̽��ֱ�� of Cambridge - Lund ̽��ֱ��

Cambridge researchers developing brain implants for treating Parkinson’s disease

sc604 — Thu, 23 Jan 2025 10:33:21 +0000

As part of a £69 million funding programme supported by the Advanced Research + Invention Agency (ARIA), Professor George Malliaras from Cambridge’s Department of Engineering will co-lead a project that uses small clusters of brain cells called midbrain organoids to develop a new type of brain implant, which will be tested in animal models of Parkinson’s disease.

̽��ֱ��project led by Malliaras and Professor Roger Barker from the Department of Clinical Neurosciences, which involves colleagues from the ̽��ֱ�� of Oxford, the ̽��ֱ�� of Lund and BIOS Health, is one of 18 projects funded by ARIA as part of its Precision Neurotechnologies programme, which is supporting research teams across academia, non-profit R&D organisations, and startups dedicated to advancing brain-computer interface technologies.

̽��ֱ��programme will direct £69 million over four years to unlock new methods for interfacing with the human brain at the neural circuit level, to treat many of the most complex neurological and neuropsychiatric disorders, from Alzheimer’s to epilepsy to depression.

By addressing bottlenecks in funding and the lack of precision offered by current approaches, the outputs of this programme will pave the way for addressing a much broader range of conditions than ever before, significantly reducing the social and economic impact of brain disorders across the UK.

Parkinson’s disease occurs when the brain cells that make dopamine (a chemical that helps control movement) die off, causing movement problems and other symptoms. Current treatments, like dopamine-based drugs, work well early on, but can cause serious side effects over time.

In the UK, 130,000 people have Parkinson’s disease, and it costs affected families about £16,000 per year on average – more than £2 billion in the UK annually. As more people age, the number of cases will grow, and new treatments are urgently needed.

One idea is to replace the lost dopamine cells by transplanting new ones into the brain. But these cells need to connect properly to the brain’s network to fix the problem, and current methods don’t fully achieve that.

In the ARIA-funded project, Malliaras and his colleagues are working on a new approach using small clusters of brain cells called midbrain organoids. These will be placed in the right part of the brain in an animal model of Parkinson’s disease. They’ll also use advanced materials and electrical stimulation to help the new cells connect and rebuild the damaged pathways.

“Our ultimate goal is to create precise brain therapies that can restore normal brain function in people with Parkinson’s,” said Malliaras.

“To date, there’s been little serious investment into methodologies that interface precisely with the human brain, beyond ‘brute force’ approaches or highly invasive implants,” said ARIA Programme Director Jacques Carolan. “We’re showing that it’s possible to develop elegant means of understanding, identifying, and treating many of the most complex and devastating brain disorders. Ultimately, this could deliver transformative impact for people with lived experiences of brain disorders.”

Other teams funded by the programme include one at Imperial College London who is developing an entirely new class of biohybridised technology focused on engineering transplanted neurons with bioelectric components. A Glasgow-led team will build advanced neural robots for closed-loop neuromodulation, specifically targeting epilepsy treatment, while London-based Navira will develop a technology for delivering gene therapies across the blood-brain barrier, a crucial step towards developing safer and more effective treatments.

Adapted from an ARIA media release.

Cambridge researchers are developing implants that could help repair the brain pathways damaged by Parkinson’s disease.

Our ultimate goal is to create precise brain therapies that can restore normal brain function in people with Parkinson’s

George Malliaras

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Substantia nigra in the human brain, illustration

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Clinical trial for new stem cell-based treatment for Parkinson’s disease given go ahead

cjb250 — Thu, 20 Oct 2022 11:29:28 +0000

̽��ֱ��Swedish Medical Products Agency has granted approval for the trial to proceed; ethical approval has already been obtained from the Swedish Ethics Review Authority. ̽��ֱ��team, led from Lund ̽��ֱ�� in Sweden, is poised to begin recruitment.

STEM-PD uses human embryonic stem cells, a type of cell that can turn into almost any type of cell in the body. ̽��ֱ��team has ‘programmed’ the cells to develop into dopamine nerve cell, which will be transplanted into the brains of patients to replace cells that are lost in Parkinson’s disease. ̽��ֱ��product has already been shown to be safe and effective at reverting motor deficits in animal models of Parkinson’s disease.

̽��ֱ��trial is a collaboration with colleagues at Skåne ̽��ֱ�� Hospital, the ̽��ֱ�� of Cambridge, Cambridge ̽��ֱ�� Hospitals NHS Foundation Trust (CUH), and Imperial College London.

Professor Roger Barker from the Wellcome-MRC Stem Cell Institute at the ̽��ֱ�� of Cambridge and CUH is clinical lead on the project. “ ̽��ֱ��use of stem cells will in theory enable us to make unlimited amounts of dopamine neurons and thus opens the prospect of producing this therapy to a wide patient population. This could transform the way we treat Parkinson’s disease”

This is the first such trial in Europe and the preclinical and clinical studies of STEM-PD have been funded by national and EU funding agencies. In addition, the STEM-PD team has obtained funding and valuable support for the current study from Novo Nordisk; a collaboration which will continue for future product development.

̽��ֱ��cells to be used in the trial have been manufactured under ‘good manufacturing practice’ at the Royal Free Hospital in London and have undergone rigorous testing in the lab.

Professor Malin Parmar who leads the STEM-PD team from Lund ̽��ֱ�� said: “We are looking forward to this clinical study of STEM-PD, hoping that it could potentially help reduce the significant burden of Parkinson’s disease. This has been a massive team effort for over a decade, and the regulatory approval is a major and important milestone.”

̽��ֱ��STEM-PD trial will assess safety and tolerability of the transplanted product one year after transplantation, measuring the effects on Parkinson’s symptoms. ̽��ֱ��trial will enrol eight patients for transplantation, starting with patients from Sweden, and with subsequent plans for enrolment of patients also from Cambridge ̽��ֱ�� Hospitals. All transplantation surgery will be performed at Skåne ̽��ֱ�� Hospital in Lund.

Parkinson’s disease is the second most common neurodegenerative disease worldwide, yet remains without a cure. Typical motor symptoms of Parkinson’s disease are slowness of movement, tremor and stiffness and later also gait difficulties. It is not well known how the disease arises or develops, but the core feature common to all patients is the loss of dopamine neurons in the midbrain.

Suitable patients will be invited to participate in the trial; it is not possible to volunteer to participate.

Adapted from a press statement from Lund ̽��ֱ��

Cambridge researchers will play a key role in clinical trials of a new treatment that involves transplanting healthy nerve cells into the brains of patients with Parkinson’s disease.

This could transform the way we treat Parkinson’s disease

Roger Barker

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Hands of an elderly man with walking stick

̽��ֱ��text in this work is licensed under a Creative Commons Attribution 4.0 International License. Images, including our videos, are Copyright © ̽��ֱ�� of Cambridge and licensors/contributors as identified. All rights reserved. We make our image and video content available in a number of ways – as here, on our main website under its Terms and conditions, and on a range of channels including social media that permit your use and sharing of our content under their respective Terms.

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Antibody designed to recognise pathogens of Alzheimer’s disease

sc604 — Mon, 25 May 2020 19:00:00 +0000

Their method is able to recognise these toxic particles, known as amyloid-beta oligomers, which are the hallmark of the disease, leading to hope that new diagnostic methods can be developed for Alzheimer’s disease and other forms of dementia.

̽��ֱ��team, from the ̽��ֱ�� of Cambridge, ̽��ֱ�� College London and Lund ̽��ֱ��, designed an antibody which is highly accurate at detecting toxic oligomers and quantifying their numbers. Their results are reported in the Proceedings of the National Academy of Sciences (PNAS).

“There is an urgent unmet need for quantitative methods to recognise oligomers – which play a major role in Alzheimer’s disease, but are too elusive for standard antibody discovery strategies,” said Professor Michele Vendruscolo from Cambridge’s Centre for Misfolding Diseases, who led the research. “Through our innovative design strategy, we have now discovered antibodies to recognise these toxic particles.”

Dementia is one of the leading causes of death in the UK and costs more than £26 billion each year, a figure which is expected to more than double in the next 25 years. Estimates put the current cost to the global economy at nearly £1 trillion per year.

Alzheimer’s disease, the most prevalent form of dementia, leads to the death of nerve cells and tissue loss throughout the brain, resulting in memory failure, personality changes and problems carrying out daily activities.

Abnormal clumps of proteins called oligomers have been identified by scientists as the most likely cause of dementia. Although proteins are normally responsible for important cell processes, according to the amyloid hypothesis, when people have Alzheimer’s disease these proteins –including specifically amyloid-beta proteins – become rogue and kill healthy nerve cells.

Proteins need to be closely regulated to function properly. When this quality control process fails, the proteins misfold, starting a chain reaction that leads to the death of brain cells. Misfolded proteins form abnormal clusters called plaques which build up between brain cells, stopping them from signalling properly. Dying brain cells also contain tangles, twisted strands of proteins that destroy a vital cell transport system, meaning nutrients and other essential supplies can no longer move through the cells.

There have been over 400 clinical trials for Alzheimer’s disease, but no drug that can modify the course of the disease has been approved. In the UK, dementia is the only condition in the top 10 causes of death without a treatment to prevent, stop, or slow its progression.

“While the amyloid hypothesis is a prevalent view, it has not been fully validated in part because amyloid-beta oligomers are so difficult to detect, so there are differing opinions on what causes Alzheimer’s disease,” said Vendruscolo. “ ̽��ֱ��discovery of an antibody to accurately target oligomers is, therefore, an important step to monitor the progression of the disease, identify its cause, and eventually keep it under control.”

̽��ֱ��lack of methods to detect oligomers has been a major obstacle in the progress of Alzheimer’s research. This has hampered the development of effective diagnostic and therapeutic interventions and led to uncertainty about the amyloid hypothesis.

“Oligomers are difficult to detect, isolate, and study,” said Dr Francesco Aprile, the study’s first author. “Our method allows the generation of antibody molecules able to target oligomers despite their heterogeneity, and we hope it could be a significant step towards new diagnostic approaches.”

̽��ֱ��method is based on an approach for antibody discovery developed over the last ten years at the Centre for Misfolding Diseases. Based on the computational assembly of antibody-antigen assemblies, the method enables the design of antibodies for antigens that are highly challenging, such as those that live only for a very short time.

By using a rational design strategy that enables to target specific regions, or epitopes, of the oligomers, and a wide range of in vitro and in vivo experiments, the researchers have designed an antibody with at least three orders of magnitude greater affinity for the oligomers over other forms of amyloid-beta. This difference is the key feature that enables the antibody to specifically quantify oligomers in both in vitro and in vivo samples.

̽��ֱ��team hopes that this tool will enable the discovery of better drug candidates and the design of better clinical trials for people affected by the debilitating disease. They also co-founded Wren Therapeutics, a spin-out biotechnology company based at the Chemistry of Health Incubator, in the recently opened Chemistry of Health building, whose mission it is to take the ideas developed at the ̽��ֱ�� of Cambridge and translate them into finding new drugs to treat Alzheimer’s disease and other protein misfolding disorders.

̽��ֱ��antibody has been patented by Cambridge Enterprise, the ̽��ֱ��’s commercialisation arm.

Reference:
Francesco A. Aprile et al. ‘Rational design of a conformation-specific antibody for the quantification of Aβ oligomers.’ Proceedings of the National Academy of Sciences (2020). DOI: 10.1073/pnas.1919464117

Researchers have found a way to design an antibody that can identify the toxic particles that destroy healthy brain cells – a potential advance in the fight against Alzheimer’s disease.

̽��ֱ��discovery of an antibody to accurately target oligomers is an important step to monitor the progression of the disease, identify its cause, and eventually keep it under control

Michele Vendruscolo

Strittmatter Laboratory, Yale ̽��ֱ��

Mouse model of Alzheimer's disease

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Cambridge spin-out company wins £18m to fight Alzheimer's

plc32 — Thu, 24 Jan 2019 10:27:38 +0000

A biopharmaceutical company set-up by Cambridge academics from St John's College to develop drugs to treat illnesses such as Alzheimer's, Parkinson’s and more than 50 other related diseases has won £18 million in a Series A financing round.

Wren Therapeutics raised the funding from an international syndicate led by ̽��ֱ��Baupost Group with participation from LifeForce Capital and a number of high net worth individual investors.

Several of the company’s scientific founders are members of St John’s, including Professor Sir Christopher Dobson, Master of St John's, Professor Tuomas Knowles, a St John's Fellow, and Dr Samuel Cohen, the St John’s Entrepreneur in Residence.

Wren Therapeutics focuses on drug discovery and development for protein misfolding diseases such as Alzheimer’s and Parkinson’s and was founded in 2016.

Protein molecules form the machinery which carry out all of the executive functions in living systems. However, proteins sometimes malfunction and become misfolded, leading to a complex chain of molecular events that can cause long-lasting damage to the health of people affected and may ultimately lead to death.

This group of medical disorders are known as protein misfolding diseases. Alzheimer’s and Parkinson’s are widely recognised protein misfolding diseases, but others include type-2 diabetes, motor neurone disease and more than 50 other related illnesses.

Dr. Cohen explained: “Protein misfolding diseases are one of the most critical global healthcare challenges of the 21st century but are highly complex and challenging to address. Current strategies - in particular those driven by traditional drug discovery and biological approaches - have proven, at least to date, to be ineffective.

“Wren’s new and unique approach is instead built on concepts from the physical sciences and focuses on the chemical kinetics of the protein misfolding process, creating a predictive and quantitatively driven platform that has the potential to radically advance drug discovery in this class of diseases.”

Wren Therapeutics is a spin-off company from the ̽��ֱ�� of Cambridge and Lund ̽��ֱ�� in Sweden. ̽��ֱ��company is based at the ̽��ֱ�� of Cambridge, in the recently opened Chemistry of Health Centre, and plans on opening a satellite office in Boston, Massachusetts.

Professor Sir Christopher Dobson said: "Wren is built on many years of highly collaborative, uniquely integrated, interdisciplinary research that has uncovered the key molecular mechanisms associated with protein misfolding diseases.

"I am hugely enthusiastic about our ability to make tangible progress against these diseases and change the course of life for millions of people around the world suffering from these debilitating and increasingly common medical disorders.”

̽��ֱ��company will announce its board of directors shortly.

Wren Therapeutics secures £18 million in funding to tackle protein misfolding diseases.

"I am hugely enthusiastic about our ability to make tangible progress against these diseases"

Professor Sir Christopher Dobson

Dr Samuel Cohen, Entrepreneur in Residence at St John's and CEO of Wren Therapeutics

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Brain cholesterol associated with increased risk of Alzheimer’s disease

sc604 — Mon, 07 May 2018 15:00:00 +0000

̽��ֱ��international team, led by the ̽��ֱ�� of Cambridge, have found that in the brain, cholesterol acts as a catalyst which triggers the formation of the toxic clusters of the amyloid-beta protein, which is a central player in the development of Alzheimer’s disease.

̽��ֱ��results, published in the journal Nature Chemistry, represent another step towards a possible treatment for Alzheimer’s disease, which affects millions worldwide. ̽��ֱ��study’s identification of a new pathway in the brain where amyloid-beta sticks together, or aggregates, could represent a new target for potential therapeutics.

It is unclear if the results have any implications for dietary cholesterol, as cholesterol does not cross the blood-brain barrier. Other studies have also found an association between cholesterol and the condition, since some genes which process cholesterol in the brain have been associated with Alzheimer’s disease, but the mechanism behind this link is not known.

̽��ֱ��Cambridge researchers found that cholesterol, which is one of the main components of cell walls in neurons, can trigger amyloid-beta molecules to aggregate. ̽��ֱ��aggregation of amyloid-beta eventually leads to the formation of amyloid plaques, in a toxic chain reaction that leads to the death of brain cells.

While the link between amyloid-beta and Alzheimer’s disease is well-established, what has baffled researchers to date is how amyloid-beta starts to aggregate in the brain, as it is typically present at very low levels.

“ ̽��ֱ��levels of amyloid-beta normally found in the brain are about a thousand times lower than we require to observe it aggregating in the laboratory – so what happens in the brain to make it aggregate?” said Professor Michele Vendruscolo of Cambridge’s Centre for Misfolding Diseases, who led the research.

Using a kinetic approach developed over the last decade by the Cambridge team and their collaborators at Lund ̽��ֱ�� in Sweden, the researchers found in in vitro studies that the presence of cholesterol in cell membranes can act as a trigger for the aggregation of amyloid-beta.

“It's exciting to see that the kinetic analysis approach that we have developed over the past few years is now allowing us to explore increasingly complex systems, including protein-lipid interactions which are likely to be central for the initiation of aberrant protein aggregation,” said co-author Professor Tuomas Knowles.

Since amyloid-beta is normally present in such small quantities in the brain, the molecules don’t normally find each other and stick together. Amyloid-beta does attach itself to lipid molecules, however, which are sticky and insoluble. In the case of Alzheimer’s disease, the amyloid-beta molecules stick to the lipid cell membranes that contain cholesterol. Once stuck close together on these cell membranes, the amyloid-beta molecules have a greater chance to come into contact with each other and start to aggregate – in fact, the researchers found that cholesterol speeds up the aggregation of amyloid-beta by a factor of 20.

So what, if anything, can be done to control cholesterol in the brain? According to Vendruscolo, it’s not cholesterol itself that is the problem. “ ̽��ֱ��question for us now is not how to eliminate cholesterol from the brain, but about how to control cholesterol’s role in Alzheimer’s disease through the regulation of its interaction with amyloid-beta,” he said. “We’re not saying that cholesterol is the only trigger for the aggregation process, but it’s certainly one of them.”

Since it is insoluble, while travelling towards its destination in lipid membranes, cholesterol is never left around by itself, either in the blood or the brain: it has to be carried around by certain dedicated proteins, such as ApoE, a mutation of which has already been identified as a major risk factor for Alzheimer’s disease. As we age, these protein carriers, as well as other proteins that control the balance, or homeostasis, of cholesterol in the brain become less effective. In turn, the homeostasis of amyloid-beta and hundreds of other proteins in the brain is broken. By targeting the newly-identified link between amyloid-beta and cholesterol, it could be possible to design therapeutics which maintain cholesterol homeostasis, and consequently amyloid-beta homeostasis, in the brain.

“This work has helped us narrow down a specific question in the field of Alzheimer’s research,” said Vendruscolo. “We now need to understand in more detail how the balance of cholesterol is maintained in the brain in order to find ways to inactivate a trigger of amyloid-beta aggregation.”

Co-author Professor Chris Dobson, also a member of the Centre for Misfolding Diseases and Master of St John's College, added “This study has added significantly to our understanding of the molecular basis of aggregation of amyloid-beta, which is associated with Alzheimer’s disease. It shows how interdisciplinary studies fostered by the Centre for Misfolding Diseases, and our international collaborators can play a major part in working out how to develop potential therapeutic strategies to reduce the risk of the onset and progression of this highly debilitating and increasingly common disease.”

Dr Tim Shakespeare of the Alzheimer’s Society said: “Previous research has shown people with high cholesterol levels in mid-life are slightly more likely to develop dementia, but until now we didn’t know why. This study has demystified the link. ̽��ֱ��findings suggest managing cholesterol levels in the brain could be a target for future treatments, but it’s still unclear whether there’s any effect from our diet.”

Dr David Reynolds of Alzheimer’s Research UK, said: “Around 20 per cent of the body’s total cholesterol is found in the brain. Cholesterol in our diet can have a big impact on heart health and maintaining a healthy blood supply to the brain can help to keep dementia risk as low as possible.”

Reference:
Johnny Habchi et al. ‘Cholesterol catalyses amyloid-β42 aggregation through a heterogeneous nucleation pathway in the presence of lipid membranes.’ Nature Chemistry (2018). DOI: 10.1038/s41557-018-0031-x

Researchers have shown how cholesterol – a molecule normally linked with cardiovascular diseases – may also play an important role in the onset and progression of Alzheimer’s disease.

̽��ֱ��question for us now is not how to eliminate cholesterol from the brain, but about how to control cholesterol’s role in Alzheimer’s disease through the regulation of its interaction with amyloid-beta.

Michele Vendruscolo

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Mouse model of Alzheimer's disease

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