Tag: 3/9/24

Categories : Ageing NeurologyTags : Leave a comment

Brain Ages at Different Paces According to Social and Physical Environments

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An international study employing advanced measurements of brain ageing on a wide range of participants found that people from more disadvantaged countries and backgrounds had older biological ages for their brains compared to chronological ages. The results are published in Nature Medicine.

The pace at which the brain ages can vary significantly among individuals.  This difference between biological and chronological ages may be affected by environmental factors like pollution and social factors like income or health inequalities, especially in older people and those with dementia. Until now, it was unclear how these combined factors could either accelerate or delay brain ageing across diverse geographical populations. 

The study used advanced brain clocks based on deep learning of brain networks, involved a diverse dataset of 5306 participants from 15 countries. By analysing data from functional magnetic resonance imaging (fMRI) and electroencephalography (EEG), the researchers quantified brain age gaps in healthy individuals and those with neurodegenerative conditions such as mild cognitive impairment (MCI), Alzheimer’s disease, and frontotemporal lobe degeneration (FTLD). 

Participants with a diagnosis of dementia, particularly Alzheimer’s disease, exhibited the most critical brain age gaps. The research also highlighted sex differences in brain ageing, with women in Latin American and Caribbean countries showing greater brain age gaps, particularly in those with Alzheimer’s disease. These differences were linked to biological sex and gender disparities in health and social conditions. Variations in signal quality, demographics, or acquisition methods did not explain the results. These findings underscore the role of environmental and social factors in brain health disparities. 

The findings of this study have profound implications for neuroscience and brain health, particularly in understanding the interaction between macro factors (exposome) and the mechanisms that underlie brain ageing across diverse populations in healthy ageing and dementia. The study’s approach, which integrates multiple dimensions of diversity into brain health research, offers a new framework for personalised medicine. This framework could be crucial for identifying individuals at risk of neurodegenerative diseases and developing targeted interventions to mitigate these risks. Moreover, the study’s results highlight the importance of considering the biological embedding of environmental and social factors in public health policies. Policymakers can reduce brain age gaps and promote healthier ageing across populations by addressing issues such as socioeconomic inequality and environmental pollution. 

Source: University of Surrey

Categories : Healthcare Politics and Regulations Medical IndustryTags : Leave a comment

Competition Law has again Worked to Fight a Bad Drug Patent, but We Need Other Solutions

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By Fatima Hassan and Leena Menghaney

A Competition Commission probe recently resulted in a patent on an important tuberculosis medicine being dropped in South Africa. Twenty years ago, a similar Competition Commission case resulted in a settlement that helped drive down the prices of several antiretrovirals, thereby helping to set the stage for the country’s HIV treatment programme. Fatima Hassan and Leena Menghaney connect the dots between the two landmark cases and map out what has and has not changed over the last two decades.

In the late 1990s and early 2000s, South Africa faced a major uncontrolled AIDS epidemic, worsened by state sponsored AIDS denialism. South Africa was at the epicentre of a global epidemic, with hundreds of thousands of people getting sick and dying, needlessly, because lifesaving antiretroviral medicines were out of reach.

This was in the main because of the Mbeki government’s deadly science denialism denying public sector patients antiretrovirals and the high cost of some of these medicines, which at the turn of the century was available in the private sector but only for the very rich or medically insured. The private sector price for the combination of three antiretrovirals needed by most people living with HIV was exorbitant.

This was because of patent monopolies held at the time by multinational pharmaceutical companies, particularly GlaxoSmithKline (GSK) and Boehringer Ingelheim (BI). In essence, people in South Africa living with HIV had to beg to live – by seeking donations and charity or pressuring their respective medical schemes to provide coverage. Meanwhile, lifesaving antiretrovirals were generally available in the Global North and in some parts of the Global South where governments like those in Thailand and Brazil had taken action to reduce prices.

Hundreds of thousands of people in South Africa died prematurely because they did not get access to these medicines in time.

The landmark Hazel Tau case

Looking for a way to challenge the high prices of key antiretrovirals, activists turned to South Africa’s newly revamped post-apartheid competition law. In September 2002, the Treatment Action Campaign, Hazel Tau, a woman living with HIV and several others lodged a complaint with the country’s Competition Commission. They alleged that the price that GSK and BI were charging for important antiretrovirals was excessive and anti-competitive, undermining not just Competition Law but also the right to health as enshrined in the country’s still fairly new Constitution.

The Competition Commission agreed to investigate. Several months later, they announced that there was a prima facie case of excessive pricing and that they would be referring the matter to the Competition Tribunal (the next phase of a complaint to the Competition authorities). Almost immediately after that announcement, TAC was approached by GSK and BI to “settle” the matter. This meant there would be no public hearings, and the companies would not have to defend their pricing decisions in the dock.

The terms of the settlement, negotiated by the TAC’s legal team, mirrored what TAC had publicly demanded at the beginning of the case. Most importantly, GSK and BI agreed to grant voluntary licenses to several generic manufacturers that would allow them to make and sell the antiretrovirals in question. It was this generic competition that would drive down the prices of antiretrovirals in the years that followed.

Even though the Competition Commission only has jurisdiction in South Africa, the licenses included many other African countries, which meant those countries could also benefit from the generic competition and lower prices. The settlement (including the terms of the voluntary licenses) was agreed to by the Competition Commission, made an order and publicly announced, leading to the conclusion of the complaint.

The case, which came to be known as the Hazel Tau case, would in the years to come be recognised as one of the foundations that made large HIV treatment programmes possible in South Africa and other African countries. Despite this victory, the ongoing effects of AIDS denialism meant that it would in reality be several years before the more affordable generic antiretrovirals would be made widely available in South Africa.

20 years later, the spotlight is on TB drugs

HIV has not been the only health crisis to affect SA. According to the World Health Organization (WHO), Tuberculosis (TB) is one of the leading infectious causes of death globally, and drug-resistant TB (DR-TB) remains a public health crisis. The WHO estimates that around 304 000 people fall ill with TB in South Africa per year, and it claims over 50 000 lives, which means it remains one of the country’s top killers. While TB rates are slowly declining, there is concern that rates of drug-resistant forms of TB (DR-TB) are increasing. DR-TB requires newer, more expensive treatments.

Republished from Spotlight under a Creative Commons licence.

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Categories : Genetics Medical Research & TechnologyTags : Leave a comment

Scientists Develop a Way to Turbocharge Genetic Therapy

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Source: Pixabay CC0

Gene therapy, the idea of fixing faulty genes with healthy ones, has held immense promise. But a major hurdle has been finding a safe and efficient way to deliver those genes.

Now, researchers at the University of Hawaiʻi’s John A. Burns School of Medicine (JABSOM) have made a significant breakthrough in gene editing technology that could revolutionise how we treat genetic diseases. Their new method offers a faster, safer, and more efficient way to deliver healthy genes into the body, potentially leading to treatments for hundreds of conditions.

Current methods can fix errors in genes, but they can also cause unintended damage by creating breaks in the DNA. Additionally, they struggle to insert large chunks of genetic material such as whole genes.

The new technique, developed by Dr Jesse Owens along with his team Dr Brian Hew, Dr Ryuei Sato and Sabranth Gupta, from JABSOM’s Institute for Biogenesis Research and Cell and Molecular Biology Department, addresses these limitations. They used laboratory evolution to generate a new super-active integrase capable of inserting therapeutic genes into the genome at record-breaking efficiencies.

“It’s like having a “paste” function for the human genome,” said Dr Owens. “It uses specially engineered ‘integrases’ to carefully insert healthy genes into the exact location needed, without causing breaks in the DNA. This method is much more efficient, with success rates of up to 96% in some cases.”

“This could lead to faster and more affordable treatments for a wide range of diseases, potentially impacting hundreds of conditions with a single faulty gene,” said Dr. Owens.

Faster treatment development and a broader application

The implications of this research extend beyond gene therapy. The ability to efficiently insert large pieces of DNA has applications in other areas of medicine.

When making cell lines to produce therapeutic proteins, the gene encoding the protein is usually randomly inserted into the genome, and it rarely lands in a location in the genome that is good for production. This is like searching for a needle in a haystack. Additionally, finding a cell with the gene inserted correctly and producing the desired protein can take many months.

Instead of searching for a needle in a haystack, Dr Owens’ technique makes a stack of needles. It delivers the gene directly to the desired location, significantly speeding up the development process.

“JABSOM takes pride in nurturing talented researchers like Jesse Owens, whose work has the power to create a global impact,” said Sam Shomaker, dean of the University of Hawaiʻi John A. Burns School of Medicine. “This research, conducted in our lab in the middle of the Pacific, has the potential to significantly improve the way we treat genetic diseases.”  

Dr Owens’ team is exploring how this technique could accelerate the development and manufacture of biologics and advanced therapies such as antibodies. Currently, finding the right cell line for efficient production can be a time-consuming process. However, Dr Owens’ new genome engineering tool can reduce the cell line development timeline and accelerate the manufacture of life-saving therapeutics. 

Source: University of Hawaii at Manoa

Categories : Neurodegenerative DiseasesTags : Leave a comment

Treatment with Dopamine Alleviates Symptoms in Alzheimer’s Disease

On By ModernMedia
Neurons in the brain of an Alzheimer’s patient, with plaques caused by tau proteins. Credit: NIH

A new way to combat Alzheimer’s disease has been discovered by Takaomi Saido and his team at the RIKEN Center for Brain Science (CBS) in Japan. Using mouse models, the researchers found that treatment with dopamine could alleviate physical symptoms in the brain as well as improve memory. Published in Science Signaling, the study examines dopamine’s role in promoting the production of neprilysin, an enzyme that can break down the harmful plaques in the brain that are the hallmark of Alzheimer’s disease. If demonstrated in human clinical trials, it could lead to a fundamentally new way to treat the disease.

The formation of hardened plaques around neurons is one of the earliest signs of Alzheimer’s disease, often beginning decades before behavioural symptoms such as memory loss are detected. These plaques are formed from pieces of the peptide beta-amyloid that accumulate over time. In the new study, Saido’s team at RIKEN CBS focuses on the enzyme neprilysin because previous experiments showed that genetic manipulation that produces excess neprilysin in the brain (a process called upregulation) resulted in fewer beta-amyloid plaques and improved memory in mice.

Neprilysin by itself cannot be a medication as it cannot enter the brain from the blood stream, so the researchers screened molecules to determine which ones can naturally upregulate neprilysin in the correct parts of the brain. The team’s previous research led them to narrow down the search to hormones produced by the hypothalamus, and they discovered that applying dopamine to brain cells cultured in a dish yielded increased levels of neprilysin and reduced levels of free-floating beta-amyloid.

Now the serious experiments began. Using a DREADD system, they inserted tiny designer receptors into the dopamine producing neurons of the mouse ventral tegmental area. By adding a matching designer drug to the mice’s food, the researchers were able to continuously activate those neurons, and only those neurons, in the mouse brains. As in the dish, activation led to increased neprilysin and decreased levels of free-floating beta-amyloid, but only in the front part of the mouse brain. But could the treatment remove plaques? Yes. The researchers repeated the experiment using a special mouse model of Alzheimer’s disease in which the mice develop beta-amyloid plaques. Eight weeks of chronic treatment resulted in significantly fewer plaques in the prefrontal cortex of these mice.

The DREADD system is an incredible system for precise manipulation of specific neurons. But it is not very useful for human clinical settings. The final experiments tested the effects of L-DOPA treatment. L-DOPA is a dopamine precursor molecule often used to treat Parkinson’s disease because it can enter the brain from the blood, where it is then converted into dopamine. Treating the model mice with L-DOPA led to increased neprilysin and decreased beta-amyloid plaques in both frontal and posterior parts of the brain. Model mice treated with L-DOPA for three months also performed better on memory tests than untreated model mice.

Tests showed that neprilysin levels naturally decreased with age in normal mice, particularly in the frontal part of the brain, perhaps making it a good biomarker for preclinical or at-risk Alzheimer’s disease diagnoses. How dopamine causes neprilysin levels to increase remains unknown, and is the next research topic for Saido’s group.

“We have shown that L-DOPA treatment can help reduce harmful beta-amyloid plaques and improve memory function in a mouse model of Alzheimer’s disease,” explains Watamura Naoto, first author of the study. “But L-DOPA treatment is known to have serious side effects in patients with Parkinson’s disease. Therefore, our next step is to investigate how dopamine regulates neprilysin in the brain, which should yield a new preventive approach that can be initiated at the preclinical stage of Alzheimer’s disease.”

Source: RIKEN

Categories : Metabolic DisordersTags : Leave a comment

Oestrogen’s Protection against Fatty Liver Points to New Drug Treatment

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Photo by The Creative Exchange on Unsplash

New research from Karolinska Institutet shows how oestrogen protects against MASLD, a fatty liver disease on the increase in the obesity epidemic. The study, published in Molecular Systems Biology, shows how a new drug under development could become a future treatment for fatty liver disease and liver cancer.

The global obesity epidemic has resulted in a dramatic increase in fatty liver, a disease in which fat that does not fit into fat cells is stored in liver cells instead.

Since last year, fatty liver due to obesity (and not excessive alcohol consumption) is known as MASLD (metabolic dysfunction-associated steatotic liver disease). According to previous research, as many as one in three adults are affected by some degree of MASLD, which in the worst cases can develop into cirrhosis and liver cancer.

Protection until menopause

However, the disease is very unevenly distributed between the sexes, with a large majority of affected individuals being men.

“Women have a natural protection until menopause due to the female sex hormone oestrogen,” explains study leader Claudia Kutter, senior researcher at the Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet.

Although women’s protection has been known for some time, the mechanism behind the protective effect has been less clear. Now Claudia Kutter’s research team may have found the answer.

Through genetic analyses of mice of both sexes fed a high-fat diet, with some of the male mice also receiving oestrogen, the researchers were able to identify a key protein in the development of fatty liver. 

The protein, called TEAD1, was found to play an overall role in regulating how liver cells absorb fat. Blocking TEAD1 protected liver cells from the harmful accumulation of fat. Mice receiving oestrogen treatment had lower TEAD1 activity and less fat accumulation in the liver.

New drug under development

In the next step, the researchers tested blocking TEAD1 in human liver cells with the same result. The fact that this was possible at all, however, was a bit of luck.

“It turned out that a pharmaceutical company is developing an anti-cancer drug that blocks TEAD1, which allowed us to test our hypothesis,” says Claudia Kutter.

The fact that TEAD1 is also involved in cancer does not worry her, quite the contrary.

“Since the activity of TEAD proteins is elevated in cancer, blocking TEAD at an early stage can also be positive from a cancer point of view,” she says. “Patients suffering from liver cancer are currently diagnosed very late. If the patient is given this drug early in the process to protect against fatty liver, it can hopefully also prevent the development of liver cancer.”

The pharmaceutical company will now start clinical trials of the drug as a protection against fatty liver disease, while Claudia Kutter’s research team will continue researching further ways to tackle the disease.

“We want to focus on how to find the disease earlier and identifying new treatment targets,” she says. “Different approaches may be needed for different patients depending on their gender and hormonal status.”

Source: Karolinska Institutet