New pathway to prevent kidney failure

 Researchers at the University of Bristol have made a breakthrough that could prevent certain kidney patients from progressing toward renal failure.

Dr. Carl May from Bristol Medical School and his team have identified a new treatment pathway for patients with non-genetic (idiopathic) nephrotic syndrome (INS), targeting a still unknown factor that causes the progression toward kidney failure. Their study is published in the journal Kidney International.

Nephrotic syndrome is a kidney condition that causes the organs to leak protein into the urine. This is caused by faults in the kidney's filtration system and in some cases, this can ultimately lead the patient to develop kidney failure. While it is a rare disease, it affects around 10,000 people each year in the U.K. with the majority of cases related to non-genetic causes. The impact that it has on patients, many of whom will be children, can be devastating.

The scientists from Bristol Renal knew that there might be one or more factors in the blood (a substance that takes part in a biological reaction within the body) that caused the kidneys in INS patients to fail but have so far been unable to find out exactly what they might be. However, the team tried a different approach as they looked to identify how the factor worked and attempted to prevent its activation.

Using plasma from the blood of INS patients who were being treated with dialysis, the Bristol team wanted to confirm if a receptor (a molecular substance that causes a specific effect in the cell) known as PAR-1 works in conjunction with the unknown factor.

Dr. May used the plasma from the patients and separately an activator of PAR-1 to investigate their effects on kidney cells in the lab. Both treatments caused distress in the kidney cells. Having confirmed the link between PAR-1 and the unknown factor, their results suggest that medications to block the receptor could be a viable option.

Steroids are currently the most effective treatment for INS, but these come with unpleasant side-effects and do not work equally well in all patients. Additionally, with the unknown factor circulating in the patient's blood, a transplant may offer some respite, however the disease often reoccurs and damages the new kidney, sometimes almost instantly. Dr. May's discovery could revolutionize treatment options for patients with INS and offers the potential to eradicate steroid use and make transplantation a more viable option.

Dr. May, a postdoctoral research associate at Bristol Medical School at the University of Bristol said, "Researchers have made many attempts to identify the unknown factor that leads to nephrotic syndrome with little success. We knew that one or more factors were present in the blood and if we could identify how it works in kidney patients, we could create a clear pathway to treat them and ultimately slow their progression towards kidney failure. Using anti-PAR-1 treatments to block the effect of the factor could not only prevent kidneys failing but could make transplants a viable option for more patients with idiopathic nephrotic syndrome."

Using anti-PAR-1 treatment options would not only eradicate the need for steroids but also allow transplantation to be a more beneficial treatment as newly transplanted kidneys would no longer be as susceptible to the effects of the unknown factor.

Dr. David Hughes, Kidney Research UK trustee and former president of the British Association for Pediatric Nephrology, added, "This discovery made by the Bristol team is a really interesting approach to tackling the issues around idiopathic Nephrotic Syndrome. Understanding how the factor reacts to anti-PAR-1 treatments sets a clear pathway for drugs that are already in development for other conditions. If successfully developed, they could drastically improve the lives of these kidney patients preventing them from having to suffer the consequences of kidney failure."

Anti-PAR-1 treatments are currently undergoing clinical trials for other health conditions to ascertain effectiveness and safety. The work conducted in Bristol opens new avenues for these treatments to be trialed for patients with non-genetic (idiopathic) nephrotic syndrome (INS).

If the safety of these treatments can be confirmed, INS patients could be taken off steroids and given new treatments in the next few years.

More information: Carl J. May et al, Podocyte protease actuated receptor 1 stimulation in mice produces focal segmental glomerulosclerosis mirroring human disease signaling events, Kidney International (2023). DOI: 10.1016/j.kint.2023.02.031

https://medicalxpress.com/news/2023-04-pathway-kidney-failure-thousands.html

Brain-penetrating drug candidate found to be effective against deadly encephalitis viruses

 A new antiviral compound designed and synthesized by researchers at the University of Wisconsin–Madison's School of Pharmacy is highly effective in mice against two types of devastating encephalitis viruses that are harmful to humans.

UW–Madison researchers developed the compound, a quinazolinone known as BDGR-49, in collaboration with cellular virologists at the University of Louisville and researchers at the University of Tennessee Health Science Center who performed animal efficacy studies. The multidisciplinary team found that BDGR-49 protects mice infected with deadly eastern equine encephalitis virus (EEEV) or Venezuelan equine encephalitis virus (VEEV).

The researchers described BDGR-49 and its efficacy against lethal infections of EEEV or VEEV in mouse models in a study published April 12 in Science Translational Medicine.

"Collaboration across disciplines and capabilities was key to this discovery," says Jennifer E. Golden, a UW–Madison professor of pharmacy and synthetic medicinal chemist who led the discovery and optimization effort. Colleen Jonsson, professor at UTHSC, tested the compound in mice. Donghoon Chung, a professor of microbiology and immunology at Louisville's Center for Predictive Medicine, performed further virology studies.

The team found that BDGR-49 potently inhibited EEEV and VEEV and was well tolerated in mice. The compound provided significant protection to EEEV-infected animals. Meanwhile, it not only fully protected VEEV-infected mice, but could also be used as a therapeutic treatment days after infection.

"We had been working on a different compound structure for years," says Golden. "Compounds that emerged from that earlier work were pivotal to understanding how to construct a better antiviral compound class that works well against VEEV and EEEV—ultimately providing a roadmap to the design and discovery of BDGR-49."

An important feature of this antiviral compound is its ability to access the brain where these viruses cause damage, while other critical attributes include its improved stability, potency and efficacy compared to earlier prototypes Golden and her collaborators developed. Based on resistance studies, BDGR-49 efficiently prevents these viruses from copying themselves, implicating that it operates by disrupting the viral machinery needed for replication.

Classified as New World alphaviruses, equine encephalitis viruses are transmitted by the bite of a mosquito and can infect the brain, causing neurological effects, serious illness and death in humans as well as horses. There currently are no FDA-approved vaccines or treatments available specifically for preventing or treating alphavirus infection in humans.

Symptoms of EEEV infection include fever, headache, chills and vomiting. Severe infection can result in seizure, coma and death. About one-third of individuals who develop encephalitis (brain inflammation) from EEEV infection die, and many of those who do recover suffer permanent neurological effects.

Although, outbreaks of eastern equine encephalitis are rare, with an average of 11 cases per year in the United States, in 2019 an outbreak across nine states resulted in 38 confirmed cases, 19 deaths and neurological effects in survivors.

Venezuelan equine encephalitis has a much lower mortality rate of 1%, but outbreaks can affect thousands of people, most often occurring in Central and South America. While insect bites are the typical source of these infections, there is also concern the viruses could be used as bioweapons.

The team has been developing and optimizing chemical structures against VEEV and EEEV for more than a decade. Golden, Jonsson and Chung are co-investigators in the Center of Excellence for Encephalitic Alphavirus Therapeutics, based at UTHSC. The center was created to refine the properties and activity of early-stage small molecule compounds discovered in the Golden lab and to develop them into clinical candidates for VEEV and EEEV that could be studied in humans.

"There are no approved prophylactic or therapeutic options in our arsenal for any human alphavirus infection, so our goal is to develop a drug against VEEV and EEEV that is safe and effective in humans," Golden says. "While there is still much work to be done, the discovery of BDGR-49 is a remarkable achievement in reaching that goal based on the compound's drug-like characteristics and ability to prevent animals from dying from these infections."

The team is evaluating BDGR-49 in advanced preclinical studies while expanding the understanding of its antiviral properties. As RNA viruses such as EEEV and VEEV are prone to develop mutations, they can potentially evolve into more lethal or transmissible versions without warning, resulting in widespread infections.

"It is essential that we develop these countermeasures for viruses of pandemic potential so we don't find ourselves unprepared to respond to an outbreak," Golden says. "We can do better, and we intend to leverage this discovery as broadly as possible with respect to VEEV, EEEV and other viruses of concern."

More information: Xufeng Cao et al, Efficacy of a brain-penetrant antiviral in lethal Venezuelan and eastern equine encephalitis mouse models, Science Translational Medicine (2023). DOI: 10.1126/scitranslmed.abl9344

https://medicalxpress.com/news/2023-04-brain-penetrating-drug-candidate-effective-deadly.html

Model suggests lowering hormone doses in contraceptives

 The dosage of hormones in common contraceptives could be reduced by as much as 92% and still effectively suppress ovulation, according to a computational model described this week in PLoS Computational Biology by Brenda Lyn A. Gavina, Ph.D. student at the University of the Philippines Diliman, and her collaborators.

A normal menstrual cycle involves multiple phases which are regulated by the endocrine system and influenced by levels of various hormones. The most contraceptive approaches, including pills, injectables and implants, involve the administration of exogenous estrogen and/or progesterone to block ovulation—the phase of the cycle in which an egg is released into the uterus.

In the new study, researchers used data on hormone levels in 23 women aged 20 to 34 with normal menstrual cycles. The team developed computational models depicting the interactions between various hormone levels as well as the impacts of exogenous hormones.

The model provided evidence that it is possible to reduce the total dose by 92% in estrogen-only contraceptives, or the total dose by 43% in progesterone-only contraceptives, and still prevent ovulation.

By combining estrogen and progesterone, the doses of each hormone could be reduced even further. In addition, the model showed the importance of timing the hormones during the cycle, pointing toward ways that exogenous estrogen and progesterone could be given during only certain phases of the menstrual cycle rather than at steady constant doses.

"These results may give clinicians insights into optimal dosing formulations and schedule of therapy that can suppress ovulation," the authors say.

More information: Toward an optimal contraception dosing strategy, PLoS Computational Biology (2023). DOI: 10.1371/journal.pcbi.1010073

https://medicalxpress.com/news/2023-04-lowering-hormone-doses-contraceptives.html

T-cell vaccine for COVID-19 may last longer than current vaccines

 The current COVID-19 vaccines are designed to trigger an antibody response to the SARS-CoV-2 spike protein, which is vulnerable to mutations that could make the vaccine less effective over time. Focusing on the T-cell instead, Penn State researchers have partnered with Evaxion Biotech on a study that is the first to demonstrate the effectiveness of an artificial intelligence-generated vaccine in a live viral challenge model. Such a vaccine may provide long-lasting immunity against future emerging variants and could be used as a model for other seasonal viral diseases like the flu.

In their study, the researchers challenged mice with a lethal dose of SARS-CoV-2 and found that 87.5% of the mice that were vaccinated with the T-cell-based vaccine survived, while only one of the control-group mice survived. Additionally, all the vaccinated mice that survived cleared the infection within 14 days post-challenge. The results were published on April 11 in Frontiers in Immunology.

"To our knowledge, this study is the first to show in vivo [in a living organism] protection against severe COVID-19 by an AI-designed T-cell vaccine," said Girish Kirimanjeswara, associate professor of veterinary and biomedical sciences, Penn State. "Our vaccine was extremely effective at preventing severe COVID-19 in mice, and it can be easily scaled up to start testing it in humans, as well. This research also paves the way for the potential rapid design of novel T-cell vaccines against emerging and seasonal viral diseases, like influenza."

According to Kirimanjeswara, the spike protein of the SARS-CoV-2 virus is under heavy selection pressure, which can result in mutations that drive the emergence of new variants.

"This means that vaccine manufacturers will have to keep creating new vaccines that target new variants, and people have to keep getting these new vaccines," he said.

Instead of targeting the constantly mutating spike protein, the team at Evaxion Biotech designed a vaccine that included 17 epitopes from various proteins of SARS-CoV-2 that are recognized by the immune system. These epitopes elicit an immune response from a broad selection of T cells, ensuring a sustained coverage of future variants.

"The virus would have to undergo too many mutations to be able to escape this T-cell-mediated immunity, so that is one advantage," said Kirimanjeswara. "The second advantage is that T-cell-mediated immunity is usually long-lasting, so you don't need repeated booster doses."

"It's harder and takes longer to produce a T-cell-based vaccine than an antibody-based one," said Kirimanjeswara. "Given the urgency with which we needed a vaccine to address the COVID-19 pandemic, it makes sense that vaccine manufacturers created an antibody-based vaccine. Now that the urgency has passed, a second-generation T-cell-based vaccine could be more effective and last longer."

According to co-author Anders Bundgaard Sørensen, project director, Evaxion Biotech, other biotechnology companies are developing T-cell-based vaccines, but this team's vaccine uses multiple types of artificial intelligence in a platform called RAVEN (Rapidly Adaptive Viral rEspoNse) to predict ideal targets for vaccines.

"RAVEN is really adaptable," Sørensen said. "We don't have to wait for a new strain of a virus to arrive to develop a vaccine. Instead, we can predict what will be needed in advance. That's not something that others are doing right now."

Sørensen noted, "It's much easier to get broad coverage with a T-cell vaccine, as we can include multiple epitopes targeting different proteins."

He added that in addition to producing better COVID-19 vaccines, the RAVEN platform could be used to develop better influenza vaccines.

"Oftentimes, the influenza vaccines that are designed work only 30-40% of the time, so a lot of people end up getting sick," he said. "As the world becomes increasingly integrated, that problem will become larger and larger. Our platform uses AI to better predict what will be needed."

Sørensen noted that Evaxion benefited from partnering with Kirimanjeswara and his Penn State colleagues because of their deep expertise in animal models of infectious disease and because the university houses a BSL-3 laboratory in which they could safely study the SARS-CoV-2 virus.

He said, "Our results are a testament to the power of industry-university partnerships."

More information: Gry Persson et al, DNA immunization with in silico predicted T-cell epitopes protects against lethal SARS-CoV-2 infection in K18-hACE2 mice, Frontiers in Immunology (2023). DOI: 10.3389/fimmu.2023.1166546

https://medicalxpress.com/news/2023-04-t-cell-vaccine-covid-longer-current.html

Balloon pulmonary angioplasty, a novel treatment for chronic blood clots in lung arteries

 Old blood clots in lung arteries can obstruct blood flow and lead to pressure build-up in the affected arteries. When this happens, symptoms such as shortness of breath, fatigue, chest pain, and fainting spells may develop, which severely impair quality of life. While this condition, known as chronic thromboembolic pulmonary hypertension (CTEPH), is often effectively treated with open heart surgery, many CTEPH patients cannot undergo surgery, because of other medical problems or because blockages in their arteries are beyond the reach of surgery.

Now, a new study by researchers at the Lewis Katz School of Medicine at Temple University shows that a novel treatment approach known as balloon pulmonary angioplasty can be effective for treating CTEPH patients who are not able to undergo surgery. The study, carried out at Temple Heart & Vascular Institute's Pulmonary Hypertension, Right Heart Failure and CTEPH Program, is one of the largest investigations of balloon pulmonary angioplasty in the United States to date. The findings appeared online in the journal JACC: Advances.

"Our study showed that opening up blockages in lung arteries of these patients markedly improved exercise capacity and quality of life," said Riyaz Bashir, MD, FACC, Professor of Medicine and Director of Vascular and Endovascular Medicine in the Section of Cardiology, Department of Medicine, at the Lewis Katz School of Medicine and Temple University Hospital, and senior investigator on the new study.

"CTEPH patients treated with balloon pulmonary angioplasty come away having fewer symptoms, and some may be able to come off medications altogether."

Temple is one of the leading centers in the nation in treating CTEPH patients with balloon pulmonary angioplasty. Dr. Bashir, along with Paul Forfia, MD, and Anjali Vaidya, MD, Co-Directors of the Pulmonary Hypertension, Right Heart Failure, and CTEPH Program; Vladimir Lakhter, DO, Assistant Professor of Medicine at the Lewis Katz School of Medicine; and Estefania Oliveros, MD, MSc, Director of Research at the Pulmonary Hypertension, Right Heart Failure, and CTEPH Program, were involved in the treatment and follow-up care of these patients.

Balloon pulmonary angioplasty was first introduced in the early 2000s but was associated with high rates of major complications. Refinements in technique over the past decade have vastly improved its efficacy and safety. The procedure is carried out by putting a small tube in the groin vein.

A long catheter over a wire is advanced through the tube and into the lung arteries, where a blockage is identified under an X-ray camera. A small balloon is then used to open the blockage slowly, while blood pressure beyond the blockage is monitored simultaneously. Patients typically are awake and are given a mild sedative and local anesthesia during the procedure.

In order to open blockages throughout the lungs, balloon pulmonary angioplasty is carried out over the course of multiple treatment sessions. The approach used at the Temple Heart & Vascular Institute is gradual and deliberate, in order to prevent complications, especially bleeding into the lungs.

Bleeding risk traditionally has been high with balloon pulmonary angioplasty. "But with continued refinement of the procedure, we have successfully decreased bleeding rates in these patients," Dr. Bashir explained. "In doing so, we are now able to show that balloon pulmonary angioplasty is not only relatively safe but also associated with key improvements in pulmonary hypertension and functional capacity."

More information: Riyaz Bashir et al, Refined Balloon Pulmonary Angioplasty in Chronic Thromboembolic Pulmonary Hypertension, JACC: Advances (2023). DOI: 10.1016/j.jacadv.2023.100291

https://medicalxpress.com/news/2023-04-balloon-pulmonary-angioplasty-treatment-chronic.html

How a virus causes chromosomal breakage, leading to cancer

 The Epstein-Barr virus (EBV) is easily spread through bodily fluids, primarily saliva, such as kissing, shared drinks or using the same eating utensils. Not surprisingly then, EBV is also among the most ubiquitous of viruses: More than 90% of the world's population has been infected, usually during childhood.

EBV causes infectious mononucleosis and similar ailments, though often there are no symptoms. Most infections are mild and pass, but the virus persists in the body, becoming latent or inactive, sometimes reactivating. Long-term latent infections are associated with several chronic inflammatory conditions and multiple cancers.

In a new paper, published April 12, 2023 in the journal Nature, researchers at University of California San Diego, UC San Diego Moores Cancer Center and Ludwig Cancer Research at UC San Diego, describe for the first time how the virus exploits genomic weaknesses to cause cancer while reducing the body's ability to suppress it.

These findings show "how a virus can induce cleavage of human chromosome 11, initiating a cascade of genomic instability that can potentially activate a leukemia-causing oncogene and inactivate a major tumor suppressor," said senior study author Don Cleveland, Ph.D., Distinguished Professor of Medicine, Neurosciences and Cellular and Molecular Medicine at UC San Diego School of Medicine.

"It's the first demonstration of how cleavage of a 'fragile DNA' site can be selectively induced."

Throughout every person's genome or full set of genes are fragile sites, specific chromosomal regions more likely to produce mutations, breaks or gaps when replicating. Some are rare, some are common; all are associated with disorders and disease, sometimes heritable conditions, sometimes not, such as many cancers.

In the new study, Cleveland and colleagues focus on EBNA1, a viral protein that persists in cells infected with EBV. EBNA1 was previously known to bind at a specific genomic sequence in the EBV genome at the origin of replication. The researchers found that EBNA1 also binds a cluster of EBV-like sequences at a fragile site on human chromosome 11 where increasing abundance of the protein triggers chromosomal breakage.

Other prior research has shown that EBNA1 inhibits p53, a gene that plays a key role in controlling cell division and cell death. It also suppresses tumor formation when normal. Mutations of p53, on the other hand, are linked to cancer cell growth.

When the scientists examined whole-genome sequencing data for 2,439 cancers across 38 tumor types from the Pan-Cancer Analysis of Whole Genomes project, they found that cancer tumors with detectable EBV revealed higher levels of chromosome 11 abnormalities, including 100% of the head and neck cancer cases.

"For a ubiquitous virus that is harmless for the majority of the human population, identifying at-risk individuals susceptible to the development of latent infection-associated diseases is still an ongoing effort," said the study's first author Julia Li, Ph.D., a postdoctoral fellow in Cleveland's lab.

"This discovery suggests that susceptibility to EBNA1-induced fragmentation of chromosome 11 depends on the control of EBNA1 levels produced in latent infection, as well as the genetic variability in the number of EBV-like sequences present on chromosome 11 in each individual. Going forward, this knowledge paves the way for screening risk factors for the development of EBV-associated diseases. Moreover, blocking EBNA1 from binding at this cluster of sequences on chromosome 11 can be exploited to prevent the development of EBV-associated diseases."

More information: Julia Su Zhou Li et al, Chromosomal fragile site breakage by EBV-encoded EBNA1 at clustered repeats, Nature (2023). DOI: 10.1038/s41586-023-05923-x

https://medicalxpress.com/news/2023-04-virus-chromosomal-breakage-cancer.html

Exelixis Advances Board Refreshment Plan

 Exelixis, Inc. (Nasdaq: EXEL) (the "Company") today announced that Carl Feldbaum, Esq. and Vincent Marchesi, M.D., Ph.D., two long-standing and valued members of the Board of Directors, will not stand for re-election at the Company’s 2023 Annual Meeting of Stockholders (the "Annual Meeting"). As part of its ongoing refreshment program, the Board is recommending Tomas Heyman, current Chief Executive Officer of Interlaken Therapeutics and former President of Johnson & Johnson’s Corporate Venture Capital Group, and Robert Oliver, former President and Chief Executive Officer of Otsuka America Pharmaceutical, for election as independent directors at the Company’s Annual Meeting to fill Mr. Feldbaum’s and Dr. Marchesi’s seats.

As previously disclosed, Messrs. Heyman and Oliver were originally nominated by Farallon Capital Management, L.L.C. ("Farallon"). As part of the Company’s efforts to reach an agreement with Farallon to avoid a proxy contest, in the third week of March numerous members of the Exelixis Board met individually with both candidates to assess their qualifications to serve as members of the Board. The Board subsequently agreed to appoint both Messrs. Heyman and Oliver to the Board as part of a proposed settlement agreement with Farallon. However, Farallon was unwilling to sign an agreement and demanded a highly unusual breadth and depth of access to company confidential and proprietary information as a non-negotiable part of any settlement, including unprecedented access to Exelixis’ pipeline, people and clinical trial data. While the Exelixis Board could not concede to Farallon’s information and access demands, the Board determined at the time of the interviews that Messrs. Heyman and Oliver were excellent candidates for the Board, and the failure of settlement negotiations with Farallon does not in any way affect that view.

https://finance.yahoo.com/news/exelixis-advances-board-refreshment-plan-201100796.html