Day: May 20, 2025

Categories : Diseases, Syndromes and Conditions GeneticsTags : Leave a comment

Baby with Rare, Incurable Disease is First to Receive Personalised Gene Therapy

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NIH-supported gene-editing platform lays groundwork to rapidly develop treatments for other rare genetic diseases.

Photo by Sangharsh Lohakare on Unsplash

A research team supported by the National Institutes of Health (NIH) has developed and safely delivered a personalised gene editing therapy to treat an infant with a life-threatening, incurable genetic disease. The infant, who was diagnosed with the rare condition carbamoyl phosphate synthetase 1 (CPS1) deficiency shortly after birth, has responded positively to the treatment.

The process, from diagnosis to treatment, took only six months and marks the first time the technology has been successfully deployed to treat a human patient. The technology used in this study was developed using a platform that could be tweaked to treat a wide range of genetic disorders and opens the possibility of creating personalised treatments in other parts of the body.

A team of researchers at the Children’s Hospital of Philadelphia (CHOP) and the Perelman School of Medicine at the University of Pennsylvania (Penn) developed the customised therapy using the gene-editing platform CRISPR. They corrected a specific gene mutation in the baby’s liver cells that led to the disorder. CRISPR is an advanced gene editing technology that enables precise changes to DNA inside living cells. This is the first known case of a personalised CRISPR-based medicine administered to a single patient and was carefully designed to target non-reproductive cells so changes would only affect the patient.

“As a platform, gene editing – built on reusable components and rapid customisation – promises a new era of precision medicine for hundreds of rare diseases, bringing life-changing therapies to patients when timing matters most: Early, fast, and tailored to the individual,” said Joni L. Rutter, Ph.D., director of NIH’s National Center for Advancing Translational Sciences (NCATS).

CPS1 deficiency is characterized by an inability to fully break down byproducts from protein metabolism in the liver, causing ammonia to build up to toxic levels in the body. It can cause severe damage to the brain and liver. Treatment includes a low protein diet until the child is old enough for a liver transplant. However, in this waiting period there is a risk of rapid organ failure due to stressors such as infection, trauma, or dehydration. High levels of ammonia can cause coma, brain swelling, and may be fatal or cause permanent brain damage.

The child initially received a very low dose of the therapy at six months of age, then a higher dose later. The research team saw signs that the therapy was effective almost from the start. The six-month old began taking in more protein in the diet, and the care team could reduce the medicine needed to keep ammonia levels low in the body. Another telling sign of the child’s improvement to date came after the child caught a cold, and later, had to deal with a gastrointestinal illness. Normally, such infections for a child in this condition could be extremely dangerous, especially with the possibility of ammonia reaching dangerous levels in the brain.

“We knew the method used to deliver the gene-editing machinery to the baby’s liver cells allowed us to give the treatment repeatedly. That meant we could start with a low dose that we were sure was safe,” said CHOP pediatrician Rebecca Ahrens-Nicklas, MD, PhD.

“We were very concerned when the baby got sick, but the baby just shrugged the illness off,” said Penn geneticist and first author Kiran Musunuru, MD, PhD. For now, much work remains, but the researchers are cautiously optimistic about the baby’s progress.

The scientists announced their work at the American Society of Gene & Cell Therapy Meeting on May 15th and described the study in The New England Journal of Medicine.

Source: NIH/Office of the Director

Categories : AllergiesTags : Leave a comment

Key Player in Childhood Food Allergies Identified: Thetis Cells

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Photo by cottonbro studio

A decade ago, a clinical trial in the UK famously showed that children who were exposed to peanuts in the early months of life had reduced risk of developing a peanut allergy compared with children who avoided peanuts.

Now, researchers at Memorial Sloan Kettering Cancer Center (MSK) have a likely answer as to why that’s the case: Thetis cells.

This recently discovered class of immune cells, which were first described by MSK researchers in 2022, plays an essential and previously unknown role in suppressing inflammatory responses to food, according to findings published in Science, one of the world’s premier scientific journals.

Moreover, the study, which was conducted in mouse models, points to a critical window in the early months of life for training the immune system not to overreact to food allergens, termed “oral tolerance.”

The study also opens the door to new therapeutic possibilities, the researchers say.

“This is a great example of how clinical studies can reveal clues to fundamental mechanisms in biology,” says physician-scientist Chrysothemis Brown, MBBS, PhD, the study’s senior author. “These new understandings can pave the way for new treatment strategies for food allergies, which are desperately needed.”

The research was led by co-first authors from the Brown Lab: paediatric hematologist-oncologist Vanja Cabric, MD, and research assistant Yollanda Franco Parisotto, PhD.

Thetis Cells Train the Immune System To Tolerate Helpful Outsiders

Thetis cells are a type of antigen-presenting cell, whose job is to present foreign substances (antigens) to other immune cells. Antigen-presenting cells must educate the immune system. These cells provide signals that tell the immune system to attack foreign bacteria and viruses – or instruct it to tolerate harmless proteins in the foods we eat.

Previous research led by Dr Brown and immunologist Alexander Rudensky, PhD, Chair of the Immunology Program at MSK’s Sloan Kettering Institute, identified a window in early life where a “developmental wave” of Thetis cells within the gut creates an opportunity for developing immune tolerance.

“We previously showed that Thetis cells train the immune system not to attack the helpful bacteria in the digestive system. So we wondered whether these cells might also be important for preventing inflammatory responses to food, and whether the increased abundance of the cells during early life would result in increased protection against food allergy,” says Dr. Brown, whose lab is in MSK’s Human Oncology and Pathogenesis Program (HOPP).

The new study found that Thetis cells not only help to broker peace accords with “good” bacteria, but also with proteins in foods that can act as allergens, such the Ara h proteins found in peanuts (though they weren’t specifically tested in the study) or the ovalbumin found in eggs.

Thetis cells got their name because they share traits with two different types of antigen-presenting cells: medullary thymic epithelial cells and dendritic cells, just as Thetis in Greek mythology had shape-shifting attributes.

A Key Role for Gut-Draining Lymph Nodes

The research team used a variety of genetically engineered mouse models to investigate oral tolerance. They attached a fluorescent dye to ovalbumin in order to visualise which cells in the gut interacted with it.

And this showed that a subset of Thetis cells, the same ones that regulated tolerance to healthy gut bacteria, took up the protein. This allowed Thetis cells to program another type of immune cell called regulatory T cells to suppress the immune response to the egg protein, essentially telling the body it was safe.

“This process is often studied in adult models, but by examining what happens when mice first encounter food proteins at the time of weaning, we could see which specific cells were critical to generating tolerance to food during early life,” Dr. Cabric says.

Although Thetis cells could also induce tolerance throughout life, there was a significant difference in the immune response when the egg protein was introduced later.

Source: Memorial Sloan Kettering Cancer Center

Categories : Cardiovascular Disease ExerciseTags : Leave a comment

The Effect of Physical Fitness on Mortality is Overestimated

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Photo by Ketut Subiyanto on Unsplash

Many observational studies have shown that people who exercise more and have good cardiorespiratory fitness early in life are at lower risk of premature death from causes such as cancer and cardiovascular disease. But a new study published in the European Journal of Preventive Cardiology suggests that the association between physical fitness and a reduced risk of mortality may be misleading.

“We found that people with high fitness levels in late adolescence had a lower risk of dying prematurely, for example from cardiovascular disease, compared to those with low fitness levels. But when we looked at their risk of dying in random accidents, we found an almost similarly strong association. This suggests that people with high and low fitness levels may differ in other important ways, which is something that previous studies have not fully taken into account,” says Marcel Ballin, associated researcher in epidemiology and lead author of the study.

Conscription data from over 1 million men

In the study, the researchers leveraged data from 1.1 million Swedish men who were conscripted for military service between the years 1972 and 1995. The men, who were on average 18 years old at the time of conscription, were divided into five groups based on their fitness level at the time. They were then followed until their 60s or until they died. With access to the National Cause of Death Register, the researchers were able to see their cause of death. They subsequently used different methods to study the association between fitness level in late adolescence and premature death.

The researchers started with a traditional analysis of mortality from cardiovascular disease, cancer and from all causes, as in previous observational studies. They adjusted their statistical models for factors such as BMI, age at conscription, year of conscription, and parents’ income and education level. The results showed that the group with the highest fitness level had a 58% lower risk of dying from cardiovascular disease, a 31% lower risk of dying from cancer, and a 53% lower risk of dying from all causes, compared with the group with the lowest fitness level.

Very similar risk of dying in random accidents

Next, the researchers examined how fitness was associated with the risk of dying in random accidents such as car accidents, drownings and homicides. They chose random accidents because they assumed that there ought to be no association between the men’s fitness in late adolescence and the risk of dying in random accidents. This method is called negative control outcome analysis and involves testing the validity of your results for a primary outcome by comparing them with an outcome where no association ought to be found. If, however, an association is found, it may indicate that the groups studied are not actually comparable, and that the study suffers from what is typically referred to as confounding. The researchers found that men with the highest fitness levels had a 53% lower risk of dying in random accidents. Yet, it is unlikely that the men’s fitness would have such a big effect on their risk of dying in random accidents.

These results were also confirmed when the researchers used the sibling comparison design. Using this method, the researchers compared the risk of premature death between siblings with different fitness levels to control for all the factors that the siblings share such as behaviours, environmental factors, and some genetic factors.

“It surprised us that the association with accidental mortality reflected the other associations, even after we controlled for all the factors that siblings share. This underlines how strong the assumptions are that you make in observational studies, since it appears to be very difficult to create comparable groups. The consequences may be that you overestimate the magnitudes of the effects you find,” says Marcel Ballin.

Picture confirmed in other studies

The study is one of the largest of its kind in which researchers used negative control outcomes to investigate whether the associations between fitness and mortality are in fact valid. The results in this study are also supported by other research.

“That the effects of good cardiorespiratory fitness may be overstated might sound controversial to some, but the fact is that if you look at the results from studies others than traditional observational studies, a more nuanced picture does emerge. A number of twin studies for example have found similar results. Some genetic studies also suggest that there are genes that affect both the propensity to be physically active or have a good fitness level, and the risk of developing diseases such as cardiovascular disease.”

Important to base interventions on correct estimates

Marcel Ballin also argues that there are many different reasons for promoting physical activity. However, large-scale interventions or policy changes intended to apply to the entire population must be based on reliable estimates – otherwise there is a risk of expecting effects that have in fact been overestimated.

“Our results should not be interpreted as if physical activity and exercise are ineffective or that you should not try to promote it. But to create a more nuanced understanding of how big the effects of fitness actually are on different outcomes, we need to use several different methods. If we just ask the question in the same way, we will always get the same answer. It’s only when we get the same answer to a question that we have asked in slightly different ways that we can be sure that the findings are accurate,” says Marcel Ballin.

Source: Uppsala University

Categories : Respiratory DiseasesTags : Leave a comment

Loss of Lung Capacity Starts Between the Ages of 20 and 25

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Photo by Ketut Subiyanto on Pexels

A study led by the Barcelona Institute for Global Health (ISGlobal), a centre supported by ”la Caixa” Foundation, in collaboration with the Clínic-IDIBAPS, has shown for the first time, how lung capacity evolves from childhood to old age. The findings, published in The Lancet Respiratory Medicine, provide a new basic framework for assessing lung health.

Until now, it was thought that lung function increased until it peaked at around 20–25 years of age, after which it stabilised. It was also thought that in later adulthood, lung function begins to decline as the lungs age. However, this model was based on studies that did not cover the whole life course.

In contrast, the current study used an “accelerated cohort design”, meaning data from several cohort studies were combined to cover the desired age range. “We included more than 30 000 individuals aged 4 to 82 years from eight population-based cohort studies in Europe and Australia,” explains Judith Garcia-Aymerich, first author of the study and co-director of the ISGlobal programme on Environment and Health over the Life Course. Lung function and lung capacity parameters were assessed using forced spirometry, a test in which the patient exhales all the air as quickly as possible after taking a deep breath. Data on active smoking and asthma diagnosis were also collected.

Two growth phases and an early decline

The study showed that lung function develops in two distinct phases: a first phase of rapid growth during childhood and a second phase of slower growth until peak lung function is reached. Lung function was assessed using two parameters: forced expiratory volume in one second (FEV1), which measures the amount of air expelled in the first second of a forced breath after a deep inhalation; and forced vital capacity (FVC), which is the maximum amount of air a person can breathe out without a time limit after a deep inhalation. 

In women, FEV1 peaks around the age of 20, while in men it peaks around the age of 23. Surprisingly, the study found no evidence of a stable phase following this peak. “Previous models suggested a plateau phase until the age of 40, but our data show that lung function starts to decline much earlier than previously thought, immediately after the peak,” explains Garcia-Aymerich.

Source: Barcelona Institute for Global Health (ISGlobal)

Categories : Metabolic Disorders NeurologyTags : Leave a comment

Could the Brain be Targeted to Treat Type 2 Diabetes?

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Source: CC0

Successfully treating type 2 diabetes may involve focusing on brain neurons, rather than simply concentrating on obesity or insulin resistance, according to a study published in the Journal of Clinical Investigation.  

For several years, researchers have known that hyperactivity of a subset of neurons located in the hypothalamus, called AgRP neurons, is common in mice with diabetes. 

“These neurons are playing an outsized role in hyperglycaemia and type 2 diabetes,” said UW Medicine endocrinologist Dr Michael Schwartz, corresponding author of the paper.

To determine if these neurons contribute to elevated blood sugar in diabetic mice, researchers employed a widely used viral genetics approach to make AgRP neurons express tetanus toxin, which prevents the neurons from communicating with other neurons. 

Unexpectedly, this intervention normalised high blood sugar for months, despite having no effect on body weight or food consumption.   

Conventional wisdom is that diabetes, particularly type 2 diabetes, stems from a combination of genetic predisposition and lifestyle factors, including obesity, lack of physical activity and poor diet. This mix of factors leads to insulin resistance or insufficient insulin production.  

Until now, scientists have traditionally thought the brain doesn’t play a role in type 2 diabetes, according to Schwartz. 

The paper challenges this and is a “departure from the conventional wisdom of what causes diabetes,” he said. 

The new findings align with studies published by the same scientists showing that injection of a peptide called FGF1 directly into the brain also causes diabetes remission in mice. This effect was subsequently shown to involve sustained inhibition of AgRP neurons.

Together, the data suggest that, while these neurons are important for controlling blood sugar in diabetes, they don’t play a major role in causing obesity in these mice, the researchers noted in their report.  

In other words, targeting these neurons may not reverse obesity, even as it causes diabetes to go into remission, Schwartz explained. 

More research is needed on how to regulate activity in these neurons, and how they become hyperactive in the first place, he said. Once these questions are answered, Schwartz said that a therapeutic approach might then be developed to calm them down. 

This approach could represent a shift in how clinicians understand and treat this chronic disease, Schwartz said.  He noted, for instance, that semaglutide and other new drugs used to treat type 2 diabetes are also able to inhibit AgRP neurons.  

The extent to which this effect contributes to the antidiabetic action of these drugs is unknown. Further research might help scientists to better understand the role of AgRP neurons in how the body normally controls blood sugar, and to ultimately translate these findings into human clinical trials, he added.  

Source: University of Washington School of Medicine/UW Medicine