), instead of being discarded, they were used for research.”
The big advantage of these cells, which were developed in the early 1970s, is that they now represent a “gold standard” in the pharmaceutical industry.
If Gambotto — who is leading a Covid-19 vaccine research project himself — one day succeeds, his vaccine can be produced anywhere in the world, thanks to HEK293.
“You can go to India and make a vaccine for all the world,” he said. To those who call for the development of alternatives, he says, “You don’t need to go back 30 years and reinvent the wheel.”
The original cells were transformed and immortalized in January 1973 by a young Canadian postdoc by the name of Frank Graham, who was working at the time in Leiden, the Netherlands in the laboratory of Professor Alex van der Eb.
Normally, a cell has a finite number of divisions, but Graham managed to modify these cells so that they divide ad infinitum.
This was his 293rd experiment, hence the name of the line (HEK stands for “human embryonic kidney cells”).
“Use of fetal tissue was not uncommon in that period,” Graham, a professor emeritus at Canada’s McMaster University who now lives in Italy, told AFP.
“Abortion was illegal in the Netherlands until 1984 except to save the life of the mother. Consequently I have always assumed that the HEK cells used by the Leiden lab must have derived from a therapeutic abortion.”
Vaccine developers like HEK293 because the cells are malleable and transformable into virus mini-factories. To grow viruses, you always need a host cell. It can be a chicken egg, but human cells are preferable in human medicine.
In the case of Covid-19 vaccines, several makers have used HEK293 to generate what are called “viral vectors.”
These are weakened versions of common cold-causing adenoviruses that are loaded with the genetic instructions for human cells to manufacture a surface protein of the coronavirus. This elicits an immune response that the body remembers when it encounters