Body

Philadelphia, May 12, 2021 - Researchers at the Center for Applies Genomics (CAG) at Children's Hospital of Philadelphia (CHOP) have revealed how variants of a gene responsible for packing and condensing genetic material present a novel cause for certain neurodevelopmental disorders. The findings were published today in Science Advances.

Many neurodevelopmental disorders classified as intellectual disabilities are linked to certain genetic variants. Despite this, the underlying molecular mechanism for most of these patients is unknown. In particular, several neurodevelopmental disorders have been linked to pathogenic variants in genes responsible chromatin remodeling, or the rearrangement of the structure of chromosomes that allows for the transcription of DNA into directions to carry out necessary functions of the cells in the body.

One of these genes responsible for encoding a chromatin remodeling complex is SMARCA5. While there was some preclinical evidence that variants of SMARCA5 may be associated with developmental changes, a specific disorder associated with such variants had never been described.

"Our study is the first to describe how certain germline mutations in SMARCA5 are responsible for a spectrum of neurodevelopmental delays," said study leader Dong Li, PhD, a research scientist with CAG. "Apart from identifying patients with such germline variants for the first time, our extended translational modeling study efforts to determine the underlying functions for these variants further elucidated their clinical relevance."

This current study reports on 12 patients (six males and six females) across 10 unrelated families. Clinical features that were similar across these patients included mild developmental delay as well as short stature and microcephaly.

Dr. Li collaborated with Yuanquan Song, PhD, a faculty member from Department of Pathology and Laboratory Medicine at CHOP.

"We used fruit flies to study the effects of losing the function of SMARCA5 and found that this led to smaller body size, reduced the complexity of sensory neuron processes, among other defects in the larvae," Song said. "In adult flies, the neural knockdown caused decreased brain size and abnormal locomotor function, and mutated SMARCA5 was unable to rescue the cells from this loss of function."

"Our findings expand the spectrum of neurodevelopmental disorders linked to chromatin remodeling genes," said Hakon Hakonarson, MD, PhD, Director of the Center for Applied Genomics at CHOP and senior author of the study. "It is very likely that this group of genetic variants may be responsible for other neurodevelopmental disorders and should be a point of focus going forward."

A Johns Hopkins University-led team has created an inexpensive portable device and cellphone app to diagnose gonorrhea in less than 15 minutes and determine if a particular strain will respond to frontline antibiotics.

The invention improves on traditional testing in hospital laboratories and clinics, which typically takes up to a week to deliver results--time during which patients can unknowingly spread their infections. The team's results appear today in Science Translational Medicine.

"Our portable, inexpensive testing platform has the potential to change the game when it comes to diagnosing and enabling rapid treatment of sexually transmitted infections," said team leader Tza-Huei Wang, a professor of mechanical engineering and core researcher at the Institute for NanoBioTechnology at Johns Hopkins Whiting School of Engineering. "It ensures that patients are diagnosed on the spot, and treatment can begin immediately, improving clinical outcomes. This will be especially valuable in low-resource settings, where well-equipped laboratories are not always available to every patient."

More than 87 million people around the world are infected with gonorrhea, a potentially devastating sexually transmitted disease with increasing resistance to antibiotics. Experts say that quickly identifying and treating those infected is the only way to prevent spiraling numbers of cases and the further rise of antibiotic-resistant strains.

Called PROMPT (portable, rapid, on-cartridge, magnetofluidic purification and testing platform), the Wang team's device runs on a simple five-volt battery and includes thermoplastic cartridges that cost about $2.

Testing is simple: A swab containing the patient's body fluid is mixed with a solution of magnetic particles in a tube, and a drop of that blend is loaded into a cartridge, which snaps into the device. The device transfers the magnetized particles to reagents in the cartridge, which runs through 40 cycles of polymerase chain reaction (PCR) testing before displaying the results on the cellphone screen. (PCR testing enables scientists to take tiny samples of DNA and amplify them to study in detail. They are the gold standard for testing for COVID-19, for example.)

During testing from sexual health clinics in Baltimore and Kampala, Uganda, PROMPT correctly detected the most common strain of gonorrhea about 97% of the time. It was 100% accurate in determining whether the tested strain of gonorrhea would respond to ciprofloxacin, a medication that targets infections that are resistant to other antibiotics.

"Our test maintains the same sensitivity and specificity currently used in hospital and clinic labs but reduces the cost and time involved," said team member Alex Trick, a Johns Hopkins graduate student in biomedical engineering. "We want these diagnostics to be available to all people who need it, when they need it."

Wang and his team are forming a university spinoff to work through regulatory approval, manufacturing, and distribution.

"We expect to be able to deliver these products to those who can really benefit from them in two to three years," he said.

People who are genetically more likely to suffer from cardiovascular diseases may benefit from boosting a biomarker found in fish oils, a new study suggests.

In a genetic study in 1,886 Asian Indians published in PLOS ONE today (Wednesday 12 May), scientists have identified the first evidence for the role of adiponectin, an obesity-related biomarker, in the association between a genetic variation called omentin and cardiometabolic health.

The team, led by Professor Vimal Karani from the University of Reading, observed that the role of adiponectin was linked to cardiovascular disease markers that were independent of common and central obesity among the Asian Indian population.

Prof Vimal Karani, Professor of Nutrigenetics and Nutrigenomics at the University of Reading said:

"This is an important insight into one way that people who are not obese may develop heart disease, through low concentrations of a biomarker in the body called adiponectin. It may also demonstrate why certain lifestyle factors such as consumption of oily fish and regular exercise are so important for warding off the risk of heart disease.

"We studied Asian Indian populations who have a particular genetic risk of developing heart disease and did see that the majority of our participants were already cardiometabolically unhealthy. However, the omentin genetic variation that we studied is prevalent across diverse ethnic groups and warrants further work to see whether omentin is playing a role in heart disease risk in other groups too."

The Asian Indian population who took part in the study were found to have a significant association between low levels of adiponectin and cardiovascular disease, even after adjusting for factors normally linked with heart disease.

Participants in the study were screened and assessed based on a range of cardiovascular measures including BMI, fasting blood sugar and cholesterol, and more than 80% of those who took part being assessed as cardiometabolically unhealthy.

Further analysis showed that those with genetic variation in omentin production also had less of the biomarker adiponectin in their body.

Professor Vimal Karani said:

"What we can see clearly from the observations is that there is a three-stage process going on where the omentin gene difference is contributing to the low biomarker adiponectin, which in turn seems to be linked to worse outcomes and risk of heart disease.

"The omentin gene itself works to produce a protein in the body that has been shown to have anti-inflammatory and cardioprotective effects, and variations in the omentin gene have previously linked to cardiometabolic diseases. The findings suggests that people can develop cardiometabolic diseases due to this specific omentin genetic risk, if they have low levels the biomarker adiponectin."

Misleading claims about COVID-19 vaccines can negatively impact public confidence in immunisation uptake, a new UNSW Sydney study reveals.

A new study published in the scientific journal PLOS ONE revealed over 103 million people globally liked, shared, retweeted or reacted with an emoji to misinformation and conspiracy theories about COVID-19 vaccines.

In 2020, a social media post claiming, "a new vaccine for COVID-19 will alter a person's DNA and result in them becoming genetically modified" was circulated on Facebook accounts in Australia. Up until August 21, 2020, this false claim had attracted 360 shares and was viewed 32,000 times.

The study, led by UNSW researchers, examined content between December 2019 to November 2020 which included news articles, social media posts, online reports and blogs.

Associate Professor Holly Seale from UNSW Medicine & Health's School of Population Health and senior author of the study said the misinformation being shared by family members, friends and other people in the wider community network was concerning.

"From previous studies, we've been able to link this misinformation with negative outcomes, including death," explained A/Prof Seale.

Also of concern was the absence of fact-based information to counter the circulation of these conspiracy theories and rumours on multiple social media platforms, which has the potential to be misinterpreted as credible information. Additionally, the study identified numerous rumours and conspiracy theories that could negatively impact public confidence in COVID-19 vaccines and the willingness to receive the vaccination.

A national survey conducted among US adults in September 2020 on willingness to receive the COVID-19 vaccine found a 21% decline when compared with another national survey conducted in May 2020 among similar groups. This decline could be attributable to the exposure to COVID-19 vaccine misinformation on social media. In another study conducted among Australian adults, 24% were unsure or not willing to accept a COVID-19 vaccine. 89% of these individuals were concerned about vaccine efficacy and safety, and 27% did not believe a COVID-19 vaccine was necessary.

The misinformation that was examined included content ranging from vaccine development to mortality due to receiving the COVID-19 vaccination.

A post that was circulated widely claimed a Russian vaccine company omitted phase three clinical trials for a COVID-19 vaccine. This claim provoked concern and criticism from the scientific community that the vaccine was not tested for effectiveness or safety, which could result in global concern and vaccine hesitancy.

Another post on social media suggested 160 doctors disapproved of the COVID-19 vaccine as it could change human DNA or that it could modify genes, cause cancers, and infertility.

The most popular conspiracy theory circulating online was the claim that the COVID-19 vaccine could monitor the human population and take over the world. One theory proposed the COVID-19 vaccine would contain a microchip through which biometric data could be collected, and large businesses could send signals to the chips using 5G networks, thereby controlling humanity.

To counter the misinformation and conspiracy theories around COVID-19 vaccines, the researchers suggest traditional methods of risk communication and community engagement needs be explored to track and fact- check misinformation as ways to immunise people against misinformation, thereby pre-empting potential vaccine program disruptions.

"We only looked at the platforms that are open and free, which included Facebook, Twitter and other similar networks. But then there are the closed networks, such as WhatsApp and WeChat. We still have very little understanding about the role of misinformation, where it is originating from and what type of impact it's having, so there is a lot more research that needs to be done in this space."

According to the British Heart Foundation, heart and circulatory diseases cause more than a quarter (27 per cent) of all deaths in the UK, which equates to more than 160,000 deaths each year - or one death every three minutes.

The research, published in the top science journal Advanced Science, found that injection of the trace mineral manganese could enhanced MRI scans so that they provided more accurate details of heart function than traditional MRI methods.

These findings, if confirmed in human subjects, could have major implications for the treatment of heart attack patients. The findings could also be of great use in the preclinical evaluation of treatments for patients who suffer from cardiac ischemia - a reduction in blood supply to the heart muscle that could lead to cardiac arrest.

The study also suggests that if manganese-enhanced MRI is performed within the first few hours of a heart attack it could be used to determine the optimal treatment regime for individual patients - helping to regulate changes in the cardiac muscle and thereby further improving survival chances. Findings were evaluated by examining the infarct size and blood supply at three key intervals: one hour, one day and 14 days after a myocardial infarction was induced.

Dr Patrizia Camelliti, Principal Investigator and Senior Lecturer in Cardiovascular Science at the University of Surrey, said:

"Magnetic resonance imaging (MRI) is increasingly used to diagnose and give information on heart conditions. This research using mice allows us to measure the health status of the heart muscle rapidly after a heart attack and could provide important information for optimising treatments in patients".

By combining two medications, researchers at Michigan Medicine optimized a therapy for people with gout, a condition that causes severe damage and disability if left untreated.

The study revealed how a second drug taken orally more than doubled the effectiveness of Pegloticase, an intravenous gout treatment used to dissolve crystalized uric acid in the joints when oral medications fail.

"Gout is a challenging disease to treat because there are only a handful of oral therapies to lower uric acid," says Puja Khanna, M.D., M.P.H., a rheumatologist at Michigan Medicine. "Now, we have a medication that works and gives us a better chance to help people who have been suffering from gout for decades."

When used alone, Pegloticase creates a potent antibody response in people with severe gout. Khanna led a team of researchers to analyze whether an immunomodulation drug called mycophenolate mofetil, or MMF, would limit this antibody production and improve Pegloticase's efficacy to sustain a low urate level.

The study included 32 subjects who randomly received either MMF or a placebo orally before starting Pegloticase infusions, which are given every two weeks for six months. After three months, they stopped receiving the oral medication and continued infusions for another 12 weeks.

Historically, only 42% of patients treated with Pegloticase saw their uric acid levels drop below the therapeutic target level of less than 6 mg/dL. That number jumped to 86% in the trial for subjects dosed with both medications, and Khanna believes the success rate could have been even higher.

"We were hoping to cut the failure rate in half, and this surpassed our expectations," she says. "This was a feasibility study to see a signal, but it raises the question: If we had continued the MMF for the whole study period, would we have seen a 100 percent response rate?"

While hospitalizations for rheumatic conditions like lupus and rheumatoid arthritis have decreased, gout is trending steeply in the opposite direction. This is, in part, due to limited therapies, an increase in comorbidities like diabetes and kidney disease and the high cost of treatment, Khanna says.

"Gout can cause as severe disability as rheumatoid arthritis, but there are nowhere near the number of modalities to treat it," she says. "Getting a new medication from inception to FDA approval can take anywhere from 10-20 years, so our team combined these drugs to optimize the efficacy of what we already have."

Aside from a larger trial, Khanna hopes future studies will examine how long subjects need to take MMF before and after starting Pegloticase transfusions - narrowing down the most effective dose and duration needed to fight this highly debilitating disease.

"We know immunomodulation needs to stay on, it just depends on how strongly the patients respond," she says. "Gout is severely underdiagnosed, and if you treat it earlier and more aggressively, you can control symptoms and limit long-term damage to the joints."

A new drug combination that is better at treating miscarriage is also more cost effective than current standard NHS treatment, finds a new study led by the University of Birmingham and Tommy's National Centre for Miscarriage Research.

A previous study by the same team and published in The Lancet * in August last year, found that a combined drug treatment is more effective than the standard medication for women having miscarriages without symptoms - also known as missed, delayed or silent miscarriage.

Missed miscarriage occurs when a baby has died in the womb but the mother hasn't had symptoms, such as bleeding or pain. Current hospital restrictions on surgery mean that many women face waiting for the miscarriage to happen by itself, which can take weeks and still might not happen, or being offered medication to speed the process along.

National guidelines recommend a treatment called misoprostol, which is successful in most cases - but some women wait anxiously for weeks, repeating the medication and eventually needing surgery.

The research published in The Lancet in August 2020 showed that misoprostol is more effective when combined with mifepristone, an anti-progesterone drug used to induce labour. The trial found that the combined drug treatment worked in 83% of cases, compared to 76% in the misoprostol and placebo group - and crucially, it reduced the need for surgery. One in four women (25%) given the placebo later needed an operation to complete the miscarriage, compared with less than one in five (18%) of those who had the new medication.

Now the team has carried out a further study to assess the cost-effectiveness of mifepristone and misoprostol combined compared with misoprostol alone for the medical management of a missed miscarriage.

The National Institute for Health Research (NIHR) funded study involved 711 women across 28 UK hospitals with a diagnosis of missed miscarriage in the first 14 weeks of pregnancy, who were randomly assigned to receive either mifepristone or a placebo drug followed by misoprostol two days later.

Published in the British Journal of Obstetrics and Gynaecology, the study found the new combined drug treatment was on average £182 cheaper for each successfully managed miscarriage than the current standard NHS medication.

As this is the largest ever study into the most effective medical treatment for missed miscarriage, and the results are so clear, researchers and campaigners are calling for guidance from the National Institute for Health and Care
Excellence (NICE) to be updated in light of the newly published findings. In the meantime, Tommy's experts encourage anyone diagnosed with missed miscarriage to ask their doctor about the combined drug treatment.

Senior author Tracy Roberts, Professor of Health Economics at the University of Birmingham, said: "Pregnancy loss causes heartbreak for millions of families, and it is crucial that we find better ways to care for everyone going through miscarriage. Our findings could have huge benefits if they're translated into clinical practice, with better outcomes for patients and lower costs for care services."

First author Dr Duby Okeke Ogwulu, of the University of Birmingham's Institute of Applied Health Research, added: "We hope the NICE guidance will be updated in light of this new evidence, so that everyone who needs it has access to the most effective treatment."

Tommy's CEO Jane Brewin commented: "Besides the physical harm, miscarriage can have serious psychological consequences, which can be made worse by the trauma of a failed treatment forcing mothers to endure weeks of carrying a baby they know has died.

"One in four pregnancies ends in loss, and while our researchers work to understand how we can prevent this, it's vital their latest findings are put into practice so that everyone going through miscarriage has the best possible care. Particularly given Covid-19 pressures on the NHS, our new study could be applied to make better use of precious resources, as well as reducing the toll miscarriage can take on parents."

An estimated 23 million miscarriages occur every year worldwide - equating to 44 pregnancy losses each minute. Miscarriage (defined as the loss of a pregnancy before 24 weeks) costs the UK at least £471 million a year, through direct impact on health services and lost productivity, but scientists expect the costs surpass £1 billion a year when factoring in longer-term physical and mental health impacts.

Claire Bromley, aged 32, from Sittingbourne in Kent, chose surgery when she had a miscarriage last year, as her previous experience when medication failed was so distressing.

Claire said: "The whole process took around 3 months and was extremely traumatic, so I hope this new drug will mean others don't have to suffer like I did. I was told medication would take a few hours to work, but started bleeding and cramping in minutes, while stuck in hospital waiting for other prescriptions. Despite taking effect so fast, the medication didn't work, so I was sent for surgery - and when that failed too, I had to take the pills again. With my second miscarriage, I chose surgery right away to avoid the risk of repeating such a long and painful treatment."

Katy Allan, aged 43, from South Yorkshire has experienced multiple miscarriages and a range of treatment, initially having surgery that caused internal scarring and later choosing medication in the hope it would cause less damage.

Katy said: "The treatment for my third miscarriage was a four-month long nightmare, with several rounds of medication and hospital staff trying to physically remove the pregnancy while I was awake, ending in painful surgery; it was one of the most horrendous experiences of my life and I remain completely traumatised. I couldn't move on physically or mentally because I was pregnant and not pregnant for months, with tests remaining positive and hormones still racing long after we heard those spine-shivering words of 'I am so sorry but there is no heartbeat'. The long ordeal of treatment made miscarriage even harder so I hope this new research can help to prevent others from going through what I did."

The COVID-19 pandemic has now claimed over 2 million deaths worldwide, and this number is only increasing. In response, health agencies have rolled out tests to diagnose and understand the disease. Besides the now widely known PCR test, there is interest in serological (blood) tests that detect "antibodies" against SARS-CoV-2, the virus that causes COVID-19. These blood tests have considerable applications, from identifying blood donors with high levels of anti-SARS-CoV-2 antibodies, whose blood can be used for convalescent plasma therapy, to measuring vaccine effectiveness.

So, what are antibodies? These are proteins produced by the body's immune system to combat foreign proteins, such as the SARS-CoV-2 virus. Antibodies function by binding to a specific part of the virus that the immune system recognizes, called "antigens." SARS-CoV-2 is composed of four major proteins, with two being highly immunogenic (capable of producing an immune response). These immunogenic proteins are called spike (S) and nucleocapsid (N) proteins. Presence of antibodies specific to the S protein means there is a higher amount of virus-neutralizing activity while antibodies specific to N protein indicate the presence of previous SARS-CoV-2 infection.

Despite this general awareness, we actually have only a vague understanding of how different antibodies (or antibody "isotypes") interact with the various antigens produced by SARS-CoV-2. Hence, a team of scientists led by Senior Assistant Professor Hidetsugu Fujigaki and Professor Yohei Doi from Fujita Health University, in collaboration with National Institute of Infectious Diseases, Japan, FUJIFILM Wako Pure Chemical Corporation, and FUJIFILM Corporation undertook the first detailed investigation of these interactions. "Our goal was to quantify the neutralizing activity of these different antibodies against SARS-CoV-2," Dr. Fujigaki explains, "We looked at antibodies specific to different parts of the S protein and the N protein to determine which of them was the best predictor of stopping the virus."

They did this through an analysis of blood samples from 41 COVID-19 patients at the Fujita Health University Hospital. The team developed assays using three common antibodies (IgG, IgM, and IgA), each of them split into isotypes that bind specifically to five antigens (three parts of the S protein, including the receptor binding domain [RBD], the full S protein, and the full N protein).

The results of their experiments showed that all antibody isotypes that bind to the S protein (full and parts) were highly specific, but antibody isotypes binding to the N protein were less so. With minor variations, all antibodies are detectable in patients at approximately 2 weeks after symptoms appear, and detection sensitivity was higher than 90% (except in the case of IgM binding to N protein). Importantly, the researchers showed that IgG specific to the RBD of S protein had the highest correlation with virus neutralizing activity and disease severity. In other words, measuring RBD-specific IgG levels could tell us a lot about the immune response of COVID-19 patients, and could be the foundation for improving COVID-19 blood tests.

"We are also very excited by our findings because of their implications for convalescent serum/plasma therapy, a type of treatment where you transfuse blood from people who recovered from COVID and have high levels of antibodies against SARS-CoV-2," Dr. Fujigaki adds, "Being able to show that the IgG antibody against RBD is highly correlated with neutralizing activity means we can identify appropriate blood donors for this treatment."

The world is hopefully moving into the final stages of the pandemic, and this information could be the tools needed to carve out the final few steps to a safe post-pandemic world.

University of Miami Miller School of Medicine researchers are the first to demonstrate that COVID-19 can be present in the penis tissue long after men recover from the virus.

The widespread blood vessel dysfunction, or endothelial dysfunction, that results from the COVID-19 infection could then contribute to erectile dysfunction, or ED, according to the study recently published in the World Journal of Men's Health. Endothelial dysfunction is a condition in which the lining of the small blood vessels fails to perform all of its functions normally. As a result, the tissues supplied by those vessels could undergo damage.

"Our research shows that COVID-19 can cause widespread endothelial dysfunction in organ systems beyond the lungs and kidneys. The underlying endothelial dysfunction that happens because of COVID-19 can enter the endothelial cells and affect many organs, including the penis," said study author Ranjith Ramasamy, M.D., associate professor and director of the Miller School's Reproductive Urology Program. "In our pilot study, we found that men who previously did not complain of erectile dysfunction developed pretty severe erectile dysfunction after the onset of COVID-19 infection."

Dr. Ramasamy and colleagues collected penile tissue from two men with a history of COVID-19 infection who underwent penile prosthesis surgery for ED. One of the men was hospitalized for COVID-19, while the other patient only had mild symptoms when he contracted the virus.

The researchers also collected tissue from two additional men with no history of COVID-19 infection undergoing the same surgery for ED. The investigators analyzed all the tissue samples for not only evidence of the virus but also endothelial dysfunction.

They found COVID-19 was present in the penile tissue of both men who had been infected, but not in the men with no history of the virus. The men had been infected six and eight months prior, respectively. These men had evidence of endothelial dysfunction, while the men who had been free of the virus did not.

"This suggests that men who develop COVID-19 infection should be aware that erectile dysfunction could be an adverse effect of the virus, and they should go to a physician if they develop ED symptoms," Dr. Ramasamy said.

The authors hypothesize that similar to other COVID-19 related complications, widespread infection and subsequent endothelial dysfunction could result in ED, and that worsening of ED could be due to the virus's presence in the penile tissue, itself.

In a previously published study, Dr. Ramasamy and Miller School colleagues found that COVID-19 can also invade testis tissue in some men who are infected with the virus, which might be the first step in understanding the virus's potential impact on male fertility and whether COVID-19 can be sexually transmitted.

"These latest findings are yet another reason that we should all do our best to avoid COVID-19," said first author Eliyahu Kresch, a medical student working with Dr. Ramasamy.

"We recommend vaccination and to try to stay safe in general," Kresch said.

An investigational gene therapy can safely restore the immune systems of infants and children who have a rare, life-threatening inherited immunodeficiency disorder, according to research supported in part by the National Institutes of Health. The researchers found that 48 of 50 children who received the gene therapy retained their replenished immune system function two to three years later and did not require additional treatments for their condition, known as severe combined immunodeficiency due to adenosine deaminase deficiency, or ADA-SCID. The findings were published today in the New England Journal of Medicine.

ADA-SCID, which is estimated to occur in approximately 1 in 200,000 to 1,000,000 newborns worldwide, is caused by mutations in the ADA gene that impair the activity of the adenosine deaminase enzyme needed for healthy immune system function. This impairment leaves children with the condition highly susceptible to severe infections. If untreated, the disease is fatal, usually within the first two years of life.

"These findings suggest that this experimental gene therapy could serve as a potential treatment option for infants and older children with ADA-SCID," said Anthony S. Fauci, M.D., director of NIH's National Institute of Allergy and Infectious Diseases (NIAID). "Importantly, gene therapy is a one-time procedure that offers patients the hope of developing a completely functional immune system and the chance to live a full, healthy life."

People with ADA-SCID can be treated with enzyme replacement therapy, but this treatment does not fully reconstitute immune function and must be taken for life, usually once or twice weekly. Transplants of blood-forming stem cells, ideally from a genetically matched sibling donor, can provide a more lasting solution. However, most people lack such a donor. Additionally, stem cell transplants carry risks such as graft-versus-host disease and side effects from chemotherapy medications given to help the donor stem cells establish themselves in the patient's bone marrow.

The new research evaluated an experimental lentiviral gene therapy designed to be safer and more effective than previously tested gene-therapy strategies for ADA-SCID. This gene therapy involves inserting a normal copy of the ADA gene into the patient's own blood-forming stem cells. First, stem cells are collected from the patient's bone marrow or peripheral blood. Next, a harmless virus is used as a "vector," or carrier, to deliver the normal ADA gene to these cells in the laboratory. The genetically corrected stem cells then are infused back into the patient, who has received a low dose of the chemotherapy medication busulfan to help the cells establish themselves in the bone marrow and begin producing new immune cells.

The experimental gene therapy, developed by researchers from the University of California, Los Angeles (UCLA) and Great Ormond Street Hospital (GOSH) in London, uses a modified lentivirus to deliver the ADA gene to cells. Previous gene-therapy approaches for ADA-SCID have relied on a different type of virus called a gamma retrovirus. Some people who have received gamma retroviral gene therapies have later developed leukemia, which scientists suspect is due to the vector causing activation of genes that control cell growth. The lentiviral vector is designed to avoid this outcome and to enhance the effectiveness of gene delivery into cells.

The results come from three separate Phase 1/2 clinical trials, two conducted in the United States and one in the United Kingdom. The U.S. trials, led by principal investigator Donald Kohn, M.D., of UCLA, enrolled 30 participants with ADA-SCID ranging in age from 4 months to 4 years at UCLA Mattel Children's Hospital and the NIH Clinical Center in Bethesda, Maryland. The U.K. study, conducted at GOSH and led by principal investigator Claire Booth, M.B.B.S., Ph.D., enrolled 20 participants ranging in age from 4 months to 16 years. Most participants acquired and retained robust immune function following gene therapy--96.7% after two years in the U.S. studies and 95% after three years in the U.K. study--and were able to stop enzyme replacement therapy and other medications. Of the two participants for whom gene therapy did not restore lasting immune function, one restarted enzyme replacement therapy and later received a successful stem cell transplant from a donor, and the other restarted enzyme replacement therapy.

The lentiviral gene therapy appeared safe overall, although all participants experienced some side effects. Most of these were mild or moderate and attributable to the chemotherapy that the participants received.

Researchers observed similar outcomes in all three trials, although there were some differences between the studies. Stem cells were collected from bone marrow in the U.S. trials and from peripheral blood in the U.K. trial. In one of the U.S. trials, 10 children were treated with genetically corrected stem cells that had been frozen and later thawed. The two other trials used fresh stem cell preparations. In the future, the freezing procedure--known as cryopreservation--may allow stem cells to be more easily transported and processed at a manufacturing facility far from the patient's home and shipped back to a local hospital, reducing the need for patients to travel long distances to specialized medical centers to receive gene therapy. A trial of the cryopreserved treatment is now underway at the Zayed Centre for Research into Rare Diseases in Children in London, in partnership with GOSH.

Low doses of a four-drug combination helps prevent the spread of cancer in mice without triggering drug resistance or recurrence, shows a study published today in eLife.

The findings suggest a new approach to preventing cancer metastasis in patients by simultaneously targeting multiple pathways within a metastasis-promoting network. They may also help identify people who would most likely benefit from such treatment.

Metastasis, the spread of cancerous cells through the body, is a common cause of cancer-related deaths. Current approaches to treating metastatic cancer have focused on high doses of individual drugs or drug combinations to hinder pathways that promote the spread of cancer cells. But these approaches can be toxic to the patient, and may inadvertently activate other pathways that cause the drugs to stop working and the tumours to return.

"There is an urgent need for new strategies to suppress cancer metastasis, especially for cancers such as triple-negative breast cancer that currently lack effective therapies," says first author Ali Yesilkanal, a postdoctoral scholar at the Ben May Department for Cancer Research at the University of Chicago, US.

In the study, Yesilkanal and colleagues analysed gene expression data from patients participating in the Cancer Genome Atlas study to understand how a metastasis-suppressing protein called Raf Kinase Inhibitory Protein (RKIP) works. They found that RKIP reduces the expression of a network of genes that promote the spread of cancer cells.

They then created a four-drug combination that mimics how RKIP suppresses the ability of cancer cells to spread. They administered low doses of this treatment to mice with metastatic cancer that mimics metastatic breast cancer, and found that it blocked the spread of cancer and increased the animals' survival. Importantly, the treatment did not trigger the compensatory mechanisms that often cause high-dose, anti-metastasis drugs to stop working and tumours to return.

Finally, the team used computer modelling to explain why reducing, but not completely stopping, the expression of this network of genes helped prevent metastasis without triggering drug resistance or relapse. They also identified patients with breast cancer in the Cancer Genome Atlas who might be most likely to benefit from such treatment based on their cancer's gene expression patterns.

"Our findings could lead to a new cancer treatment strategy where patients first receive low-dose combination drugs that block metastasis and then receive traditional cancer treatments such as radiation, chemotherapy or immunotherapy," says co-senior author Marsha Rosner, the Charles B. Huggins Professor at the Ben May Department of Cancer Research at UChicago.

"Our results challenge current approaches to cancer treatment and suggest an alternative strategy for controlling metastasis in breast cancer and potentially other types of cancer," concludes co-senior author Alexandre Ramos, Group Leader at the School of Arts, Sciences and Humanities, University of São Paulo, Brazil.

A University of Alberta virology lab has uncovered how an oral antiviral drug works to attack the SARS-CoV-2 virus, in findings published May 10 in the Journal of Biological Chemistry.

The researchers demonstrated the underlying mechanism of action by which the antiviral drug molnupiravir changes the viral genome, a process known as excessive mutagenesis or “error catastrophe.”

“The polymerase, or replication engine of the virus, mistakes molnupiravir molecules for the natural building blocks required for viral genome replication and mixes them in,” explained Matthias Götte, professor and chair of the Department of Medical Microbiology & Immunology in the Faculty of Medicine & Dentistry and member of the Li Ka Shing Institute of Virology. “It causes the polymerase to make sloppy copies—nonsense genomes that are useless and not viable.”

Molnupiravir is currently in Phase 3 human clinical trials, which are expected to report preliminary data by the end of June. Phase 2 trial results recently revealed that the drug eliminated SARS-CoV-2 infectivity in newly diagnosed patients after five days of treatment.

The drug is taken as a pill, making it much easier to administer than other approved treatments such as remdesivir or monoclonal antibodies, which must be given intravenously. It has not yet been shown to be effective in treating hospitalized COVID-19 patients with advanced disease, so current trials are focused on determining how well it works for newly diagnosed patients. It is hoped the drug could also be used as a preventive measure to protect household members against infection.

“Molnupiravir is one of the few compounds under investigation that is orally available,” Götte said. “Data reported so far demonstrate that this drug is well tolerated with no signs of severe side-effects, and it shows an antiviral effect after five days. Whether it can also reduce hospitalizations remains to be seen.”

“Our work to demonstrate that the effect of the drug is indeed mediated by the viral polymerase is reassuring, because if the drug somehow generates mistakes in the virus and you don’t know how it happens, there could be other mechanisms at work that could also harm the cell,” he said. “Still, the safety of the drug for COVID-19 patients remains to be evaluated and monitored."

Another step in the hunt for a weapon against future pandemics

Molnupiravir was first identified as a broad spectrum antiviral at Emory University in Atlanta, Georgia. In 2003 it was developed as a treatment for chronic hepatitis C, but it was dropped due to possible side-effects associated with long-term use. The drug was then tested in humans with influenza, because the course of treatment for flu is much shorter. The focus of testing switched to SARS-CoV-2 after the COVID-19 pandemic emerged. The drug is now being developed in partnership by Merck and Ridgeback Biotherapeutics.

Merck has made deals with five generic drugmakers in India to make molnupiravir, and at least one of them has applied for approval to use it on an emergency basis, as at least 350,000 new infections are diagnosed in that country every day and vaccination levels are low.

Götte and his team previously uncovered the mechanisms of action for remdesivir, a now-approved treatment that inhibits replication of the SARS-CoV-2 virus, and baloxavir, an influenza drug. 

Next, they will test molnupiravir’s mechanism of action against the polymerases of some of the other viruses the World Health Organization has identified as having high epidemic potential.

“All are recognized as emerging pathogens where we need to develop countermeasures,” Götte said. “We need to be prepared with broad-spectrum antivirals that can serve as a first line of defence.”

“Even once vaccines are developed, we can’t get them into all the arms at once,” he said. “To really fight outbreaks and epidemics, one tool is unlikely to be sufficient.”

The researchers were supported by grants from the Canadian Institutes of Health Research, the Alberta Ministry of Jobs, Economy and Innovation, and the U.S. National Institutes of Health Centers for AIDS Research. The other authors were graduate student Calvin Gordon and research associate Egor Tchesnokov of the U of A, and Raymond Schinazi of the Emory School of Medicine.

Journal

Journal of Biological Chemistry

DOI

10.1016/j.jbc.2021.100770

Rheumatic heart disease (RHD) remains a major cause of cardiovascular disease in Africa, even as acute rheumatic fever and RHD have become rare in high-income countries. In a new study led by investigators at Brigham and Women's Hospital, the team modeled the investment case for control of RHD in the African Union (AU) region. Results showed the potential to reduce RHD death by almost a third by increasing coverage of RHD interventions in regions of the AU to 2030, with a high return on investment in both the long and short term. Their results are published in The Lancet Global Health.

"Investing in early detection of rheumatic fever and rheumatic heart disease and providing cardiac surgery to those who need it could have a dramatic effect, saving around 70,000 lives by 2030," said corresponding author Gene Bukhman, MD, PhD, of the Division of Cardiovascular Medicine and Division of Global Health Equity. "Our findings illustrate the importance and high return on investments in the PEN-Plus package of integrated disease management as well as cardiac surgery."

Rheumatic heart disease is the most commonly acquired heart disease in people under age 25 and causes more than 280,000 globally deaths each year. The disease is the result of accumulated damage to the heart valves caused by rheumatic fever. Rheumatic fever is an autoimmune inflammatory reaction to strep throat and frequently occurs in childhood, potentially leading to death or life-long disability.

Rheumatic heart disease can be averted by preventing streptococcal infections or treating them with antibiotics when they do occur. Bukhman and colleagues constructed a model to estimate the health effects, costs, and monetized health gains from increasing coverage of a set of RHD interventions between 2021 and 2030. These interventions include strategies for expanding integrated outpatient care for severe, chronic noncommunicable diseases (NCDs) at district hospitals, encompassing the WHO's Package of Essential NCD Services (PEN-Plus). Examples include preliminary echocardiographic RHD diagnosis, medical treatment of RHD, and postoperative anticoagulation.

The team's modelling approach estimates a 30 percent reduction in death from RHD by increasing coverage of these interventions. The authors note that in the short term, investment in primary prevention would not avert a large number of deaths and would be costly because of the large number of childhood pharyngitis cases. But in the longer term, primary prevention would offer a significant return on investment by preventing costly secondary effects.

"Investing in these measures could avert large amounts of morbidity and mortality and provide returns in economic welfare," said Bukhman. "Our findings indicate that these achievable interventions could accelerate progress towards eliminating RHD in the AU."

CORVALLIS, Ore. - A team of Oregon State University scientists has discovered a new class of anti-cancer compounds that effectively kill liver and breast cancer cells.

The findings, recently published in the journal Apoptosis, describe the discovery and characterization of compounds, designated as Select Modulators of AhR-regulated Transcription (SMAhRTs).

Edmond Francis O'Donnell III and a team of OSU researchers conducted the research in the laboratory of Siva Kolluri, a professor of cancer research at Oregon State. They also identified the aryl hydrocarbon receptor (AhR) as a new molecular target for development of cancer therapeutics.

"Our research identified a therapeutic lead that acts through a new molecular target for treatment of certain cancers," Kolluri said.

O'Donnell added: "This is an exciting development which lays a foundation for a new class of anti-cancer therapeutics acting through the AhR."

The researchers employed two molecular screening techniques to discover potential SMAhRTs and identified a molecule - known as CGS-15943 - that activates AhR signaling and kills liver and breast cancer cells.

Specifically, they studied cells from human hepatocellular carcinoma, a common type of liver cancer, and cells from triple negative breast cancer, which account for about 15% of breast cancers with the worst prognosis.

"We focused on these two types of cancers because they are difficult to treat and have limited treatment options," said Kolluri, a professor in the Department of Environmental and Molecular Toxicology in the College of Agricultural Sciences. "We were encouraged by the results because they are unrelated cancers and targeting the AhR was effective in inducing death of both of these distinct cancers."

The researchers also identified the AhR-mediated pathways that contribute to the anti-cancer actions of CGS-15943. Developing cancer treatments requires a detailed understanding of how they act to induce anti-cancer effects. The researchers determined that CGS-15943 increases the expression of a protein called Fas Ligand through the AhR and causes cancer cell death.

These results provide exciting new leads for drug development, but human therapies based on these results would not be available to patients for years, the researchers said.

BUFFALO, N.Y. - Americans are in chronic pain, and a comprehensive new study exploring trends in this major public health concern reveals that what has been a long-standing and under-acknowledged problem is getting substantially worse.

The findings, published in the latest issue of the journal Demography, suggest blanket increases across multiple measures, with pain rising in every adult age group, in every demographic group, and at every site of pain for which data exists. People today are experiencing more pain than individuals of the same age in earlier decades. In fact, each subsequent birth group is in greater pain than the one that came before it.

"We looked at the data from every available perspective including age, gender, race, ethnicity, education, and income, but the results were always the same: There was an increase in pain no matter how we classified the population," says Hanna Grol-Prokopczyk, associate professor of sociology in the University at Buffalo College of Arts and Sciences, and co-author of the paper with Zachary Zimmer, professor of sociology at Mount St. Vincent University, and first author Anna Zajacova, associate professor at Western University.

"You might think that with medical advances we'd be getting healthier and experiencing less pain, but the data strongly suggest the exact opposite," Grol-Prokopczyk says.

While some other recent research has examined trends in chronic pain, those earlier studies focused on narrower age groups, usually those over age 50. The current paper examines a more comprehensive range of adults, aged 25-84. In addition, it relies on the 2002-20018 National Health Interview Survey (NHIS) -- a nationally representative data set with more than 441,000 participants -- to show how pain, which was already alarmingly high at the start of the research period in 2002, increased substantially based on annual data over 16 years.

In the United States, chronic pain affects more people and has a greater economic cost than heart disease, diabetes and cancer combined, according Grol-Prokopczyk, a medical sociologist and an expert in chronic pain.

"It's important for policymakers to understand trends in chronic pain so we can wisely and appropriately invest resources in research and treatment," says Grol-Prokopczyk. "We hope this paper can help illustrate the issue."

In addition to revealing trends, the paper also provides a glimpse of what might be causing the increase.

The information necessary for a detailed explanation isn't part of the NHIS data set, but the researchers did look at a host of variables to determine which ones were most closely associated with the pain trends.

In the oldest age group (65-84), physical health conditions such as body mass index (BMI), hypertension, diabetes and kidney conditions correlate most with increases in pain. While BMI again surfaces as a correlate in young and middle-aged people, distress and alcohol use also have strong associations with chronic pain trends in these age groups.

"What we're seeing in the younger age groups demonstrates how pain in some ways functions as much as a mental health problem as it does a physical health problem," says Grol-Prokopczyk. "Pain can be exacerbated by stress, and stress can bring about alcohol use."

The paper's findings are so robust that they inspire questions about why chronic pain hasn't previously been a larger part of the national dialogue on the country's biggest health challenges.

Information on cancer mortality is readily available. There is plenty of research on obesity and other health concerns, but until approximately five years ago there were no national studies on general chronic pain trends, according to Grol-Prokopczyk.

"It's likely that the opioid epidemic brought about some awareness of the importance of pain," says Grol-Prokopczyk. "The timing of the opioid crisis' arrival suggests that it began to open the public's eyes to the problem."

What's clear is that chronic pain is having a profoundly detrimental effect on the U.S. population and demands closer monitoring by public health officials.

"Pain is a leading cause of disability and there is evidence that pain has an impact on life expectancy," she says. "So the problem is one not only affecting quality of life, but potentially even quantity of life."