Tag: Lungs

Researchers identify new therapeutic for patients with a rare autoimmune disease EGPA

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An international team, including researchers from McMaster University and St. Joseph’s Healthcare Hamilton, has identified a new therapeutic for patients with a rare autoimmune disease called eosinophilic granulomatosis with polyangiitis (EGPA). A biologic drug called benralizumab has been shown to be non-inferior to mepolizumab in the treatment of EGPA.

In a clinical trial involving 140 patients with the rare disease, researchers directly compared two biologic drugs, mepolizumab and benralizumab. Patients received monthly subcutaneous injections of either 300 mg of mepolizumab or 30 mg of benralizumab for one year. The findings of the trial were published on Feb. 23, 2024, in the New England Journal of Medicine.

Our findings show that benralizumab was just as effective as mepolizumab at reducing exacerbations and providing disease remission during the 52 weeks of the study.”

Parameswaran Nair, professor with McMaster’s Department of Medicine and respirologist at St. Joe’s Firestone Institute for Respiratory Health

Nair was one of the study’s principal investigators who led the Canadian team. He worked closely with Nader Khalidi, a professor with McMaster’s Department of Medicine and a rheumatologist with St. Joe’s, to design the study and recruit patients.

“The single 30 mg subcutaneous dosing of benralizumab offers an advantage to patients over the three 100 mg subcutaneous dosing of mepolizumab,” says Nair.

EGPA, also known as Churg-Strauss Syndrome, is a rare autoimmune disease caused by inflammation of small and medium sized blood vessels and is associated with very high blood and tissue eosinophil counts. This can lead to damage of the lungs, skin, heart, gastrointestinal tract, and nerves. Most patients with EGPA experience breathing and lung issues.

The researchers noted that approximately 16 per cent more patients in the benralizumab group were able to abstain from using oral corticosteroids compared to the mepolizumab group. Typically, patients with EGPA use oral corticosteroids like prednisone for symptom control despite the adverse effects.

“Without biologics, we’re relying predominantly on oral corticosteroids to control EGPA symptoms. Prolonged treatment with prednisone reduces the risk of a relapse of EGPA symptoms, but it comes with progressive toxic effects,” says Khalidi. “In our study, treatment with benralizumab allowed more patients to discontinue prednisone over a 52-week period compared to mepolizumab.”

Mepolizumab and benralizumab are biologic drugs. Biologics are a class of drugs that come from living organisms or from their cells, often made using biotechnology.

The two biologics used in this study work by targeting either the signals or the receptors of eosinophils, a type of immune cell that is found in high concentrations in the blood and tissue of EGPA patients. By blocking the signals or receptors that draw eosinophils into various tissues, such as the lungs, mepolizumab and benralizumab effectively decrease eosinophils, reducing symptoms.

“Benralizumab was associated with greater blood eosinophil depletion than mepolizumab from week one onwards,” says Nair. “Both drugs were well tolerated without any new adverse events.”

The study builds on a long history of research on eosinophilic conditions from the Firestone Institute for Respiratory Health at St. Joe’s. Pioneering work into the study of severe eosinophilic asthma by Freddy Hargreave led to a method for enumerating eosinophils in sputum samples for accurate asthma diagnoses.

For patients with severe prednisone-dependent asthma, Hargreave, Nair, and their colleagues were the first to demonstrate the efficacy of mepolizumab in 2009. By 2017, Nair had further demonstrated the efficacy of benralizumab for the same condition. Both landmark studies were published in the New England Journal of Medicine.

“It is very gratifying that our research program at the Firestone Institute at St. Joe’s has led to the development of these new treatment options for patients with severe eosinophilic diseases,” Nair says.

Funding for this study was provided by AstraZeneca.

Source:

Journal reference:

Wechsler, M. E., et al. (2024). Benralizumab versus Mepolizumab for Eosinophilic Granulomatosis with Polyangiitis. The New England Journal of Medicine. doi.org/10.1056/nejmoa2311155.

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February 24, 2024
Fluid-filled lung sac found to be the hub for virus-eating cells

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Scientists have long thought of the fluid-filled sac around our lungs merely as a cushion from external damage. Turns out, it also houses potent virus-eating cells that rush into the lungs during flu infections.

Not to be confused with phages, which are viruses that infect bacteria, these cells are macrophages, immune cells produced in the body.

“The name macrophage means ‘big eater.’ They gobble up bacteria, viruses, cancer cells, and dying cells. Really, anything that looks foreign, they take it up and destroy it,” said UC Riverside virologist Juliet Morrison, who led the discovery team. “We were surprised to find them in the lungs because nobody has seen this before, that these cells go into the lung when there’s an infection.”

A paper published in the Proceedings of the National Academy of Sciences details how during an influenza infection, macrophages leave the exterior cavity and cross into the lungs where they decrease inflammation and reduce levels of disease.

This study shows it’s not just what happens in the lung that matters, but also what’s outside of the lung. Cell types not normally connected to the lung can have outsized impacts on lung disease and health.”

Juliet Morrison, UC Riverside virologist

There are three main cavities in the body: one around the heart, the abdominal cavity, and the pleural cavity surrounding the lungs. “Because it contains fluid, it prevents the lungs from collapsing. However, people have not thought much about the pleural cavity being a whole organ within itself. This research may change that perception,” Morrison said.

Initially, the researchers set out to understand the more general question of what types of cells are present in the lungs during flu infections. They took existing data on lung-related genes from studies of mice that either died from the flu or survived. They then mined the data using an algorithm to predict cell types that change in the lungs during infections.

“We took big data and broke it down to assign which potential immune cells are in the lung tissues. That’s where I got a hint that maybe we had a previously unknown external source of cells in the lung,” Morrison said.

Next, using a laser-based technique, the team tracked macrophages going into the lungs of mice, and observed what happened if they took these cells out of the equation. “When you take them out of the mouse you see more disease and more lung inflammation,” Morrison said.

Morrison says she hopes this study will encourage other scientists to reevaluate data sets from older studies. “Our approach was to take information already out there and put it to new use, and we were able to see something new,” she said.

Moving forward, the research team is hoping to determine which proteins “tell” the macrophages to move into the lungs. Once the protein signals have been identified, it may be possible to create drugs that boost either the number of macrophages, or their activity.

The strategy of boosting human defenses to infection, rather than developing another antiviral, could offer people a flu treatment that would be more effective for much longer. Morrison became interested in host therapeutics because antibiotic and antiviral resistance to drugs is a growing problem.

This problem occurs when germs like bacteria and fungi develop the ability to defeat the drugs designed to kill them. Misuse and overuse of the drugs is accelerating the problem. According to the Centers for Disease Control and Prevention, more than 2.8 million drug-resistant infections occur each year in the U.S., and more than 35,000 people die as a result.

“If we can boost what resolves infection in us, we probably have a better shot. We’re less likely to have resistance. The immune system is so complicated, but it’s our best bet in the long run to work with what we have rather than chase viruses that continue to escape our therapeutics,” Morrison said.

Source:

University of California – Riverside

Journal reference:

Stumpff, J. P., et al. (2023). Pleural macrophages translocate to the lung during infection to promote improved influenza outcomes. PNAS. doi.org/10.1073/pnas.2300474120.

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February 14, 2024
New guideline aims to improve diagnosis and treatment of cryptococcosis

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A group of international mycology experts led by Professor Dr Oliver A. Cornely at the University of Cologne has jointly drafted a guideline for the diagnosis and treatment of cryptococcosis, which aims at improving infection management and thus the survival rate of patients. Cryptococcosis is a fungal infection of mainly the lungs that might lead to meningitis. The article ‘Global guideline for the diagnosis and management of cryptococcosis’ was published in the journal The Lancet Infectious Diseases.

Cryptococcosis, especially cryptococcal meningitis (CM) as the most fatal form, is responsible for a high fatality rate among patients. It is one of the most widespread invasive fungal infections in the world and is a major threat particularly to people suffering from immunodeficiencies. For example, around one million cases of cryptococcal meningoencephalitis are diagnosed worldwide every year in people with HIV alone, and more than 600,000 people die from the disease each year. Patients who have undergone a bone marrow transplant or organ transplant are also at high risk of infection. It is transmitted through the inhalation of spores from soil. Other organs are then also infected via the bloodstream. The lungs, brain, skin and bones are most frequently affected.

Invasive fungal infections are often difficult to recognize in everyday work in clinics because they occur so rarely. However, it is particularly important for patients at risk to be treated quickly and appropriately. At the same time, we must not forget that the conditions for recognizing the infection at an early stage are not equally good everywhere in the world and that resources are sometimes very limited. There are many countries with a high number of cases that are poorly equipped in this respect. As part of our Global Guideline Programme, we would like to contribute to improving this situation.”

Dr Oliver A. Cornely from Department I of Internal Medicine at University Hospital Cologne and Director of the Institute of Translational Research at the University of Cologne’s CECAD Cluster of Excellence for Aging Research

The cryptococcosis guideline is designed to support medical staff in handling invasive fungal infections. It is intended to provide practical guidance and support in decision-making and thus improve clinical approaches, diagnosis, management, and aftercare for the benefit of patients.

The project was carried out by the mycological societies ECMM (European Confederation of Medical Mycology) and ISHAM (International Society for Human and Animal Mycology) in collaboration with the ASM (American Society for Microbiology). “More than 70 other international specialist institutions were involved in developing this new guideline. This is a great help for our scientific work and shows how great the interest, but also the need for such recommendations is,” explained Cornely. Authors from 22 countries contributed to this guideline. Dr Christina Chang from Monash University in Melbourne, Australia, and Professor Dr John Robert Perfect from Duke University in Durham, USA, were in charge of the project.

Invasive fungal infections are emergencies. However, as a single pathogen often only occurs very rarely, it is often only discovered late. But patients’ lives depend on rapid detection and well-practiced procedures. Since 2017, University Hospital Cologne has been home to one of the European Centres of Excellence recognized by the ECMM. At the center, patients have access to modern testing procedures and treatment options. In addition, the experts under the direction of Professor Cornely serve as advisory contacts for colleagues in Germany and abroad.

Source:

Journal reference:

Chang, C. C., et al. (2024). Global guideline for the diagnosis and management of cryptococcosis: an initiative of the ECMM and ISHAM in cooperation with the ASM. The Lancet Infectious Diseases. doi.org/10.1016/s1473-3099(23)00731-4.

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February 14, 2024
Drug repurposing study finds lonafarnib effective against RSV

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In a study published in the journal Nature Communications, researchers screened ReFRAME (short for repurposing, focused rescue, and accelerated Medchem), a drug-repurposing library, for drugs against respiratory syncytial virus (RSV). They identified lonafarnib as a potent inhibitor of RSV fusion protein and investigated its therapeutic potential against an RSV infection.

Study: Drug repurposing screen identifies lonafarnib as respiratory syncytial virus fusion protein inhibitor. Image Credit: joshimerbin / Shutterstock

Background

RSV causes severe lower respiratory tract infections in young children, immunosuppressed individuals, and older adults, with millions of annual hospital admissions and deaths. The recent coronavirus disease 2019 (COVID-19) pandemic and associated interventions have led to altered RSV epidemiology, with a transient suppression and resurgence of RSV circulation, raising concerns about increased infections.

RSV infection treatment is currently symptomatic. While ribavirin shows in vitro efficacy, it is not very efficacious in patients. Palivizumab provides prophylaxis but is costly, offers only a partial reduction in hospitalization rates, and faces challenges like rapid resistance development. Although nirsevimab was recently approved for RSV prevention in newborns, there remains a dearth of therapeutic options.

Various antiviral strategies against RSV, including immunoglobulins, are being developed. Repurposing libraries containing licensed drugs or compounds in clinical development serve as repositories with potential for accelerated therapeutic applications. Researchers in the present study screened the ReFRAME library and identified lonafarnib as an RSV fusion protein inhibitor while demonstrating its therapeutic ability.

About the study

The library (of 12,000 molecules) was screened using a recombinant RSV subtype A strain GFP (short for green fluorescent protein) reporter virus. Cell viability was determined using an MTT (short for 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide) assay. The primary hit criteria were RSV infection ≤ 16% and cell viability ≥ 80%. Fourteen molecules met the primary criteria, and 16 additional molecules were selected. Two farnesyl-S-transferase inhibitors, lonafarnib, and tipifarnib, were evaluated and compared for their inhibitory effects on RSV infection. To identify the potential viral target of lonafarnib, passages of the RSV reporter virus were conducted with increasing doses of lonafarnib. The resulting virus populations were sequenced, and mutations were analyzed. The study additionally involved orthogonal infection assays, plaque reduction assays, RSV lentiviral pseudotype assays, and RSV F protein cell-to-cell membrane fusion assays. Surface plasmon resonance and crystallization experiments were conducted to investigate the interaction of lonafarnib with a recombinant RSV subtype A pre-fusion F protein.

Therapeutic effects of lonafarnib were evaluated by inoculating A549 cells with HRSV-A-GFP, treating with lonafarnib or ribavirin 24 hours post-inoculation, and monitoring virus spread over time. The drug’s effect in a more natural model of RSV infection and cell entry was investigated using the immortalized human basal cell line BCi-NS1.1, which was further differentiated into the pseudostratified ciliated epithelium.

Six mice were treated with oral lonafarnib or solvent control and infected with an RSV reporter virus. The animals’ weight was monitored, and on day 4, tissues were extracted, and lung RSV copy number was measured.

A Screening and validation procedure. B HEp-2 cells were infected with rHRSV-A-GFP in presence of 5 µM compound. 48 hours later, infection and cell viability were quantified via GFP and MTT readouts. Dotted lines indicate primary hit criteria and dots represent means of two technical replicates. C HEp-2 cells were infected with HRSV-A-Luc at MOI 0.01 and treated with the indicated compound concentrations. 24 hours later, supernatant was transferred onto new cells for a second round of infection. Luminescence was quantified 24 hours post inoculation of both infection rounds. Cell viability was measured via MTT readout in treated, but uninfected cells. Mean ± SD of three independent experiments. Known RSV inhibitors (F protein: presatovir; N protein: RSV604, IMPDH inhibitors (AVN944, mycophenolic acid), HSP90 inhibitors (radiciol, HSP990). 4-Sulfocalix[6]arene Hydrate (4SC6AH, unknown target). Source data are provided as a Source Data file.

Results and discussion

Twenty-one molecules, including lonafarnib, demonstrated antiviral activity against RSV. Lonafarnib is approved for Hutchinson-Gilford progeria syndrome and is in phase III clinical trials for hepatitis delta virus infections. Lonafarnib, but not tipifarnib, demonstrated inhibition of RSV infection, as evidenced by reduced reporter virus activity, plaque reduction, and suppressed syncytia formation in infected cells. Further, lonafarnib, not tipifarnib, was found to interact with the pre-fusion F protein in a binding site that has been previously observed for other fusion inhibitors.

Lonafarnib-exposed virus populations accumulated two coding mutations (T335I and T400A) within the RSV fusion protein, leading to phenotypic resistance to lonafarnib. Further, lonafarnib was found to inhibit RSV’s entry into the cells by binding to the fusion protein and inhibiting membrane fusion. This inhibition was found to be overcome by resistance mutations in the fusion protein.

In vitro, combinations of lonafarnib and ribavirin showed minor inhibitory or slightly synergistic activity at selected doses. Lonafarnib treatment post-inoculation in A549 cells restricted the spread of the HRSV GFP virus by 30% as compared to controls. In the BCi-NS1.1 cell culture model, prophylactic lonafarnib treatment from both the apical and basolateral sides dose-dependently inhibited RSV infection, resulting in a 10- to 15-fold reduction in virus load. Therapeutic application of lonafarnib only from the basolateral side also reduced virus load by approximately 50% in a clinical RSV isolate infection.

In vivo, lonafarnib-treated animals showed a significantly reduced reporter virus signal in the lung and nose compared to controls. On day 4, a dose-dependent decline was observed in viral ribonucleic acid in the lungs of treated mice, and there was a lesser weight loss compared to controls. However, cellular infiltrates were observed in the lungs of lonafarnib-treated mice.

Conclusion

In conclusion, the study identified lonafarnib as a potential therapeutic candidate for RSV treatment, highlighting the utility of drug-repurposing studies. The findings demonstrate the promising antiviral activity of lonafarnib in cell culture as well as mice models of RSV infection. Further research is warranted to confirm the findings.

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February 12, 2024
Study shows how low dose of cadmium produces deleterious stress in lung epithelial cells

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Cigarette smoke exposure is associated with the development and severity of chronic obstructive pulmonary disease, or COPD, which is the third leading cause of death worldwide.

Cigarette smoke contains 2 to 3 micrograms of cadmium, a highly toxic metal and environmental pollutant, per cigarette. Burning tobacco releases cadmium oxide that can be adsorbed onto microparticles in smoke that travel deep into the lungs. Furthermore, the body is not able to remove cadmium, which accumulates in longtime smokers.

In a Scientific Reports study, University of Alabama at Birmingham researchers show how a low dose of cadmium produces a deleterious stress in lung epithelial cells, and their findings highlight potential therapeutic targets to be explored in cadmium-exposure and subsequent lung injury.

The research, led by Veena Antony, M.D., a professor in the UAB Department of Medicine, focuses on microRNA-381, and the expression of a chloride channel gene called ANO1 in lung tissue samples and airway epithelial cells. ANO1 helps produce mucus in the airway; but overproduction of mucus in chronic lung disease can lead to airway thickening and mucus blockage, adding to severity of the disease. Thus, overexpression of ANO1 can exacerbate COPD.

The UAB researchers compared lung tissue samples from nine “never” smokers, who had zero history of cigarette smoking, and lung tissue samples from 13 “ever” smokers with COPD who had a history of smoking that ranged from 15 to 25 pack years per person. One pack year is generally defined as smoking one pack of cigarettes a day for one year. The researchers found that “ever” smokers, in contrast to “never” smokers, had upregulated ANO1 expression in airway epithelial cells.

Similarly, airway epithelial cells in a bronchoalveolar lavage fluid from one non-COPD subject and one smoker with COPD showed greater ANO1 expression in the COPD-subject cells.

The researchers next tested the direct effect of very low doses of cadmium on normal human airway epithelial cells. These cells were grown on an air-liquid interface that allows the airway cells to differentiate normally. Two weeks of exposure to 0.5 or 1.0 micromolar cadmium chloride in the liquid layer increased expression of ANO1 12 to 14 times.

MicroRNAs have the ability to downregulate expression of a gene by direct interaction with that gene’s mRNA sequence. The UAB team used computer software analysis to identify microRNA-381 as the microRNA with most interaction with ANO1 mRNAs, suggesting that microRNA-381 is a negative regulator of ANO1. Some heavy metals are known to negatively regulate microRNAs.

Antony and colleagues used a synthetic inhibitor for microRNA-381 to inhibit the expression of microRNA-381 in primary human airway epithelial cells from subjects with COPD, and found that ANO1 expression was upregulated significantly. In contrast, adding a microRNA-381-mimic -; a synthetic RNA that acts like microRNA-381 to increase the amount of negative regulation -; to those cells decreased ANO1 expression. These results strengthened the premise of the UAB researchers that cadmium negatively regulates microRNA-381 expression to upregulate ANO1 expression in airway epithelial cells.

Lastly, researchers found that, even when primary human airway epithelial cells from subjects with COPD were also exposed to 1 micromolar cadmium chloride, the microRNA-381 inhibitor still upregulated ANO1 and the mimic still downregulated ANO1.

Our observations from experiments involving low-dose cadmium-exposure of epithelial cells suggest that ANO1 is a direct target for miR-381, which is downregulated upon low-dose cadmium exposure. Thus, cigarette-induced cadmium-toxicity may alter cellular homeostasis mechanisms at very low concentrations, and cadmium-exposure in a person with an existing pulmonary condition can have an additive or adverse effect with increased susceptibility toward infections and environmental allergens.

This interaction of cadmium, microRNA-381 and ANO1 suggests that microRNAs may act as potential therapeutic targets to be explored further in cadmium-exposure and subsequent lung injury.”

Veena Antony, M.D., Professor, UAB Department of Medicine

At UAB, Antony holds the Endowed Professorship in Environmental Medicine, directs the Superfund Research Center, and is a member of the Division of Pulmonary, Allergy and Critical Care Medicine.

Co-authors with Antony in the study, “Low dose cadmium exposure regulates miR‑381–ANO1 interaction in airway epithelial cells,” are Pooja Singh, Fu Jun Li, Kevin Dsouza, Crystal T. Stephens, Huaxiu Zheng and Mark T. Dransfield, UAB Department of Medicine Division of Pulmonary, Allergy and Critical Care Medicine; and Abhishek Kumar, UAB Superfund Center Advisory Board, Gainesville, Florida.

Support came from National Institute of Environmental Health Sciences grant ES027723.

Source:

University of Alabama at Birmingham

Journal reference:

Singh, P., et al. (2024). Low dose cadmium exposure regulates miR-381–ANO1 interaction in airway epithelial cells. Scientific Reports. doi.org/10.1038/s41598-023-50471-z.

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February 3, 2024
The FTC is attacking drugmakers’ ‘patent thickets’

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The Federal Trade Commission has challenged the validity of over 100 drug product patents, focusing on devices used to deliver medicines, like inhalers and autoinjectors, in an effort to increase competition and potentially lower some prices.

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January 31, 2024