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Neurodegenerative disease research backed by £58.6m

AviadoBio has secured investment to further its pioneering work into frontotemporal dementia and ALS

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Pioneering research which sees the use of a gene therapy platform to explore treatments for neurodegenerative diseases has been backed by new investment of £58.6million. 

AviadoBio has raised the funds to use its patented platform to initially look into therapies for Frontotemporal dementia (FTD) and Amyotrophic Lateral Sclerosis (ALS, or motor neurone disease, MND).

The substantial investment to the venture – developed at the UK DRI at King’s – follows £12million in seed funding, and will allow King’s spinout AviadoBio to take their research into human clinical trials in FTD patients for the first time. 

The funds will also help advance other pre-clinical work into ALS and ultimately other neurogenerative diseases.

Frontotemporal dementia is a progressive neurodegenerative disease affecting the frontal and temporal lobes of the brain and is the second most common form of young-onset dementia (over 65 years). FTD is characterised by changes in personality, behaviour and language, rather than short-term memory deficits seen in Alzheimer’s disease. 

ALS/MND causes progressive muscle paralysis affecting limb movements speech and swallowing, leading to death from respiratory failure within three to five years. 

Crucially, there are no treatments that can slow or halt progression of either disease.

Gene therapy is a promising approach for the treatment of neurodegenerative diseases, based on the principle of delivering DNA into cells to supplement or knock down mutated genes. 

AviadoBio – founded by Professor Christopher Shaw, Dr Youn Bok Lee and Dr Do Young Lee – is using the Adeno-associated virus (AAV), which can be engineered to carry theses gene therapies to target specific cells such as neurons in the brain and spinal cord. This technology proved life changing for babies with the genetic motor neuron disease, spinal muscular atrophy (SMA), who rarely lived beyond two years without being ventilated. 

A single injection in infancy protected their motor neurons such that they could walk, talk and did not need ventilation.

The therapy will target the gene encoding the protein progranulin, which is mutated in about 20 per cent of inherited and five per cent of non-inherited or sporadic cases. 

Progranulin is important for biological processes such as inflammation and the growth of neurons, and mutations of the gene in FTD cause a significant reduction in the levels of the protein. Delivering unmutated copies of the gene will help restore this imbalance in progranulin and improve the symptoms experienced in the disease.

“AviadoBio’s unique platform combines next-generation gene therapy design with deep neuroscience expertise and a novel neuroanatomy-led approach to drug delivery,” says Professor Christopher Shaw, professor of neurology and neurogenetics at the Institute of Psychiatry, Psychology & Neuroscience (IoPPN) at King’s College London, and co-founder, chief scientific and clinical advisor of AviadoBio.

“Precision micro dosing achieves extensive gene expression throughout the nervous system, maximising the therapeutic potential for patients living with devastating neurological diseases.

“While many neurodegenerative conditions start in a specific region gene, the pathology eventually spreads throughout the nervous system. 

“We have seen that modifying gene expression can be curative, but achieving widespread distribution is the greatest challenge. We have shown that precision micro dosing to neural networks will deliver broad central nervous system (CNS) expression, providing safe and effective treatments.”

The investment marks a huge milestone for the new company, as well as for Professor Shaw personally, whose decades of discovery research into FTD and ALS have set the groundwork for these promising new disease therapies.

Professor Shaw continues “After spending my entire career to date researching the causes of these diseases and designing therapies that bring hope of a cure for patients, I believe that AviadoBio has the potential to achieve this.”

Professor Shitij Kapur, president and principal of King’s College London, said: “Chris has worked with King’s for over 25 years. 

“I’m honoured that he chose our university to develop this ground-breaking research, and that staff and students have benefited from his world leading science along the way. I am pleased King’s is helping to take that work forward that has the potential to change the world and make a huge impact on many people’s lives.”

Research

Blood test for Glioblastoma moves closer

University of Sussex breakthrough hailed as ‘major step forward’ in the development of an accurate, non-invasive and time-saving diagnosis method

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The quest to develop a blood test capable of diagnosing the most aggressive form of brain tumour – Glioblastoma – has moved one step closer. 

Researchers at the University of Sussex have identified distinctive biomarkers within patient blood samples, which could signal the presence of Glioblastoma. 

The biomarkers were identified within extracellular vesicles – small particles which all cells secrete which carry different information, such as DNA or proteins. 

The ability to identify these biomarkers within the extracellular vesicles suggests that a liquid biopsy approach could be a viable option for glioblastoma diagnosis, providing both a quicker and less invasive alternative to current diagnostic methods.

More than 11,000 people are diagnosed with a primary brain tumour in the UK each year, with efforts ongoing to find effective treatments. 

Glioblastoma is the most common high grade primary brain tumour in adults, which means it can grow and spread exceptionally quickly. As a result, it is important for diagnosis to be quick, so patients can access treatment as soon as possible.

Professor Georgios Giamas and his team are leading the research in collaboration with Mr Giles Critchley, consultant neurosurgeon and spinal surgeon at University Hospitals Sussex.

“Currently, Glioblastoma detection relies on the display of symptoms, magnetic resonance imaging and invasive tissue biopsies – all of which can delay the identification of the rapidly growing malignant mass,” said Prof Giamas. 

“A growing body of research is looking into the possibility of developing liquid biopsies which would afford timely and non-invasive assessment of the disease in patients, starting from just a small sample of blood.

“Our study, which effectively does this in a small patient group, is a major step forward in the development of an accurate, non-invasive and time-saving diagnosis method.”

In November 2019, Prof Giamas’s lab at Sussex identified specific biomarkers that Glioblastoma cell lines are able to ‘package’ within extracellular vesicles allowing for better classification between those cell lines (e.g. less vs more aggressive). 

Biomarkers can be considered as biological signatures for a disease, and can therefore indicate the presence of cancer in the body. 

This new stage of research now proves that a liquid biopsy approach can successfully determine the presence of such biomarkers in a Glioblastoma patient and therefore improve the disease diagnosis and ultimately the patients’ prognosis and quality of life.

Funded by Action Against Cancer, Prof Giamas now hopes to conduct further research into the clinical value of their findings, by analysing blood samples of a larger cohort of Glioblastoma patients obtained from Genomics England.

The team also aims to investigate the presence and levels of such biomarkers in response to specific cancer treatments in an attempt to monitor the progression of the disease and evaluate the importance and role of these biomarkers.

He added: “If we can show that the biomarker signatures of extracellular vesicles obtained from blood samples change/disappear then this could be a huge breakthrough for monitoring the success of treatments too.”

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Neuropsychology

COVID cognitive symptoms linked to cerebrospinal fluid

The study could help increase understanding of ‘brain fog’ among people recovering from COVID and those with Long COVID

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Cognitive symptoms experienced by people recovering from COVID-19 may be linked to abnormalities found in cerebrospinal fluid, new research has revealed. 

The new findings around the role of cerebrospinal fluid, which saw similar changes in those recovering from a mild bout of COVID as people with other infectious diseases, may provide new insight into how the SARS-CoV-2 virus impacts the brain.

‘Brain fog’ has become recognised as a common after effect of COVID and symptom of Long COVID, which can cause varying degrees of cognitive issues.

In a small study with 32 adults, comprising 22 with cognitive symptoms and ten control participants without, researchers from UC San Francisco and Weill Cornell Medicine, New York, analysed the cerebrospinal fluid of 17 of the participants who consented to lumbar puncture. 

All participants had had COVID but had not required hospitalisation.

They found that ten of 13 participants with cognitive symptoms had anomalies in their cerebrospinal fluid – but all four of the cerebrospinal samples from participants with no post-COVID cognitive symptoms were normal. 

Participants with these symptoms presented with executive functioning issues, said senior author Dr Joanna Hellmuth, of the UCSF Memory and Aging Center. 

“They manifest as problems remembering recent events, coming up with names or words, staying focused, and issues with holding onto and manipulating information, as well as slowed processing speed,” she said.

Examinations of the cerebrospinal fluid revealed elevated levels of protein, suggesting inflammation, and the presence of unexpected antibodies found in an activated immune system. 

Some were found in the blood and cerebrospinal fluid, implying a systemic inflammatory response, or were unique to the cerebrospinal fluid, suggesting brain inflammation. 

While the targets of these antibodies are unknown, it is possible that these could be “turncoat” antibodies that attack the body itself.

“It’s possible that the immune system, stimulated by the virus, may be functioning in an unintended pathological way,” said Dr Hellmuth, who is principal investigator of the UCSF Coronavirus Neurocognitive Study and is also affiliated with the UCSF Weill Institute for Neurosciences. 

“This would be the case even though the individuals did not have the virus in their bodies,” she said, noting that the lumbar punctures took place on average ten months after the participants’ first COVID symptom.

The researchers also found that the participants with cognitive symptoms had an average of 2.5 cognitive risk-factors, compared with an average of less than one risk factor for participants without the symptoms. 

These risk-factors included diabetes and hypertension, which can increase the risk of stroke, mild cognitive impairment and vascular dementia; and a history of ADHD, which may make the brain more vulnerable to executive functioning issues. Other risk factors included anxiety, depression, a history of  heavy alcohol or repeated stimulant use, and learning disabilities.

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Brain injury

New light shed on Brazilian Jiu-Jitsu and brain injury

Athletes may be at less risk of causing long-lasting injury than has previously been feared, new research has revealed

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Brazilian Jiu-Jitsu (BJJ) athletes may be at less risk of causing long-lasting injury to the brain than has previously been feared, new research has revealed. 

BJJ is a popular martial art that exposes participants to recurrent intermittent asphyxiation due to controlled application of neck chokes. 

Unlike several combat sports, BJJ categorically prohibits strikes to the body, especially the head, favouring limb manipulation and neck chokes to coerce an opponent into submission.

However, concerns have been raised regarding the potential link between repetitive neck chokes, structural brain damage and implications for cognitive function.

But now, in the first study of its kind, researchers at the University of South Wales (USW) – who have previously led pioneering research to show the extent of rugby players’ cognitive decline in just one season – have shed new light on BJJ. 

The team from the Neurovascular Research Laboratory at USW examined blood flow to the brain using Duplex ultrasonography and cognitive function via neuropsychological tests in elite BJJ athletes. 

They found preliminary evidence that the BJJ athletes had a higher resting blood flow to the brain, alongside intact cognitive function, when compared to a control group of athletes matched by age, gender, and cardiorespiratory fitness.

Benjamin Stacey, lecturer in clinical science, said: “The popularity of BJJ is growing exponentially and is likely attributable to many people witnessing its effectiveness in Mixed Martial Arts (MMA) on promotions such as the Ultimate Fighting Championship (UFC) and Bellator. 

“The inclusivity of BJJ allows for all individuals to train together, regardless of age, sex or physical ability and when compared to other combat sports, BJJ carries a lesser risk to injury.

“Our unique findings argue against the notion that BJJ predisposes an individual to greater risk of long-lasting brain damage and conversely, provides evidence for enhanced protection for the brain. 

“These observations may be attributed to choke-induced pre-conditioning and/or exposure to BJJ-specific high-intensity interval training, which we know can confer protective benefits for the brain.

“These findings can help to inform much-needed follow-up research to extensively examine both the short and long-term implications of participation in the sport.”

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