Rewriting DNA to Cure Killer Genetic Cardiomyopathy

Cardiomyopathies are heart muscle diseases that affect 1 person in every 250. Treatment is life-long, expensive and doesn’t change the underlying disease, let alone cure it. Now a research organization, CureHeart, will seek to develop the first cures for inherited heart muscle diseases by pioneering revolutionary and ultra-precise gene therapy technologies that could edit or silence the faulty genes that cause these deadly conditions. The team, is made up of world-leading scientists from the UK, US and Singapore.

Inherited heart muscle diseases can cause the heart to stop suddenly or cause progressive heart failure in young people. Every week in the UK, 12 people under the age of 35 die of an undiagnosed heart condition, very often caused by one of these inherited heart muscle diseases, also known as genetic cardiomyopathies. Around half of all heart transplants are needed because of cardiomyopathy and current treatments do not prevent the condition from progressing. It’s estimated that one in 250 people worldwide – around 260,000 people in the UK – are affected by genetic cardiomyopathies, with a 50:50 risk they will pass their faulty genes on to each of their children.

In many cases, multiple members of the same family will develop heart failure, need a heart transplant, or are lost to sudden cardiac death at a young age. BHF Professor Hugh Watkins, from the Radcliffe Department of Medicine at the University of Oxford and lead investigator of CureHeart, said: “This is our once-in-generation opportunity to relieve families of the constant worry of sudden death, heart failure and potential need for a heart transplant. After 30 years of research, we have discovered many of the genes and specific genetic faults responsible for different cardiomyopathies, and how they work. We believe that we will have a gene therapy ready to start testing in clinical trials in the next five years.”

Source:  https://www.rdm.ox.ac.uk/
AND
https://cureheart.org/

Synthetic Neurons

Synthetic neurons made of hydrogel could one day be used in sophisticated artificial tissues to repair organs such as the heart or the eyes. Hagan Bayley at the University of Oxford and his colleagues devised a synthetic material that can act in a similar way to a human neuron. Made from hydrogel, the artificial neurons are about 0.7 millimetres across ­– about 700 times wider than a human neuron, but similar to giant axons found in squid. They can also be made up to 25 millimetres long, which is similar in length to a human optic nerve running from the eye to the brain.
When a light is shone on the synthetic neuron, it activates proteins that pump hydrogen ions into the cell. These positively charged ions then move through the neuron, carrying an electrical signal. The speed of transmission was too fast to measure with the team’s equipment and is probably faster than the rate in natural neurons, says Bayley. When the positive charge reaches the tip of the neuron, it makes adenosine triphosphate (ATP) – a neurotransmitter chemicalmove from one water droplet to another. In future work, the researchers hope to make the synthetic neuron interact with another via an ATP signal, just as neurons connect with each other at synapses.
The team bundled seven of the neurons together to work in parallel as a synthetic nerve. “This allows us to send multiple signals simultaneously,” says Bayley. “They can all have very different frequencies and so it’s a very versatile signal.” The main purpose is to send different pieces of information down the same pathway, he says.

Artificial nerve cells made from biocompatible materials have been made in a lab for the first time. The innovation may one day be used in synthetic tissues to repair organs such as the heart or the eyes. 

However, the artificial neurons still have a long way to go. Unlike real neurons, there is no mechanism to recycle and create new neurotransmitters in the synthetic system. The neurons therefore only work for a few hours, says Bayley. “The more you do science, the more you find out how clever science is by virtue of evolution.” Alain Nogaret at the University of Bath in the UK says the innovation could play a major role in improving neuro-implants such as artificial retinas by the end of the decade. “The emulation of nervous activity in soft materials is a major step towards non-invasive brain-machine interfaces and solutions addressing neurodegenerative disease.”

Bayley hopes to eventually use these synthetic neurons to deliver different types of drugs simultaneously to treat wounds more quickly and precisely. “Using light, we could maybe release drug molecules in a patterned way,” he says.
Source: https://www.nature.com/ 
AND
https://www.scientiststudy.com/

Cognitive Deficits Months After Mild COVID

A novel study led by researchers from the University of Oxford has investigated the lingering cognitive effects of mild COVID-19 in the months following infection. The research revealed minor deficits in attention and memory can be seen for up to six months following a mild infection. It is becoming increasingly clear that a severe case of COVID-19 can result in lasting impacts to the brain. Alongside these acute impacts on the brain, there are persistent cognitive deficits being reported by long COVID patients that last months past an initial infection.

This new study, published in the journal Brain Communications, set out to investigate the other end of the disease spectrum. Here, the focus was on cognitive impacts in asymptomatic to moderate COVID-19 patients who do not report symptoms of long COVID.

More than 150 subjects were recruited for the study, with around 60 reporting a PCR-confirmed case of mild COVID-19 up to nine months prior. The cohort completed 12 different online tests designed to measure a range of cognitive functions, from sustained attention and semantic reasoning to mental rotation and spatial–visual attention.

Even a mild case of COVID-19 can lead to long-term neurological problems

“What is surprising is that although our COVID-19 survivors did not feel any more symptomatic at the time of testing, they showed degraded attention and memory,” said Zhao. “Our findings reveal that people can experience some chronic cognitive consequences for months.”

It is unclear exactly what could be causing these specific impairments so many months after an initial infection. The researchers hypothesize the virus may be causing a variety of immunological and microvascular changes in the brain. But the good news is, as study co-author Masud Husain explained, these potential cognitive impairments seem to disappear between six and nine months after initial infection.

We still do not understand the mechanisms that cause these cognitive deficits, but it is very encouraging to see that these attention and memory return largely to normal in most people we tested by six to nine months after infection, who demonstrated good recovery over time,” Husain said. “Reassuringly, COVID-19 survivors performed well in most abilities tested, including working memory, executive function, planning and mental rotation,” the authors write in the new study. “However, they displayed significantly worse episodic memory (up to six months post-infection) and greater decline in vigilance with time on task (for up to nine months).”

The vigilance task is used to evaluate how quickly a person is fatigued during a cognitive exercise demanding consistent attention. Compared to a control group the COVID patients displayed rapid declines in accuracy on the task after about four minutes of concentration. Sijia Zhao, an author on the new study from the University of Oxford, said it was surprising to see these minor cognitive deficits in the recovered COVID-19 subjects because none of the cohort were subjectively reporting any neurological problem.

The full paper, ‘Rapid vigilance and episodic memory decrements in COVID-19 survivors‘, can be read in Brain Communications

Source: https://www.ox.ac.uk/

Viagra Users Are 69% Less Likely to Develop Alzheimer’s

Viagra could be a useful treatment against Alzheimer’s disease, according to a US study. Alzheimer’s disease, the most common form of age-related dementia, affects hundreds of millions of people worldwide. Despite mounting numbers of cases, however, there is currently no effective treatment.

Using a large gene-mapping network, researchers at the Cleveland Clinic integrated genetic and other data to determine which of more than 1,600 Food and Drug Administration-approved drugs could be an effective treatment for Alzheimer’s disease. They gave higher scores to drugs that target both amyloid and tau – two hallmarks of Alzheimer’s – compared with drugs that targeted just one or the other.

US scientists say users of sildenafil – the generic name for Viagra – are 69% less likely to develop the form of dementia than non-users

“Sildenafil, which has been shown to significantly improve cognition and memory in preclinical models, presented as the best drug candidate,” said Dr Feixiong Cheng, the study lead.

Researchers then used a database of claims from more than 7 million people in the US to examine the relationship between sildenafil and Alzheimer’s disease outcomes by comparing sildenafil users to non-users.

They found sildenafil users were 69% less likely to develop Alzheimer’s disease than non-sildenafil users after six years of follow-up. To further explore the drug’s potential effect on Alzheimer’s disease, researchers developed a lab model that showed that sildenafil increased brain cell growth and targeted tau proteins, offering insights into how it might influence disease-related brain changes. Cheng cautioned that the study does not demonstrate a causal relationship between sildenafil and Alzhemer’s disease. Randomised clinical trials involving both sexes with a placebo control were needed to determine sildenafil’s efficacy, he said.

Dr Ivan Koychev, a senior clinical researcher at the University of Oxford, who was not involved in the study, said it was “an exciting development” because “it points to a specific drug which may offer a new approach to treating the condition”.

Prof Tara Spires-Jones, deputy director of the Centre for Discovery Brain Sciences at the University of Edinburgh, said there were several important limitations to consider. “While these data are interesting scientifically, based on this study, I would not rush out to start taking sildenafil as a prevention for Alzheimer’s disease.”

Dr Susan Kohlhaas, director of research at Alzheimer’s Research UK, said: “Being able to repurpose a drug already licensed for other health conditions could help speed up the drug discovery process and bring about life-changing dementia treatments sooner. “Importantly, this research doesn’t prove that sildenafil is responsible for reducing dementia risk, or that it slows or stops the disease. The only way to test this would be in a large-scale clinical trial measuring sildenafil effect against the usual standard of care.”

The findings were published in Nature Aging.

Source: https://www.theguardian.com/

Revolutionary Cancer Vaccine Trials Inspired by COVID Jab Begin

The team behind the OxfordAstraZeneca COVID-19 vaccine have used the same techniques to create a vaccine that could potentially ‘revolutionise’ cancer treatment.The researchers have designed a two-dose cancer vaccine using the same viral vector technology used in the Oxford COVID vaccine to increase the levels of anti-tumour T cells and shrink tumours in mice. The vaccine targets specific structures, known as MAGE proteins, found on the surface of many cancers.

We knew from our previous research that MAGE-type proteins act like red flags on the surface of cancer cells to attract immune cells that destroy tumours. MAGE proteins have an advantage over other cancer antigens as vaccine targets since they are present on a wide range of tumour types,” said Benoit Van den Eynde, Professor of Tumour Immunology at the University of Oxford.

This broadens the potential benefit of this approach to people with many different types of cancer. “Importantly for target specificity, MAGE-type antigens are not present on the surface of normal tissues, which reduces the risk of side-effects caused by the immune system attacking healthy cells.”

When combined with existing anti-PD-1 immunotherapy treatments, the vaccine showed a greater reduction in tumour size and improved the survival of the mice. Anti-PD-1 immunotherapy is a promising method of cancer treatment that works by ‘taking the brakesoff anti-tumour T cells and inciting them to kill cancer cells. However, it has so far proven to be largely ineffective thanks in part to the low levels of T cells in the majority of cancer patients.

This is where the tech borrowed from the Oxford-AstraZeneca vaccine comes in – a two-dose treatment can help to boost the levels of cancer-fighting CD8+ T cells. “Our cancer vaccines elicit strong CD8+ T cell responses that infiltrate tumours and show great potential in enhancing the efficacy of immune checkpoint blockade therapy and improving outcomes for patients with cancer,” said Prof Adrian Hill, Director of the Jenner Institute, University of Oxford.”

The team now plan to begin their first human clinical trial of the vaccine used in combination with anti-PD-1 immunotherapy in 80 patients with non-small cell lung cancer later this year as part of a collaboration between Vaccitech Oncology Limited (VOLT) and Cancer Research UK’s Centre for Drug Development. “This new vaccine platform has the potential to revolutionise cancer treatment. The forthcoming trial in non-small cell lung cancer follows a Phase 2a trial of a similar cancer vaccine in prostate cancer undertaken by the University of Oxford that is showing promising results,” said Hill.

Source: https://www.ox.ac.uk/
AND
https://www.sciencefocus.com/

AstraZeneca’s COVID-19 Vaccine Produces An Immune Response in Older People

Immunogenicity responses similar between older and younger adults

One of the world’s leading COVID-19 experimental vaccines produces a immune response in both old and young adults, raising hopes of a path out of the gloom and economic destruction wrought by the novel coronavirus.  The vaccine, developed by the University of Oxford, also triggers lower adverse responses among the elderly, British drug maker AstraZeneca Plc AZN.L, which is helping manufacture the vaccine, said on Monday. A vaccine that works is seen as a game-changer in the battle against the novel coronavirus, which has killed more than 1.15 million people, shuttered swathes of the global economy and turned normal life upside down for billions of people.

It is encouraging to see immunogenicity responses were similar between older and younger adults and that reactogenicity was lower in older adults, where the COVID-19 disease severity is higher,” an AstraZeneca spokesman said.

https://uk.reuters.com

Coronavirus Vaccine: When Will We Have One?

There are around 40 different coronavirus vaccines in clinical trials – including one being developed by the University of Oxford that is already in an advanced stage of testing. The virus spreads easily, and the majority of the world’s population is still vulnerable to it. A vaccine would provide some protection by training people’s immune systems to fight the virus so they should not become sick. This would allow lockdowns to be lifted more safely, and social distancing to be relaxed.

Research is happening at breakneck speed. About 240 vaccines are in early development, with 40 in clinical trials and nine already in the final stage of testing on thousands of peopleTrials of the Oxford vaccine show it can trigger an immune response, and a deal has been signed with AstraZeneca to supply 100 million doses in the UK alone. The first human trial data back in May indicated the first eight patients taking part in a US study all produced antibodies that could neutralise the virus. A group in China showed a vaccine was safe and led to protective antibodies being made. It is being made available to the Chinese military.

Other completely new approaches to vaccine development are in human trials. However, no-one knows how effective any of these vaccines will be. A vaccine would normally take years, if not decades, to develop. Researchers hope to achieve the same amount of work in only a few months. Most experts think a vaccine is likely to become widely available by mid-2021, about 12-18 months after the new virus, known officially as Sars-CoV-2, first emerged. That would be a huge scientific feat, and there are no guarantees it will work. But scientists are optimistic that, if trials are successful, then a small number of people – such as healthcare workers – may be vaccinated before the end of this year. It is worth noting that four coronaviruses already circulate in human beings. They cause common cold symptoms and we don’t have vaccines for any of them.

https://www.bbc.com/

Cheap Steroid Reduces Covid-19 Death Toll by 35%

The steroid dexamethasone has been found to reduce the risk of death in seriously ill coronavirus patients by about a third, according to clinical trial results hailed on Tuesday as a “major breakthrough.” The drug did not appear to help less severely ill patients.

Researchers led by a team from the University of Oxford administered the inexpensive, widely available drug to more than 2,000 severely ill COVID-19 patients. Among those who could only breathe with the help of a ventilator, dexamethasone reduced deaths by 35%. It reduced deaths by about 20% among patients who were receiving oxygen only, according to preliminary results.

Dexamethasone is an anti-inflammatory drug normally used to treat a range of allergic reactions as well as rheumatoid arthritis and asthma.

Source: https://www.cbsnews.com/

CRISPR Reverses Duchenne Muscular Dystrophy Mutation

CRISPR-Cas9 has, for the first time, been tested by systemic delivery in a large animal—and the results are striking. Working in a dog model of Duchenne muscular dystrophy (DMD), the gene editing not only restored the expression of the protein dystrophin, it also improved muscle histology in the dogs.

Our technology was developed using human cells and mice to correct the same type of mutation as in these dogs. It was critical for us to test gene editing in a large animal because it harbors a mutation analogous to the most common mutation in DMD patients,” said Eric Olson, Ph.D., professor and chair of molecular biology at the University of Texas Southwestern Medical Center and lead author. The researchers wrote that this is “an essential step toward clinical translation of gene editing as a therapeutic strategy for DMD.”

Indeed, Dame Kay E. Davies, Ph.D., professor of anatomy and director of the MRC Functional Genomics Unit at the University of Oxford and a pioneer in the field of DMD research, echoes this sentiment explains, “This is a very exciting paper as it shows that gene editing can be reasonably affective in a large animal model of DMD.”

The paper, “Gene editing restores dystrophin expression in a canine model of Duchenne muscular dystrophy,” appears in the last issue of Science.

Source: https://www.genengnews.com/