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SharecloseShare pageCopy linkAbout sharingImage source, Nicola ElsonThe NHS has struck a confidential deal for what’s thought to be the most expensive drug ever developed. The gene therapy Libmeldy is used to treat an extremely rare condition, MLD, which causes severe damage to a child’s nervous system and organs.Around four babies are born with the disorder in England every year. The one-off treatment has a list price of £2.8 million but can be offered on the NHS after the health service negotiated a confidential discount.NHS chief executive Amanda Pritchard said: “This revolutionary drug is a life-saver for the babies and young children who suffer from this devastating hereditary disorder and will spare their families untold heartache and grief.”‘Completely out the blue’Nicola Elson’s daughter, Connie, first displayed symptoms of the condition as a toddler – tripping up and losing her concentration more easily. “It was not long after that, that we got the diagnosis of MLD,” she said. “It was completely out of the blue, there was nothing like this in my family or my husband’s family.”Nicola was told there was a one-in-four chance any child she had with her husband would be affected. She had Connie’s younger brother Joe tested and was told he was also carrying the defective gene. “It’s the most unimaginable situation you can ever think of being in,” said Nicola. “For too long, doctors were saying, we’re sorry but there is no hope and there’s nothing we can do.”Both children were referred onto an early clinical trial in Italy for a new treatment. By then Connie’s condition had deteriorated and she was not well enough to be given the drug – which needs to be taken at a very early stage after symptoms develop.MLD, or Metachromatic Leukodystrophy, is an extremely rare hereditary disorder caused by a crucial enzyme deficiency. Over time the nerves in the brain and other parts of the body stop working properly. It first develops in babies and toddlers younger than 30 months and can lead to loss of sight, speech and hearing, as well as difficulty moving and seizures. Average life expectancy is between just five and eight years old. Libmeldy is a form of gene therapy that works by replacing the faulty gene that causes the disorder. On 5 December 2014 – on what his family now call his re-birthday – Joe had an operation to remove stem cells from his bone marrow. They were treated and re-injected back into his body as part of the clinical trial.Image source, Nicola ElsonSeven years later, his mum says he is a typical 11-year-old boy now helping to look after his older sister. “If you were a stranger on the street, you wouldn’t know Joe even had this condition,” says Nicola. “He swims, he is in mainstream school, and he plays far too many computer games for my liking.”The long-term prognosis for children given the drug is still unknown, and Joe will need to be monitored for years to come, but both doctors and families are hopeful it could offer a permanent cure for the condition. ‘Orphan drug’Libmeldy is a so-called orphan drug – a pharmaceutical agent developed to treat a medical condition which, because it is so rare, may not be profitable to produce without some form of government assistance.Last year, it was reviewed and rejected by the drug price watchdog for England. In draft guidance, the National Institute for Health Care Excellence (NICE) said it was too expensive and yet to be proven in the long term. Costing £2.8 million at its list price, the watchdog said it was the most expensive single treatment it has ever evaluated. But following discussions, specialist drugmaker Orchard Therapeutics increased a confidential discount to the price the NHS actually pays. It has now been recommended for children with no symptoms or who can still walk independently.It will be delivered by a specialist service through the Centre for Genomic Medicine at Saint Mary’s hospital in Manchester, one of five European sites that will administer the treatment. Professor Simon Jones, a consultant at Manchester University NHS Foundation Trust, described the announcement as a “major deal”. “These kinds of therapies are going to be expensive, they are going to be hard to deliver and only a few centres are going to be able to do that,” he said. “There are probably quite a few different disorders which can be treated with this approach, but Libmeldy is the first to really break ground.”The drug has been recommended for use by Nice in England only at this stage. Patients from Scotland, Wales and Northern Ireland would need their national health systems to fund the treatment in Manchester.You can follow Jim on twitter.

A new study published in Diabetologia (the journal of the European Association for the Study of Diabetes (EASD) finds that the timing of exposure to bright light can have a significant influence on postprandial (post-meal) glucose metabolism, thermoregulation, and energy expenditure during sleep in overweight, insulin-resistant adults.
The research was conducted by Jan-Frieder Harmsen, Patrick Schrauwen, and colleagues at the Department of Nutrition and Movement Sciences, NUTRIM School for Nutrition and Translational Research in Metabolism, Maastricht University Medical Center, Maastricht, The Netherlands. It aimed to determine whether redesigning indoor lighting to more closely mimic the natural light-dark cycle could help improve metabolic health. The authors say: “Optimising indoor light conditions to more closely mimic the natural light/dark cycle holds promise to prevent adverse effects on whole-body energy and glucose metabolism associated with the nowadays prevailing constant indoor lighting conditions.”
Light levels are known to be the most important time cue to synchronise the body’s circadian clock to the 24-hour day-night cycle. Previous research has shown that exposure to bright light during the evening or night influences glucose metabolism and is associated with being overweight or obese, as well as an increased risk of cardiovascular diseases.
In the modern world light exposure — including artificial light — is widespread and available around the clock, resulting in most people being exposed to light at home, in the workplace, or from the screens of electronic devices during the hours of darkness. The detrimental effects of light at night (LAN) include acutely elevated blood glucose and insulin levels after meals, and LAN exposure is associated with an increased incidence of type 2 diabetes mellitus (T2DM) in elderly people. The researchers note: “Our modern society also faces a lack of sufficient time spent under bright light conditions during daytime and in fact, most time is spent indoors under artificial lighting under much lower light levels compared to natural daylight outdoors.”
A mixed-sex group of 14 overweight (average BMI of 29.6kg/m2, on the borderline between overweight and obese), insulin-resistant volunteers between the ages of 40 and 75 were recruited for the study which was split into two sessions. Subjects were all non-smokers, had an average age of 67 years, and were in general good health. Participants stayed in a respiration chamber for the whole of each session, which lasted 40-hours from 18:00h on day 1 to 12:00h on day 3 and included two overnight sleep periods. A respiration chamber enabled the measurement of oxygen consumption and carbon dioxide production, allowing the calculation of total energy expenditure and sleeping metabolic rate (SMR).
One session (Bright day — Dim evening) comprised a period of bright light during daylight hours (08:00-18:00h), followed by dim light during the evening (18:00-23:00h), while the situation was reversed in the other Dim day — Bright evening session. Participants were in darkness during the night from 23:00h to 07:00h in both sessions, and meals were provided at 08:00h for breakfast; 13:00h for lunch; and 18:00h for dinner.

Rather than constantly repainting a new canvas with a picture of the surrounding world each time it takes in information, the human brain appears to build a working model supported by predictions constantly checked and rechecked against the sights and sounds it already expects.
Researchers from the University of Wisconsin-Madison have demonstrated the top-down nature of this world view by disrupting it with tiny doses of an anesthetic drug called ketamine. Their study reveals the importance of a specific type of connection between brain cells and may also explain ketamine’s promise as a treatment for depression.
A bottom-up understanding of perception has been prevalent for decades and says that sensory information moves from lower-order parts of the brain to “higher” parts that use it to perform executive functions like focusing and planning. But the top-down approach has roots in the 19th century. Now called predictive coding, the idea is that the frontal lobe of the brain makes predictions about what will happen next based on learned associations.
“You come to expect that if you hear a bark, you will see a dog,” says Sounak Mohanta, a graduate student in the lab of UW-Madison psychology and neuroscience professor Yuri Saalmann. “We used those sorts of associations to show how predictions affect behavior.”
For their study, published recently in the Journal of Neuroscience, the researchers taught 32 volunteers associations that were completely new to them by playing them a three-syllable nonsense word and following it with a picture from an assortment of unique animal-like shapes called greebles.
Through feedback, the volunteers learned which sound was paired with which picture. The researchers then tested the volunteers by playing them a sound, showing them a picture, and asking the volunteers to say whether the pair matched. The researchers also mapped the patterns in volunteers’ brains specific to correct sound-shape pairs by recording electrical activity as the sounds and shapes appeared.

Smoking cannabis leads to lung damage, but in a different way to tobacco, new University of Otago research has found.
Study co-author Professor Bob Hancox says until recently, it was assumed that cannabis would have similar effects to tobacco, but this does not seem to be the case.
“Although the effects of cannabis were detrimental, the pattern of lung function changes was not the same. The research found that prolonged cannabis use led to over-inflated lungs and increased the resistance to airflow to a greater extent than tobacco,” he says.
“It was also found that cannabis use may also impair the ability of the lungs to extract oxygen from the breath. This is a known consequence of smoking tobacco, but has not been demonstrated with cannabis until now.”
The findings come from the long-running Dunedin Multidisciplinary Health and Development Study, which has documented cannabis use and measured lung function throughout adult life up to age 45 in more than 1000 individuals born in Dunedin in 1972/73.
The Dunedin Study may have the world’s most complete data on lifetime cannabis use and lung function in a large population sample, Professor Hancox says.

A new cloud-based data resource co-developed by scientists at Cedars-Sinai provides the research community with a comprehensive set of tools to help identify new subtypes of amyotrophic lateral sclerosis (ALS), a fatal neurological disorder.
The web-based tool is part of a collaborative effort with more than 100 scientists called Answer ALS, which includes biological and clinical data from more than 1,000 ALS patients. The information is intended to help investigators across the globe better understand ALS, also known as Lou Gehrig’s disease. Details of the resource are described in the peer-reviewed journal Nature Neurosciences.
“This is one of the largest resources for ALS samples in the world,” said Clive Svendsen, PhD, executive director of the Cedars-Sinai Board of Governors Regenerative Medicine Institute and a co-author of the paper and co-director of the Answer ALS program. “It’s a critical step forward in finding new treatments for a very complex disease that has really no effective treatments available.”
ALS is a progressive neurodegenerative disease that damages nerve cells known as motor neurons in the brain and spinal cord, leading to the loss of muscle control. With no known cure, it is usually fatal within five years of diagnosis.
Discovering new subtypes of ALS can provide clues to how an individual may respond to treatment. This information is useful for guiding disease management and can help lead to the development of new drugs that target specific cells and pathways that may only be found in certain subgroups.
“We don’t think ALS is one disease,” said Svendsen, who is also a professor of Biomedical Sciences and Medicine. “It’s very complex and we think there are different subtypes that can be targeted differently. We just need to uncover them.”
To successfully build the database, scientists first had to create a model of the disease that could be used to help study how ALS develops. Creating models of neurodegenerative diseases has been notoriously challenging because of the lack of reliable animal models or patient samples at early disease stages.

A study led by researchers at The University of Texas MD Anderson Cancer Center reported that the MEK inhibitor trametinib reduced the risk of disease progression or death by 52% compared to standard-of-care therapies for the treatment of low-grade serous ovarian carcinoma. The findings were published today in The Lancet.
The international, multi-center Phase II/III trial led by David Gershenson, M.D., professor of Gynecologic Oncology & Reproductive Medicine, is the first positive randomized clinical trial of any therapy to demonstrate significantly increased progression-free survival (PFS) and objective response rate (ORR) in low-grade serous carcinoma, a rare and understudied form of ovarian cancer.
Median PFS for patients receiving trametinib was 13 months compared to 7.2 months in those receiving standard-of-care therapies. The ORR with trametinib was 26%, with 59% having stable disease for at least eight weeks. The median duration of response on trametinib and standard-of-care were 13.6 months and 5.9 months, respectively. Median overall survival was 37.6 months in the trametinib group and 29.2 months in the standard-of-care group.
“Previous treatment recommendations for patients with low-grade serous carcinoma were based on studies that focused on the more common high-grade serous carcinoma, despite the subtypes having distinct developmental pathways, molecular biology and clinical behaviors. Now we have encouraging data for this specific group of patients,” Gershenson said. “The results from our study show trametinib should be considered a new standard-of-care option for women with progressive or relapsed low-grade serous carcinoma.”
Low-grade serous carcinoma accounts for approximately 5% of all cases of epithelial ovarian cancer and is often diagnosed at a younger age in advanced stages, with a relapse rate of more than 70%. Frontline treatment typically consists of chemotherapy followed by aromatase inhibitor therapy. However, because this rare subtype is relatively resistant to platinum-based chemotherapy, finding an effective targeted therapy remains an unmet clinical need.
Trametinib emerged as a novel therapeutic approach for low-grade serous carcinoma due to a high prevalence of activating mutations in the MAPK signaling pathway, which includes the MEK protein. The drug is approved by the Food and Drug Administration for use in combination with BRAF inhibitor dabrafenib for a range of BRAFV600 mutation-positive cancers, including unresectable or metastatic melanoma, non-small-cell lung cancers and anaplastic thyroid cancer.
In the study, researchers enrolled and randomly assigned 260 patients 18 years or older with recurrent low-grade serous carcinoma of the ovary or peritoneum from 84 hospitals in the United States and United Kingdom between February 2014 and April 2018. Half received oral trametinib once daily, while the other half received one of five standard-of-care treatment options, including paclitaxel, pegylated liposomal doxorubicin, topotecan, letrozole or tamoxifen. The racial breakdown of participants was 229 White (88%), 9 Black or African American (3%), 7 Asian (3%), 1 Native Hawaiian or Pacific Islander (0.4%) and 14 undisclosed (5%), with a median age of 56.6 in the trametinib group and 55.3 in the standard-of-care group.
The most frequent grade 3 or 4 adverse events related to trametinib were skin rash (13%), anemia (13%), hypertension (12%), diarrhea (10%), nausea (9%) and fatigue (8%). In the standard-of-care group, the most frequent grade 3 or 4 adverse events were abdominal pain (17%), nausea (11%), anemia (10%) and vomiting (8%). No treatment-related death occurred.
Median PFS in patients in the standard-of-care group who crossed over to trametinib following disease progression was 10.8 months, and the ORR was 15%. Of the 66 standard-of-care patients who progressed or died after crossing over to trametinib, 43 (65%) had a longer time to disease progression on trametinib than they had on their preceding standard-of-care therapy.
“The findings associated with this trial are hypothesis-generating and provide important clues for future investigations,” Gershenson said. “While the results of this study represent a major advance in the treatment of women with this rare ovarian and peritoneal cancer subtype, we need to accelerate our efforts toward the discovery of additional novel drugs or regimens. Ongoing trials include combinations of endocrine therapy and CDK 4/6 inhibitors and combinations of drugs directed at the MAPK signaling pathway plus other targeted agents.”
The study was funded by NRG Oncology, Cancer Research UK, Target Ovarian Cancer and Novartis.

Nonsense-mediated RNA decay, or NMD, is an evolutionarily conserved molecular mechanism in which potentially defective messenger RNAs, or mRNAs, are degraded. By reducing errors in gene expression, it serves as an RNA quality control and gene regulatory mechanism. Its disruption can lead to neurological disorders, immune diseases, cancers, and other pathologies.
A team of biomedical scientists at the University of California, Riverside, has designed a simple and robust method to determine the effects of drugs on NMD. The researchers profiled all current Food and Drug Administration-approved drugs to identify NMD modulators, which could potentially help treat hundreds of disorders associated with NMD.
“These drugs, by modulating cellular NMD efficiency, can potentially alleviate symptoms of genetic disorders caused by nonsense mutations,” said Sika Zheng, an associate professor of biomedical sciences in the School of Medicine, who led the study that appears in the journal Molecular Therapy — Nucleic Acids. “Two examples are Duchenne muscular dystrophy and cystic fibrosis.”
Cells have surveillance mechanisms to target defective mRNAs. Without these mechanisms, which operate in the cell nucleus and cytoplasm, errors in the synthesis of proteins could result. NMD is one of the best-studied RNA surveillance pathways. The term “nonsense” in its name refers to a type of mutation. NMD plays an important role in cell cycle regulation, cell viability, and DNA damage response. It also serves as a barrier to virus infection.
“NMD degrades aberrant mRNAs and prevents their expression,” Zheng said. “More than 20% of monogenic diseases — which means hundreds of rare diseases, including sickle cell anemia — are attributed to genetic mutations directly targeted by NMD. Excessive aberrant mRNAs also play a role in Lou Gehrig’s disease and myelodysplastic syndromes. Therefore, NMD modulation can help modify diseases outcomes. Several NMD modulators we identified can be tested in animal models of aforementioned diseases.”
Zheng explained that current FDA-approved drugs are not known to target NMD. They have not been examined closely for their effect on cellular NMD activity. For this study, Zheng and his team first developed a robust sensitive assay or test, termed AS-NMD assay, that quantitatively measures cellular NMD activity. They then obtained a library of 704 FDA-approved drugs. They treated cells with each of these drugs and measured the cellular responses using the AS-NMD assay.
“We wanted to know whether the FDA-approved drugs can be repurposed to modulate NMD,” he said. “So we treated cells with each FDA-approved drug and tested whether cellular NMD activity was affected. We found one drug had a strong effect on NMD; four drugs had mild effects. We now have solid information for the effect of 704 FDA-approved drugs on NMD. What made this possible is the method we developed, without which profiling 704 drugs to such a precision level would be unthinkable. Old methods are either too tedious or not precise enough.
Zheng believes the NMD-modulatory drugs should be further investigated for their molecular targets and be optimized and repurposed for NMD-associated diseases.
“Nonsense mutation-associated disorders are orphan diseases with a wide range of varied symptoms,” he said. “We should think of targeting their commonality: the associated NMD pathway.”
Next, the research team plans to do animal testing of some drug candidates. They also plan to scale up their assay to profile larger chemical libraries.
The research was funded by the National Institutes of Health and the UCR Center for Molecular and Translational Medicine.
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Materials provided by University of California – Riverside. Original written by Iqbal Pittalwala. Note: Content may be edited for style and length.

New research sheds light on the lifespans and location of the cells that are responsible for producing HIV, preventing its eradication. Understanding the cells’ dynamics may help scientists develop new ways to reduce their number with the ultimate goal of curing HIV infection.
“When chronically HIV-1 infected individuals are put on potent antiretroviral drug therapy, the amount of virus in their blood decreases,” said Los Alamos National Laboratory Senior Fellow Alan Perelson. He and collaborator David D. Ho, MD, now at Columbia University School of Medicine, found that “the viral decline occurred in two distinct phases, a fast first phase followed by a slow second phase.”
Using a mathematical model of viral infection and treatment developed by Perelson, the team concluded that the two-phase decline reflected the fact that HIV infected two distinct cell populations that produced HIV. One population produced the majority of the virus, but lived only a day or so. The decay of this population according to the model was responsible for the first phase decline of the virus in the blood.
The second cell population, which released virus at a slower rate, lived a matter of weeks while producing virus, and their loss according to the model was responsible for the second phase of viral decay seen in the blood.
Now, in a new paper published in the journal PNAS this week, Robert Siliciano, MD, from Johns Hopkins University School of Medicine and his team working with Perelson and Ruy Ribeiro from the Theoretical Biology and Biophysics Group at Los Alamos National Laboratory searched for these hypothesized cells with different decay rates. Siliciano’s group isolated HIV-infected cells in the blood of 17 people living with HIV on antiretroviral therapy twice a month for the first three months after the initiation of the therapy, and then every month for a year. They found that very few of the short-lived infected cells responsible for the first phase of viral decay were circulating in the blood, suggesting that these cells most likely reside in tissues, such as lymph nodes and the spleen.
Instead, they found cells in the blood that carried an intact HIV genome and which decayed with a half-life of about two weeks. These are presumably the cells responsible for the second phase of viral decay predicted by Perelson and Ho. After about three months on treatment, the remaining infected cells with intact HIV genomes decayed even more slowly, now with a half-life of about 19 months. These cells may become part of the latent-infected cell reservoir, which if therapy is stopped re-seeds the infection and virus then becomes detectable usually in a matter of weeks.
The funding: National Institutes of Health (NIH)
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Materials provided by DOE/Los Alamos National Laboratory. Note: Content may be edited for style and length.

If the United States ignores COVID-19 in Nigeria, we forgo global genomic surveillance at our own peril, reports a new Northwestern Medicine study.
The study found global efforts to track variants grossly underreported a probable variant of concern, eta, circulating in Nigeria in early 2021. This was followed by the circulation of a rare delta sublineage in the region that was different from the delta variant that circulated in most other parts of the globe.
“Nigeria is the seventh-most populated country on the planet, but there was very little viral sequencing data available from Nigeria until we started this study,” said co-corresponding study author Judd Hultquist. “The concern in having these gaps in surveillance is there may be new variants popping up in places across the globe we are not seeing. We do not want to be caught unprepared if all of a sudden a new variant with unique properties emerges onto the world stage.”
Hultquist is associate director of the Center for Pathogen Genomics and Microbial Evolution at Northwestern University Feinberg School of Medicine. He also is an assistant professor of medicine in infectious diseases at Feinberg.
“This study demonstrates the critical need for international cooperation in infectious disease surveillance in undersampled regions for the monitoring and ‘early-warning’ detection of new SARS-CoV-2 variants with concerning potential,” said Ramon Lorenzo-Redondo, co-corresponding study author.
Lorenzo-Redondo is an assistant professor of medicine and the bioinformatics director of the Center for Pathogen Genomics and Microbial Evolution at Feinberg.

Variations in the genes for the newly discovered scent receptors for musk and underarm odor add to a growing body of research suggesting that humans’ sense of smell is gradually becoming less sensitive. Sijia Wang of the Chinese Academy of Sciences and Joel Mainland of the Monell Chemical Senses Center report these findings in a new study publishing Feb. 3 in the journal PLOS Genetics.
Everyone experiences smells in their own unique way — the same scent can be pleasant, too intense or even undetectable to different noses. Scientists can combine these differences in scent perception with a person’s genetics to discover the role of various scent receptors. In a new study, researchers screened the genomes of 1,000 Han Chinese people to find genetic variations linked to how the participants perceived 10 different scents. Then they repeated the experiment for six odors in an ethnically diverse population of 364 people to confirm their results. The team identified two new receptors, one that detects a synthetic musk used in fragrances and another for a compound in human underarm odor.
Participants carried different versions of the musk and underarm odor receptor genes, and those genetic variations affected how the person perceived the scents. In combination with previously published results, the researchers find that people with the ancestral versions (the version shared with other non-human primates) of the scent receptors tend to rate the corresponding odor as more intense. These findings support the hypothesis that the sensitivity of humans’ and other primates’ sense of smell has degraded over time due to changes in the set of genes that code for our smell receptors.
The genetic analysis also identified three associations between genes for scent receptors and specific odors that scientists had previously reported. These earlier studies include primarily Caucasian participants. The new results from East Asian and diverse populations suggest that the genetics underlying the ability to detect odors remains constant across people from different backgrounds.
The authors add, “Genome-wide scans identified novel genetic variants associated with odor perception, providing support for the hypothesis that the primate olfactory receptor repertoire has degenerated over time.”
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