Pulmonary Emphysema

While we often think of diseases as caused by foreign bodies -- bacteria or viruses -- there are hundreds of diseases affecting humans that result from errors in cellular production of its proteins. A team of researchers recently leveraged the power of cutting-edge technology, including an innovative technique called glycoproteomics, to unlock the carbohydrate-based code that governs how certain classes of proteins form themselves into the complex shapes necessary to keep us healthy. While we often think of diseases as caused by foreign bodies -- bacteria or viruses -- there are hundreds of diseases affecting humans that result from errors in cellular production of its proteins. A team of researchers led by the University of Massachusetts Amherst recently leveraged the power of cutting-edge technology, including an innovative technique called glycoproteomics, to unlock the carbohydrate-based code that governs how certain classes of proteins form themselves into the complex shapes necessary to keep us healthy. The research, published in the journal Molecular Cell, explores members of a family of proteins called serpins, which are implicated in a number of diseases. The research is the first to investigate how the location and composition of carbohydrates attached to the serpins ensure that they fold correctly. Serious diseases -- ranging from emphysema and cystic fibrosis to Alzheimer's disease -- can result when the cellular oversight of protein folding goes awry. Identifying the glyco-code responsible for high-fidelity folding and quality control could be a promising way for drug therapies to target many diseases. Scientists once thought that the single code governing life was DNA, and that everything was governed by how DNA's four building blocks -- A, C, G and T -- combined and recombined. But in recent decades, it has become clear that there are other codes at work, and especially in building the intricately folded, secreted proteins that are created in the human cell's protein factory, the endoplasmic reticulum (ER), a membrane-enclosed compartment where protein folding begins. Approximately 7,000 different proteins -- one third of all the proteins in the human body -- mature in the ER. The secreted proteins -- collectively known as the "secretome" -- are responsible for everything from our body's enzymes to its immune and digestive systems and must be formed correctly for the human body to function normally. Special molecules called "chaperones," help fold the protein into its final shape. They also help to identify proteins that haven't folded quite correctly, lending them additional help in refolding, or, if they're hopelessly misfolded, targeting them for destruction before they cause damage. However, the chaperone system itself, which comprises a part of the cell's quality control department, sometimes fails, and when it does, the results can be catastrophic for our health. The discovery of the carbohydrate-based chaperone system in the ER was due to the pioneering work that Daniel Hebert, professor of biochemistry and molecular biology at UMass Amherst and one of the paper's senior authors, initiated as a postdoctoral fellow in the 1990s. "The tools we have now, including glycoproteomics and mass spectrometry at UMass Amherst's Institute for Applied Life Sciences, are allowing us to answer questions that have remained open for over 25 years," says Hebert. "The lead author of this new paper, Kevin Guay, is doing things I could only dream of when I first started." Among the most pressing of these unanswered questions is: how do chaperones know when 7,000 different origami-like proteins are correctly folded? We know now that the answer involves an "ER gatekeeper" enzyme known as UGGT, and a host of carbohydrate tags, called N-glycans, which are linked to specific sites in the protein's amino acid sequence. Guay, who is completing his Ph.D. in the molecular cellular biology program at UMass Amherst, focused on two specific mammalian proteins, known as alpha-1 antitrypsin and antithrombin. Using CRISPR-edited cells, he and his co-authors modified the ER chaperone network to determine how the presence and location of N-glycans affected protein folding. They watched as the disease variants were recognized by the ER gatekeeper UGGT and, in order to peer more closely, developed a number of innovative glycoproteomics techniques using mass spectrometry to understand what happens to the glycans that stud the surface of the proteins. What they discovered is that the enzyme UGGT "tags" misfolded proteins with sugars placed in specific positions. It's a sort of code that the chaperones can then read to determine exactly where the folding process went wrong and how to fix it. "This is the first time that we've been able to see where UGGT puts sugars on proteins made in human cells for quality control," says Guay. "We now have a platform for extending our understanding of how sugar tags can send proteins for further quality control steps and our work suggests that UGGT is a promising avenue for targeted drug therapy research." "What's so exciting about this research," says Lila Gierasch, distinguished professor of biochemistry and molecular biology at UMass Amherst and one of the paper's co-authors, "is the discovery that glycans act as a code for protein folding in the ER. The discovery of the role that UGGT plays opens the door to future advancement in understanding and eventually treating the hundreds of diseases that result from misfolded proteins."

CHICAGO , Nov. 28, 2023 /PRNewswire/ -- Smoking marijuana in combination with cigarettes may lead to increased damage of the lung's air sacs, according to research being presented today at the annual meeting of the Radiological Society of North America (RSNA). It is commonly believed that smoking marijuana is not harmful to the lungs. There is an abundance of established research that identifies the harms of cigarette smoking. In contrast, very little is known about the effects of marijuana smoking, and even less research has been done on the combined effects of smoking marijuana and cigarettes. "Marijuana is the most widely used illicit psychoactive substance in the world, and its use has increased in Canada since the legalization of non-medical marijuana in 2018," said study co-author Jessie Kang, M.D., cardiothoracic radiologist and assistant professor in the Department of Diagnostic Radiology at Dalhousie University in Halifax, Nova Scotia, Canada. "Currently, not much research exists on the effects of marijuana smoking on the lungs." To determine the effects of marijuana and cigarette smoking, researchers for the multicenter prospective study examined the chest CT images of four patient groups: non-smokers, cigarette smokers, marijuana smokers, and combined marijuana and cigarette smokers. Marijuana smokers included in the study had smoked marijuana at least four times a month for two years. Patients who ingested marijuana via edibles or oral drops were excluded from the study. The researchers found that people who combined marijuana and cigarettes were 12 times more likely to have centrilobular emphysema than non-smokers. Centrilobular emphysema is a type of pulmonary emphysema where the air sacs within the lungs are damaged. This can lead to breathing difficulties and other serious respiratory symptoms. "The mean number of marijuana smoking years was less than compared to cigarette smokers and combined marijuana and cigarette smokers," Dr. Kang said. "However, marijuana that is smoked is often unfiltered, which can potentially lead to more damaging particles entering the airways and lungs." Combined marijuana and cigarette smokers were three to four times more likely to have airway wall thickening, which can lead to infections, scarring and further airway damage. Association with marijuana only and smoking only with bronchial wall thickening was not as significant. Similar results were seen with centrilobular and paraseptal emphysema, suggesting that the combination of cigarette and marijuana smoking may have a synergistic role on the lungs and airways. "With our study, we show that there are physical effects of marijuana smoking on the lungs and that cigarette smoking and marijuana smoking may have a combined damaging effect on the lungs," Dr. Kang said. According to Dr. Kang, further research is needed to identify the long-term effects of smoking marijuana. "There is a common public misconception that marijuana smoking is not harmful," Dr. Kang said. "More research needs to be done in this area, so the public can make an informed decision on their recreational usage of marijuana." Co-authors are Sebastian Karpinski, B.Sc., Paul Sathiadoss, M.B.B.S., Eric Lam, M.Sc., Eric Hutfluss, M.D., O. Osorio, M.D., D. A. Hashem, M.D., Matthew D. F. McInnes, M.D., and Giselle Y. Revah, M.D. Note: Copies of RSNA 2023 news releases and electronic images will be available online at RSNA.org/press23. RSNA is an association of radiologists, radiation oncologists, medical physicists and related scientists promoting excellence in patient care and health care delivery through education, research and technologic innovation. The Society is based in Oak Brook, Illinois. (RSNA.org) Editor's note: The data in these releases may differ from those in the published abstract and those actually presented at the meeting, as researchers continue to update their data right up until the meeting. To ensure you are using the most up-to-date information, please call the RSNA Newsroom at 1-312-791-6610. For patient-friendly information on chest CT, visit RadiologyInfo.org. SOURCE Radiological Society of North America (RSNA)

Up to 60,000 patients in the United States may have PPF, with only one approved therapy available SILVER SPRING, Md. & RESEARCH TRIANGLE PARK, N.C.--(BUSINESS WIRE)-- United Therapeutics Corporation (Nasdaq: UTHR), a public benefit corporation, announced today that the first patient has enrolled in the registration-phase TETON PPF study, which will evaluate nebulized Tyvaso® (treprostinil) Inhalation Solution in 698 adult patients with progressive pulmonary fibrosis (PPF). This is in addition to two separate ongoing registration-phase studies, TETON 1 and TETON 2, of nebulized Tyvaso in patients with another type of pulmonary fibrosis (PF) known as idiopathic pulmonary fibrosis (IPF). The 52-week study will evaluate the impact of nebulized Tyvaso on a key prognostic indicator for PPF known as forced vital capacity (FVC). PPF is a progressive form of interstitial lung disease (ILD) characterized by the loss of the ability of the lungs to transfer oxygen into the blood, ultimately resulting in respiratory failure and death. Nebulized Tyvaso is currently approved by the U.S. Food and Drug Administration (FDA) to treat both pulmonary arterial hypertension and pulmonary hypertension (PH) associated with interstitial lung disease (PH-ILD). The PH-ILD indication, which includes patients with PH associated with IPF and PPF, was added to the nebulized Tyvaso label in March 2021 based on the successful results of the INCREASE study. Nebulized Tyvaso is only approved for use for PPF patients who may also have documented PH, to improve exercise capacity. The TETON PPF study seeks to evaluate the use of nebulized Tyvaso in PPF patients irrespective of whether or not they have PH. “The progressive pulmonary fibrosis phenotype represents a group of ILD patients who only have limited treatment options currently available to them,” said Steven Nathan, M.D., Medical Director of the Advanced Lung Disease and Lung Transplant Program at Inova Fairfax Hospital in Falls Church, Virginia, who is also chair of the TETON program steering committee. “The broader ILD data set from the INCREASE study showed improvements in FVC beyond just IPF patients, and the data provide the foundation for further study of inhaled treprostinil’s anti-fibrotic and disease modifying mechanism of action in patients with other forms of fibrotic lung disease like PPF.” “The initiation of the global TETON PPF study illustrates confidence in nebulized Tyvaso as a potential treatment option for patients with fibrotic lung disease,” said Natalie Breytenbach, Pharm.D., Associate Director, Global Product Development at United Therapeutics and the company’s lead for the TETON PPF study. “The expansion of TETON into the PPF patient population allows us to continue to evaluate inhaled treprostinil’s potential for treating this vulnerable group of patients in a robust global pivotal study.” The TETON program in IPF and PPF was prompted by data from the INCREASE study of nebulized Tyvaso for the treatment of PH-ILD, which demonstrated improvements in certain key parameters of lung function in pulmonary hypertension patients with fibrotic lung disease (improved absolute FVC and reduced exacerbations of underlying lung disease). Specifically, in the INCREASE study, treatment with nebulized Tyvaso resulted in significant improvements in percent predicted FVC at weeks 8 and 16, with subjects having an underlying etiology of IPF showing the greatest improvement (week 8: 2.5%; p=0.0380 and week 16: 3.5%; p=0.0147). In May 2022, data from the INCREASE open-label, long-term extension trial were presented at a medical conference, indicating that improvements in FVC were sustained for at least 64 weeks for PH-ILD patients with underlying IPF. For those patients who received placebo during the INCREASE study, marked improvements in FVC were observed following transition to nebulized Tyvaso during the open-label extension study. These data points, combined with substantial preclinical evidence of antifibrotic activity of treprostinil, suggest that nebulized Tyvaso may offer a treatment option for patients with IPF and PPF. Tyvaso DPI® (treprostinil) Inhalation Powder is not being evaluated in the TETON program, but United Therapeutics intends to seek FDA approval to expand the Tyvaso DPI label to include IPF and PPF, following completion of the TETON studies and any FDA-required bridging studies. About TETON PPF The TETON PPF study is a 698-patient, multicenter, randomized, double-blind, placebo-controlled phase 3 registration study to evaluate the safety and efficacy of nebulized Tyvaso in subjects with progressive pulmonary fibrosis (PPF) over a 52-week period. This third registration study is part of the global TETON program evaluating nebulized Tyvaso for the treatment of idiopathic pulmonary fibrosis (IPF) and PPF and will be conducted at sites globally. Subjects will be randomly allocated 1:1 to receive nebulized Tyvaso or placebo. All subjects will initiate nebulized Tyvaso or placebo at a dose of three breaths administered four times daily (QID) and will titrate to a target dosing regimen of 12 breaths QID. Study drug doses may be titrated up as tolerated, until the target dose or maximum clinically tolerated dose is achieved. The primary endpoint of the study is the change in FVC from baseline to week 52. Secondary endpoints include: (1) time to clinical worsening; (2) time to first acute exacerbation of interstitial lung disease (ILD); (3) overall survival at week 52; (4) change in percent predicted FVC from baseline to week 52; (5) change in the King’s Brief Interstitial Lung Disease questionnaire; and (6) change in the diffusing capacity of the lungs for carbon monoxide. Other data collected in the study will include the plasma N-terminal pro-brain natriuretic peptide (NT-proBNP) concentration and supplemental oxygen use. Safety assessments include adverse event and serious adverse event monitoring, vital signs, clinical laboratory parameters, and electrocardiogram parameters. About PPF Progressive pulmonary fibrosis (PPF) is a group of interstitial lung disease (ILD) conditions that exhibit progressive, self-sustaining fibrosis, and display a similar disease course to idiopathic pulmonary fibrosis (IPF). PPF includes idiopathic interstitial pneumonias (other than IPF), autoimmune ILDs, chronic fibrosing hypersensitivity pneumonitis, and fibrotic ILDs related to environmental or occupational exposure. It is estimated that 13% to 40% of patients with these various ILDs will go on to develop PPF1. Patients with PPF exhibit decreased lung function, poor quality of life, and increased mortality despite usual treatments for the underlying ILD. Estimates for median transplant free survival and overall survival are approximately 2.9 years and 3.7 years, respectively.2,3 Further, United Therapeutics estimates there are up to 60,000 PPF patients in the United States. About Tyvaso® Inhalation Solution and Tyvaso DPI® Inhalation Powder INDICATION TYVASO (treprostinil) Inhalation Solution and TYVASO DPI (treprostinil) Inhalation Powder are prostacyclin mimetics indicated for the treatment of: Pulmonary arterial hypertension (PAH; WHO Group 1) to improve exercise ability. Studies with TYVASO establishing effectiveness predominately included patients with NYHA Functional Class III symptoms and etiologies of idiopathic or heritable PAH (56%) or PAH associated with connective tissue diseases (33%). The effects diminish over the minimum recommended dosing interval of 4 hours; treatment timing can be adjusted for planned activities. While there are long-term data on use of treprostinil by other routes of administration, nearly all clinical experience with inhaled treprostinil has been on a background of an endothelin receptor antagonist (ERA) and/or a phosphodiesterase type 5 (PDE-5) inhibitor. The controlled clinical experience with TYVASO was limited to 12 weeks in duration. Pulmonary hypertension associated with interstitial lung disease (PH-ILD; WHO Group 3) to improve exercise ability. The study with TYVASO establishing effectiveness predominately included patients with etiologies of idiopathic interstitial pneumonia (IIP) (45%) inclusive of idiopathic pulmonary fibrosis (IPF), combined pulmonary fibrosis and emphysema (CPFE) (25%), and WHO Group 3 connective tissue disease (22%). IMPORTANT SAFETY INFORMATION WARNINGS AND PRECAUTIONS TYVASO and TYVASO DPI are pulmonary and systemic vasodilators. In patients with low systemic arterial pressure, either product may produce symptomatic hypotension. Both products inhibit platelet aggregation and increase the risk of bleeding. Co-administration of a cytochrome P450 (CYP) 2C8 enzyme inhibitor (e.g., gemfibrozil) may increase exposure (both Cmax and AUC) to treprostinil. Co-administration of a CYP2C8 enzyme inducer (e.g., rifampin) may decrease exposure to treprostinil. Increased exposure is likely to increase adverse events associated with treprostinil administration, whereas decreased exposure is likely to reduce clinical effectiveness. Like other inhaled prostaglandins, TYVASO and TYVASO DPI may cause acute bronchospasm. Patients with asthma or chronic obstructive pulmonary disease (COPD), or other bronchial hyperreactivity, are at increased risk for bronchospasm. Ensure that such patients are treated optimally for reactive airway disease prior to and during treatment with TYVASO and TYVASO DPI. DRUG INTERACTIONS/SPECIFIC POPULATIONS The concomitant use of either product with diuretics, antihypertensives, or other vasodilators may increase the risk of symptomatic hypotension. Human pharmacokinetic studies with an oral formulation of treprostinil (treprostinil diolamine) indicated that co-administration of the cytochrome P450 (CYP) 2C8 enzyme inhibitor, gemfibrozil, increases exposure (both Cmax and AUC) to treprostinil. Co-administration of the CYP2C8 enzyme inducer, rifampin, decreases exposure to treprostinil. It is unclear if the safety and efficacy of treprostinil by the inhalation route are altered by inhibitors or inducers of CYP2C8. Limited case reports of treprostinil use in pregnant women are insufficient to inform a drug-associated risk of adverse developmental outcomes. However, pulmonary arterial hypertension is associated with an increased risk of maternal and fetal mortality. There are no data on the presence of treprostinil in human milk, the effects on the breastfed infant, or the effects on milk production. Safety and effectiveness in pediatric patients have not been established. Across clinical studies used to establish the effectiveness of TYVASO in patients with PAH and PH‑ILD, 268 (47.8%) patients aged 65 years and over were enrolled. The treatment effects and safety pro in geriatric patients were similar to younger patients. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of hepatic, renal, or cardiac dysfunction, and of concomitant diseases or other drug therapy. ADVERSE REACTIONS Pulmonary Arterial Hypertension (WHO Group 1) In a 12-week, placebo-controlled study (TRIUMPH I) of 235 patients with PAH (WHO Group 1 and nearly all NYHA Functional Class III), the most common adverse reactions seen with TYVASO in ≥4% of PAH patients and more than 3% greater than placebo were cough (54% vs 29%), headache (41% vs 23%), throat irritation/pharyngolaryngeal pain (25% vs 14%), nausea (19% vs 11%), flushing (15% vs <1%), and syncope (6% vs <1%). In addition, adverse reactions occurring in ≥4% of patients were dizziness and diarrhea. In a 3-week, open-label, single-sequence, safety and tolerability study (BREEZE) conducted in 51 patients on stable doses of TYVASO who switched to a corresponding dose of TYVASO DPI, the most commonly reported adverse events seen with TYVASO DPI in ≥4% of PAH patients during the 3-week treatment phase included cough (35.3%), headache (15.7%), dyspnea (7.8%), and nausea (5.9%). Pulmonary Hypertension Associated with ILD (WHO Group 3) In a 16-week, placebo-controlled study (INCREASE) of 326 patients with PH-ILD (WHO Group 3), adverse reactions with TYVASO were similar to the experience in studies of PAH. Please see Full Prescribing Information for TYVASO or TYVASO DPI, Instructions for Use manuals for TD-100 and TD-300 TYVASO® Inhalation System and TYVASO DPI™ Inhalation Powder, and additional information at or call 1‑877‑UNITHER (1-877-864-8437). TYVISIhcpMAY2022 United Therapeutics: Enabling Inspiration At United Therapeutics, our vision and mission are one. We use our enthusiasm, creativity, and persistence to innovate for the unmet medical needs of our patients and to benefit our other stakeholders. We are bold and unconventional. We have fun; we do good. We are the first publicly traded biotech or pharmaceutical company to take the form of a public benefit corporation. Our public benefit purpose is to provide a brighter future for patients through the development of novel pharmaceutical therapies; and technologies that expand the availability of transplantable organs. You can learn more about what it means to be a PBC here: unither.com/pbc. Forward-looking Statements Statements included in this press release that are not historical in nature are “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995. Forward-looking statements include, among others, statements regarding the planned enrollment, conduct, and design of the TETON 1, TETON 2, and TETON PPF clinical studies, the potential for Tyvaso to become a treatment option for patients with fibrotic lung disease, our plans to seek IPF and PPF indications for the Tyvaso DPI label, and our goals of innovating for the unmet medical needs of our patients and to benefit our other stakeholders and furthering our public benefit purpose of developing novel pharmaceutical therapies and technologies that expand the availability of transplantable organs. These forward-looking statements are subject to certain risks and uncertainties, such as those described in our periodic reports filed with the Securities and Exchange Commission, that could cause actual results to differ materially from anticipated results. Consequently, such forward-looking statements are qualified by the cautionary statements, cautionary language and risk factors set forth in our periodic reports and documents filed with the Securities and Exchange Commission, including our most recent Annual Report on Form 10-K, Quarterly Reports on Form 10-Q, and Current Reports on Form 8-K. We claim the protection of the safe harbor contained in the Private Securities Litigation Reform Act of 1995 for forward-looking statements. We are providing this information as of October 31, 2023, and assume no obligation to update or revise the information contained in this press release whether as a result of new information, future events, or any other reason. TYVASO and TYVASO DPI are registered trademarks of United Therapeutics Corporation. 1 Olson AL, Patnaik P, Hartmann N, et al. Prevalence and incidence of chronic fibrosing interstitial lung diseases with a progressive phenotype in the United States estimated in a large claims database analysis. Adv Ther. 2021;38:4100-4114. 2 Platenburg MGJP, van der Vis JJ, Grutters JC, van Moorsel CHM. Decreased survival and lung function in progressive pulmonary fibrosis. Medicina. 2023;59:296. 3 Cottin V, Teague R, Nicholson L, et al. The burden of progressive-fibrosing interstitial lung disease. Front Med. 2022;9:799912. View source version on businesswire.com: Contacts Dewey Steadman at (202) 919-4097 Source: United Therapeutics Corporation View this news release online at: