Medical Bulletin 12/ September/ 2024
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Gene Therapy Improves Vision in hereditary blindness: Study Finds
Bothnia dystrophy is a form of hereditary blindness that leads to progressive visual impairment due to the destruction of the visual cells in the retina. A new study at Karolinska Institutet published in Nature Communications shows that gene therapy can improve vision in patients with the disease.
The disease is caused by an inherited genetic mutation that leads to damage to a particular protein in the eye. There is currently no treatment for the disease.
Researchers at the Karolinska Institute have now investigated whether gene therapy can improve vision in people with the disease.
The researchers used a so-called viral vector, a specially designed virus that was genetically modified to contain a functioning RLBP1 gene, the gene that is damaged in Bothnia dystrophy.
The viral vector was injected under the retina through an advanced surgical procedure in 12 people with the disease. The aim is that after treatment, the viral vector will be taken up by the cells of the retina, where it can produce normal protein.
The preliminary results of the study show that the visual function of 11 of the subjects improved significantly.
"The results are important because hereditary blindness is the most common cause of blindness in younger and able-bodied people, and there is no treatment for the vast majority of those affected," says Helder André, one of the researchers behind the study, who works at the Department of Clinical Neuroscience, Karolinska Institutet.
After the procedure, the researchers followed the study subjects for a year to study the safety and effect of the drug on visual function.
In eleven of the twelve study subjects, night vision, among other things, improved significantly, and in several participants, this led to improved self-perceived quality of life.
No serious side effects linked to the drug were noted in the study.
"Our study gives hope that this large group of patients can have their vision restored in the future. The results also support the idea that gene therapy can work for hereditary diseases in general," says Anders Kvanta, professor of ophthalmology at the same department and the person who led the study.
Reference: Anders Kvanta, Nalini Rangaswamy, Karen Holopigian, Christine Watters, Nicki Jennings, Melissa S. H. Liew, Chad Bigelow, Cynthia Grosskreutz, Marie Burstedt, Abinaya Venkataraman, Sofie Westman, Asbjörg Geirsdottir, Kalliopi Stasi, Helder André. Interim safety and efficacy of gene therapy for RLBP1-associated retinal dystrophy: a phase 1/2 trial. Nature Communications, 2024; 15 (1) DOI: 10.1038/s41467-024-51575-4
Women With Asthma More Likely To Miscarry And Need Fertility Treatment: Study At ERS Meeting
Women who are being treated for asthma are more likely to miscarry and need fertility treatment to get pregnant, according to a large study presented at the European Respiratory Society (ERS) Congress in Vienna, Austria. However, the study also suggests that most women with asthma are able to have babies.
The study was presented by Dr Anne Vejen Hansen from the department of respiratory medicine at Copenhagen University Hospital, Denmark.
She said: "Asthma is common in women of reproductive age. Previous studies have shown that it takes women with asthma longer to get pregnant than those without asthma when undergoing fertility treatment, and that asthmatic women who succeed in getting pregnant have more often had fertility treatment than non-asthmatic women. But most existing studies are on women who have actually got pregnant, so we wanted to examine fertility outcomes on a national scale, to also include those that might not become pregnant at all."
The team analysed reproductive outcomes for all Danish women born from 1976 to 1999, following them from 1994 to 2017. In total, 769,880 women were included and followed; anyone who took anti-asthma medication on a regular basis was classified as asthmatic.
They found that women with asthma experienced a higher degree of foetal loss compared to women without asthma (17.0% vs. 15.7%) and more use of fertility treatment (5.6% vs. 5.0%). However, the proportion who subsequently gave birth was 77% in women with and without asthma, suggesting that asthma does not seem to affect the number of live births.
Dr Vejen Hansen said: "We found that women fulfilling the definition of asthma had a higher rate of foetal loss and an increased use of fertility treatment. The more severe the asthma and the more flare ups the women experienced, the more likely they were to need fertility treatment. Why this is, is not clear. It might be related to systemic inflammation throughout the body, including women's reproductive organs.
"But the numbers also show that these same women who redeem asthma medication still have as many live births in the end as women who don't. This suggests that most women with asthma probably do manage to become pregnant and have babies in the end.
"We also plan to investigate the possible effect of male asthma on fertility, and, therefore, have another similar registry-based study in the pipeline."
Reference: Abstract no: OA5579 “Asthma and reproductive outcomes: A Danish nationwide cohort study”, by Dr Anne Vejen Hansen et al; Presented in session, “Determinants, diagnosis, incidence and management of respiratory health in populations” at 15.45-17.00 CEST on Tuesday 10 September 2024. [https://k4.ersnet.org/prod/v2/Front/Program/Session?e=549&session=17783]
8-Hour Eating Window Improves Glucose Control in Type 2 Diabetes, Regardless of Timing: Randomised Crossover Trial Finds
Restricting the eating window to 8 hours a day significantly improves blood glucose control in adults at risk of type 2 diabetes irrespective of whether it is earlier or later in the day, according to a randomised crossover trial presented at this year’s Annual Meeting of The European Association for the Study of Diabetes (EASD), Madrid.
The lead author Dr Kelly Bowden Davies from Manchester Metropolitan University, UK, said, “Our study found that restricting eating to a window of 8 hours per day significantly improved the daily time spent in the normal blood glucose range and reduced fluctuations in blood glucose levels. However, altering the 8-hour restricted eating period to earlier or later in the day did not appear to offer additional benefits,” The lead author Dr Kelly Bowden Davies from Manchester Metropolitan University, UK.
She added: “Our findings, which can be attributed to the 16-hour fasting window rather than the time of eating or changes in energy intake, also highlight that the benefit of time-restricted eating can be seen within just three days. Although time-restricted eating is becoming increasingly popular, no other studies have examined tightly controlled diet and altered the clock time of an eight-hour eating window on glycaemic control in people at risk of type 2 diabetes.”
Previous studies indicate that TRE (which limits when, but not what, individuals eat) can improve insulin sensitivity (the body’s ability to respond to insulin) and glycated haemoglobin (HbA1c; average blood sugar levels over a period of weeks and months) in people at risk of type 2 diabetes.
However, the effect on glycaemic variability (fluctuations in blood glucose levels) is not clear and previous studies have attributed the positive effects of TRE to reduced energy intake. This study sought to understand alterations in meal timing when participants were in energy balance (energy intake was matched with energy expenditure).
To find out more, researchers investigated the impact of TRE in a eucaloric manner—with diets provided to match energy requirements (taking into account sex, age, weight, height, activity level—comparing an early (ETRE; between 8:00 and 16:00 hours) versus a late (LTRE; between 12:00 and 20:00 hours) eating window on glycaemic control in overweight sedentary adults.
The analyses found that in comparison to habitual eating (more than 14 h/day), TRE (8 h/day) significantly increased time spent within the normal blood glucose range by on average 3.3%, and also reduced markers of glycaemic variability MAG by 0.6 mmol/l, CV by 2.6%, and MAGE by 0.4 mmol/l.
However, no significant differences in glycaemic control were found between the ETRE and LTRE regimens.
Reference: Annual Meeting of The European Association for the Study of Diabetes (EASD), Madrid, Diabetologia.
Randomised Trial Finds Obesity Medication Liraglutide Safe and Effective For Children Under 12
The obesity medication liraglutide is safe and effective in children aged 6 to <12 years, new research presented at the annual meeting of the European Association for the Study of Diabetes (EASD) in Madrid, Spain and published simultaneously in the New England Journal of Medicine (NEJM), has found.
Childen aged six to <12 years who took liraglutide for just over a year experienced a reduction in BMI of 7.4% compared to placebo and experienced improvements in blood pressure and blood sugar control.
The results of the SCALE Kids trial, the first study to examine the safety and efficacy of liraglutide in the paediatric population, offer hope that children who are living with obesity can lead healthier, more productive lives, say the researchers.
Lead author Professor Claudia Fox, of the Center for Pediatric Obesity Medicine, University of Minnesota Medical School, Minneapolis, USA, says: “Obesity is the most common chronic disease of childhood. Left untreated, obesity in childhood almost universally persists into adulthood and is associated with significant ill health, including diabetes and cardiovascular disease, and for some, premature death. Early intervention is therefore critical.
“However, effective treatment options to date are limited. The backbone of obesity treatment is lifestyle therapy – changes in diet and physical activity – but when used alone, the effect is modest and, as yet, no medication is approved for the treatment of general obesity in children who are younger than 12.
“Liraglutide is approved as an adjunct to lifestyle therapy in adults and adolescents with obesity and, in this study, we explored its safety and efficacy in under-12s.”
The phase 3 study, which was funded by liraglutide maker Novo Nordisk, involved 82 children (53.7% male) aged 6 to <12 years. At baseline, average age was 10 years, BMI was 31.0 kg/m2 and body weight was 70.2 kg (11st 1lb). 54.9% of children had ≥1 obesity-related complication, such as insulin resistance or early puberty.
56 children received daily injections of liraglutide (3mg or maximum tolerated dose) and 26 received weekly injections of placebo for 56 weeks. All of the participants received individualised counselling at every visit to encourage adherence to a healthy diet and regular physical activity (with the aim of doing 60 minutes a day of moderate to high intensity exercise).
At the end of the treatment period, the mean change in BMI was −5.8% for liraglutide and +1.6% for placebo – a difference of 7.4%.
Mean change in body weight was +1.6% for liraglutide and +10% for placebo – a difference of 8.4%.
A reduction in BMI of at least 5% was observed in 46.2% of children receiving liraglutide and 8.7% receiving placebo.
Children of this age are constantly growing and so body weight would be expected to increase over the course of a year. BMI takes into account height, as well as weight, and so is more informative, say the researchers.
Professor Fox says: “Although there is no consensus on the definition of a clinically meaningful BMI reduction in children, a 5% reduction has previously been shown to be associated with improvement in some obesity-related health conditions.
“In our study, diastolic blood pressure and haemoglobin A1c [HbA1c], a measure of blood sugar control, improved more in children receiving liraglutide than in those receiving the placebo.”
Professor Fox adds: “The results of this study offer considerable promise to children living with obesity.
“To date, children have had virtually no options for treating obesity. They have been told to ‘try harder’ with diet and exercise.
“Now with the possibility of a medication that addresses the underlying physiology of obesity, there is hope that children living with obesity can live healthier, more productive lives.”
Reference: Fox, C. K., Barrientos-Pérez, M., Bomberg, E. M., Dcruz, J., Gies, I., Harder-Lauridsen, N. M., Jalaludin, M. Y., Sahu, K., Weimers, P., Zueger, T., & Arslanian, S. (Year). Liraglutide for children 6 to <12 years of age with obesity — A randomized trial. The New England Journal of Medicine.
13% Weight Loss Achieved Over Three Months With Amycretin: Novo Nordisk Phase 1 Trial Finds
Individuals who received a once-a-day oral weight loss drug lost up to 13% of their body weight over three months, new research was presented at the annual meeting of the European Association for the Study of Diabetes (EASD) in Madrid, Spain.
Amycretin, which is being developed by the Danish pharmaceutical company Novo Nordisk A/S, mimics the action of two peptide hormones in one single molecule.
Amycretin is both an amylin and glucagon-like peptide-1 (GLP-1) receptor agonist. Both of these play a key role in appetite regulation and feeling of hunger and have been shown to lead to weight loss.
Currently, GLP-1 based treatment options are mainly administered via injections, a delivery method also used for the amylin-based treatments undergoing clinical development. To date, there are no tablet-form treatment options targeting both of these biologies.
In a single-centre, placebo-controlled, double-blinded phase 1 study, adult participants with a BMI of 25.0-39.9 kg/m2 without diabetes were randomised to receive amycretin or a placebo once-a-day for up to 12 weeks.
The study, which was conducted by Novo Nordisk A/S, and a clinical research unit in the US, consisted of single- and multiple ascending dose parts, where different doses of amycretin were tested orally: single-ascending dose (increasing from 1 mg a day to 25 mg)10-day multiple-ascending doses (investigating from 3 to 12 mg), and 12-week multiple-ascending doses (by introducing step wise dose escalation, investigating from a start dose of 3 mg and up to a final dose of 2x50 mg).
In the first-in-human trial, amycretin appeared to have a safe and tolerable profile in line with the drug receptor classes. Side-effects were mainly mild to moderate in severity and of gastrointestinal nature including nausea and vomiting.
At the end of the trial, average weight loss was greater with amycretin than with the placebo. Participants taking amycretin 50 mg reduced their body weight by 10.4%, on average, within 12 weeks of treatment, while those taking amycretin 2x50mg, the maximum dose tested, achieved a body weight reduction of 13.1%. This compares to an average weight loss of 1.1% among those taking placebo during the same time.
Notably, at the end of the treatment period, weight loss had not reached a plateau for participants taking amycretin, indicating the potential for further weight loss with extended use.
The study’s authors conclude that daily oral amycretin treatment in adults with overweight or obesity and without diabetes demonstrated a safe and tolerable profile in line with the drug receptor classes, and with notable reductions in body weight.
They add: “A single molecule that targets both amylin and GLP-1 biology in a tablet form could offer a more convenient approach to achieving better outcomes for individuals with overweight or obesity.
“However, larger and longer studies are needed to fully assess the drug’s safety profile and potential.”
Reference: “Safety, tolerability and weight reduction findings of oral amycretin: a novel amylin and glucagon-like peptide-1 receptor co-agonist, in a first-in-human study” EASD 2024, Abstract 74
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