̽��ֱ�� of Cambridge - Giovanna Mallucci

Gene therapy approach to boost ‘cold shock protein’ in the brain without cooling protects mice against neurodegenerative disease

cjb250 — Fri, 24 Mar 2023 08:00:07 +0000

̽��ֱ��discovery is a step towards harnessing the protective effects of cooling the brain to treat patients with acute brain injury and even to prevent dementias, such as Alzheimer’s.

When the body cools down significantly, it increases its levels of RBM3, a molecule known as the cold shock protein – a phenomenon first observed in hibernating animals. It is thought that during hibernation, the protein helps protect the brain from damage and allows it to continue to form new connections.

In 2015, Professor Giovanna Mallucci and colleagues showed in mice that RBM3 can protect the brain against damage associated with build-up of misfolded proteins, which can lead to various forms of dementia, such as Alzheimer’s and Parkinson’s disease, and from prion diseases such as Creutzfeldt-Jakob Disease (CJD).

Induced hypothermia is used to treat patients in intensive care units – including newborn babies and traumatic brain injury patients – with the patients placed into a coma and their brains cooled to protect against damage. But this comes with associated risks, such as blood clotting and pneumonia. Could the cold shock protein be harnessed to treat patients without having to cool the body, offering a safer treatment for acute brain injury or a way of protecting the brain against dementia?

In research published in EMBO Molecular Medicine, scientists at the UK Dementia Research Institute, ̽��ֱ�� of Cambridge, and the Institute of Chemistry and Biochemistry, Freie Universität Berlin, studied whether a form of gene therapy known as antisense oligonucleotides (ASOs) could increase levels of the cold shock protein in the brains of mice – and hence protect them.

̽��ֱ��team examined the gene that codes for production of the cold shock protein and found that it contains a key element which under normal conditions prevents its expression. Removing, or ‘dialling down’ this element using an ASO, results in a long-lasting boost to production of RBM3.

To test whether this approach could protect the brain, the researchers used mice infected with prions. Some of these mice were injected with a single dose of the ASO three weeks later, while the others were given a control treatment.

Twelve weeks after being administered the prions, those mice that had received the control treatment succumbed to prion disease and showed extensive loss of neurons in the hippocampus, an area of the brain important for memory.

̽��ֱ��story was very different for the mice that had received the ASO. At the same time as the other mice were succumbing to prion disease, the ASO-treated mice had levels of RBM3 twice as high as in the other mice. Seven of the eight ASO-treated mice showed extensive preservation of neurons in the hippocampus.

Professor Giovanna Mallucci, who led the work while at the UK Dementia Research Institute at the ̽��ֱ�� of Cambridge, said: “Essentially, the cold shock protein enables the brain to protect itself – in this case, against the damage to nerve cells in the brain during prion disease. Remarkably, we showed that just a single injection with the ASO was sufficient to provide long-lasting protection for these mice, preventing the inevitable progression of neurodegeneration.”

Professor Florian Heyd from Freie Universität Berlin added: “This approach offers the prospect of being able to protect against diseases such as Alzheimer’s and Parkinson’s disease, for which we have no reliable preventative treatments.

“We are still a long way off this stage as our work was in mice, but if we can safely use ASOs to boost production of the cold shock protein in humans, it might be possible to prevent dementia. We are already seeing ASOs being used to successfully treat spinal muscular atrophy and they have recently been licenced to treat motor neurone disease.”

If the findings can be replicated in humans, this approach could have major implications for the treatment of patients beyond neurodegeneration. These include acute brain injury from newborn babies with hypoxia through protecting the brain in heart surgery, stroke and head injury in adults who would otherwise be treated by therapeutic hypothermia.

Professor Mallucci is now based at the Alto Labs, Cambridge Institute of Science.

̽��ֱ��research was supported by core funding from the Freie Universität Berlin and by the UK Dementia Research Institute, which in turn is funded by the Medical Research Council, Alzheimer’s Society and Alzheimer’s Research UK.

Reference
Preußner, M et al. ASO targeting temperature-controlled RBM3 poison exon splicing prevents neurodegeneration in vivo. EMBO Molecular Medicine; 22 March 2023; DOI: 10.15252/emmm.202217157

Scientists in Cambridge and Berlin have used a form of gene therapy to increase levels of the so-called ‘cold shock protein’ in the brains of mice, protecting them against the potentially devastating impact of prion disease.

Essentially, the cold shock protein enables the brain to protect itself – in this case, against the damage nerve cells in the brain during prion disease

Giovanna Mallucci

Mika Ruusunen (Unsplash)

Cold water swimming

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Cambridge Science Festival returns for milestone 25th year

Anonymous — Fri, 25 Jan 2019 15:48:27 +0000

Celebrating its 25th year, the Festival runs for two weeks from 11-24 March and explores the theme of ‘discoveries’. An impressive line-up of acclaimed scientists includes microscopist Professor Dame Pratibha Gai, Astronomer Royal Professor Lord Martin Rees, 2018 Nobel prize winner Sir Gregory Winter, geneticist Dr Giles Yeo, statistician Professor David Spiegelhalter, engineer Dr Hugh Hunt, marine biologist and author Helen Scales, THIS Institute Director Professor Mary Dixon-Woods, futurist Mark Stevenson, and science presenter Steve Mould.

̽��ֱ��full programme is teeming with events ranging from debates, talks, exhibitions, workshops and interactive activities to films, comedy and performances, held in lecture theatres, museums, cafes and galleries around Cambridge. There are events for all ages and most are free.
With so many events on offer, audiences will be spoilt for choice. Some of the biggest events in week one include:

Is technology making us miserable? (11 March). Virtually every interaction we have is mediated through technology. Despite being ‘always-on’, are we any better off? Are we better connected? Or is technology making us miserable?
Putting radioactivity in perspective (12 March). Following a renewal of electricity generated by nuclear power, Professors Ian Farnan and Gerry Thomas, Imperial College London, discuss radioactivity in the natural world and the outcomes of decades of study on the health effects of radiation. Could these research outcomes reset attitudes towards radiation and the risks?
̽��ֱ��universe of black holes (13 March). Christopher Reynolds, Plumian Professor of Astronomy, describes how future research into black holes may yet again change our view of reality.
̽��ֱ��long-term perspective of climate change (14 March). Professors Ulf Büntgen, Mike Hulme, Christine Lane, Hans W Linderholm, Clive Oppenheimer, Baskar Vira, and Paul J Krusic discuss how we investigate past climate and the challenges we face in applying this to the policy-making process.
Catalytic activation of renewable resources to make polymers and fuels (15 March). Professor Charlotte Williams, ̽��ֱ�� of Oxford, discusses the development of catalysts able to transform carbon dioxide into methanol, a process which may deliver more sustainable liquid transport fuels in the future.
Does the mother ever reject the fetus? (15 March). Professor Ashley Moffett discusses fetal rejection and explores new discoveries that show that there are multiple mechanisms to ensure there is a peaceful environment in the uterus, where the placenta is allowed to grow and develop to support the fetus.

Top picks for the second week include:

Cambridge gravity lecture: Sir Gregory Winter (18 March). Sir Gregory is a molecular biologist and 2018 Nobel Laureate best known for his work on developing technologies to make therapeutic monoclonal antibodies. His research has led to antibody therapies for cancer, rheumatoid arthritis and multiple sclerosis.
Discoveries leading to new treatments for dementia (18 March). Professor of Clinical Neurosciences and Associate Director of the UK Dementia Research Institute, Giovanna Mallucci discusses how new research leading to insights into dementia and degenerative brain diseases may lead to new treatments.
Improving quality and safety in healthcare (19 March). THIS Institute Director Professor Mary Dixon-Woods looks at the challenges to improving quality and safety in healthcare and considers why it’s so hard to answer the question: Does quality improvement actually improve quality? With Dr Fiona Godlee, Editor in Chief of ̽��ֱ��BMJ.
Immunology: the future of medicine? (19 March) Professor Clare Bryant and a panel of Cambridge immunologists discuss how understanding disease triggers may enable entirely new approaches to treating and potentially preventing disease.
Polar ocean: the dead end of plastic debris (19 March). An estimated 80% of all the litter in our oceans is plastic, and a significant concentration of plastics debris is found in both polar oceans. ̽��ֱ��impact of this debris on the sensitive polar ecosystem could be profound. Pelagic marine ecologist Dr Clara Manno, British Antarctic Survey, explores the current research and existing situation in the polar regions.
Reluctant futurist (19 March). Old models for healthcare, education, food production, energy supply and government are creaking under the weight of modern challenges. Futurist Mark Stevenson looks at the next 30 years and asks, how can we re-invent ourselves for the future?
Adolescent mental health: resilience after childhood adversity (20 March). Adolescence is characterised by huge physiological changes as well as a rapid rise in mental health disorders. Around 45% of adolescent mental health problems are caused by childhood difficulties but fortunately not all who experience difficulties develop mental health disorders. Dr Anne-Laura van Harmelen discusses mechanisms that may help adolescents with a history of childhood difficulty to become more resilient.
Making algorithms trustworthy (21 March). Increasingly, algorithms are being used to make judgements about sensitive parts of our lives. How do we check how their conclusions were arrived at, and if they are valid and fair? Professor David Spiegelhalter looks at efforts to make algorithms transparent and trustworthy, using systems that make predictions for people with cancer as an example.
On the future: prospects for humanity (22 March). Professor Lord Martin Rees argues that humanity’s prospects on Earth and in space depend on our taking a different approach to planning for tomorrow.

This year’s Cambridge Science Festival also celebrates significant milestones in science, including the 200th anniversary of Cambridge Philosophical Society, Cambridge’s oldest scientific society, and 150 years since the publication of the modern Periodic Table.

Speaking ahead of the Festival, Dr Lucinda Spokes, Festival Manager, said: “We are tremendously proud of this year’s programme due to the variety of events and the calibre of our speakers from a range of institutions and industries.

“Alongside the meatier topics we have an array of events for all ages and interests across both weekends. We have everything from the science of perfumery and how your mood affects your taste, to a science version of 'Would I Lie to You?'

“One of my personal top picks are the open days at the various institutes and departments based at the West Cambridge site on Saturday 23 March. As always, the site is hosting some truly fascinating events, everything from the future of construction and how to make Alexa smarter, to how nanotechnology is opening up new routes in healthcare, and state-of-the-art approaches to low-cost solar energy and high-efficiency lighting solutions.

“A Festival of this magnitude would not be possible without the help from many people; we thank all our scientists, supporters, partners and sponsors, without whom the Festival would not happen. Most of all, we thank the audiences – there are more than 60,000 visits to the Festival events every year. We very much look forward to welcoming everyone from all ages to join us in March to explore the fabulous world of science.”

You can download the full programme here.

Bookings open on Monday 11 February at 11am.

This year’s Festival sponsors and partners are Cambridge ̽��ֱ�� Press, AstraZeneca, MedImmune, Illumina, TTP Group, Science AAAS, Anglia Ruskin ̽��ֱ��, Astex Pharmaceuticals, Cambridge Science Centre, Cambridge Junction, IET, Hills Road 6th Form College, British Science Week, Cambridge ̽��ֱ�� Health Partners, Cambridge Academy for Science and Technology, and Walters Kundert Charitable Trust. Media Partners: BBC Radio Cambridgeshire and Cambridge Independent.

̽��ֱ��2019 Cambridge Science Festival is set to host more than 350 events as it explores a range of issues that affect today’s world, from challenges around climate change policy, improving safety and quality in healthcare, and adolescent mental health, to looking at what the next 25 years holds for us and whether quantum computers can change the world.

We have everything from the science of perfumery and how your mood affects your taste, to a science version of 'Would I Lie to You?'

Dr Lucinda Spokes

̽��ֱ��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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̽��ֱ��Academy of Medical Sciences announces new Fellows for 2017

cjb250 — Mon, 08 May 2017 09:00:39 +0000

̽��ֱ��Fellows have been elected for their contribution to biomedical and health research, the generation of new knowledge in medical sciences and its translation into benefits to society.

This year's elected Fellows have expertise that spans women’s health, immunology, public health and infectious disease among many other fields.

Professor Sir Robert Lechler PMedSci, President of the Academy of Medical Sciences said: “As we elect new Fellows each year, the Academy continues to grow as a unique and productive hub of the best minds in UK medical science. Our expanding and evolving Fellowship allows the Academy to play a vital role in tackling the major health challenges facing society today and in the future.

“ ̽��ֱ��election of these 46 exceptional biomedical and health researchers is a well-deserved honour. Each newly elected Fellow has made an outstanding impact in the community, contributing to the development of better healthcare - from fundamental scientific understanding to the prevention, diagnosis and treatment of disease. I am delighted to welcome them to the Academy and greatly look forward to working with them all in the future.”

̽��ֱ��newly elected Fellows include Professor Giovanna Mallucci, whose research is pioneering new treatments for dementia and who was recently announced as one of the five associate directors of the UK Dementia Research Institute.

Professor Giovanna Mallucci said: “Election to the Fellowship is a great honour and distinction, internationally recognised, and I am delighted and proud to be awarded it. This is a tremendous achievement in any medical research career: a milestone in a scientific and personal journey. It is a real privilege to join this this community of distinguished, inspirational and luminary leaders in the medical sciences.”

Four of Cambridge’s Fellows are cancer specialists, including CRUK Cambridge Centre Director Professor Richard Gilbertson.

Professor Gilbertson said: “I am deeply honoured to have received this recognition of our work and feel privileged to join such a wonderful organisation dedicated to promoting excellence in medical science, ultimately for the good of patients. This honour belongs to my many postdocs, PhD students, technicians and wonderful collaborators who over the years who have worked with me to pursue fantastic science. ̽��ֱ��cadre of scientists elected from Cambridge also reflects the vibrant cancer research community in our city and the terrific support of the clinical school.”

̽��ֱ�� ̽��ֱ�� of Cambridge Fellows elected in 2017 are:

Professor Sheila Bird OBE FRSE, Visiting Senior Fellow, MRC Biostatistics Unit, ̽��ֱ�� of Cambridge School of Clinical Medicine and Institute of Public Health and Visiting Professor at Department of Mathematics and Statistics, Strathclyde ̽��ֱ��
Dr Jason Carroll, Senior Group Leader, Cancer Research UK Cambridge Institute, ̽��ֱ�� of Cambridge
Professor Richard Gilbertson, Li Ka Shing Chair of Oncology, Head of Department of Oncology, Director, Cancer Research UK Cambridge Centre, ̽��ֱ�� of Cambridge
Professor Gregory Hannon, Royal Society Wolfson Research Professor of Molecular Cancer Biology, ̽��ֱ�� of Cambridge
Dr Roman Hovorka, Director of Research, WT-MRC Institute of Metabolic Science, ̽��ֱ�� of Cambridge
Professor Arthur Kaser, ̽��ֱ�� Chair of Gastroenterology, Honorary Consultant Physician, ̽��ֱ�� of Cambridge
Professor Giovanna Mallucci, van Geest Professor of Clinical Neurosciences, Clinical Neurosciences, ̽��ֱ�� of Cambridge; Associate Director UK Dementia Research Institute at ̽��ֱ�� of Cambridge; Programme Leader and Head of Neurobiology, MRC Toxicology Unit, ̽��ֱ�� of Leicester
Professor Hugh Markus, Professor of Stroke Medicine, Clinical Neurosciences, ̽��ֱ�� of Cambridge
Professor Christine J. Watson, Professor of Cell and Cancer Biology, ̽��ֱ�� of Cambridge

In addition, two Fellows were elected from the MRC Laboratory of Molecular Biology and Wellcome Trust Sanger Institute:

Dr Anne Bertolotti, Programme Leader, MRC Laboratory of Molecular Biology
Dr Matthew Hurles, Senior Group Leader, Human Genetics, Wellcome Trust Sanger Institute

̽��ֱ��new Fellows will be formally admitted to the Academy at a ceremony on 28 June 2017.

Nine researchers from the ̽��ֱ�� of Cambridge are among 46 world leading UK researchers who have been elected to the prestigious Fellowship of the Academy of Medical Sciences.

Academy of Medical Sciences

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Scientists discover two repurposed drugs that arrest neurodegeneration in mice

cjb250 — Thu, 20 Apr 2017 00:11:20 +0000

Misfolded proteins build up in the brain in several neurodegenerative diseases and are a major factor in dementias such as Alzheimer’s and Parkinson’s as well as prion diseases. Previously, the team found that the accumulation of misfolded proteins in mice with prion disease over-activates a natural defence mechanism, ‘switching off’ the vital production of new proteins in brain cells. They then found switching protein production back on with an experimental drug halted neurodegeneration. However, the drug tested was toxic to the pancreas and not suitable for testing in humans.

In the latest study, published today in Brain, the team tested 1,040 compounds from the National Institute for Neurological Disorders and Stroke, first in worms (C.elegans) which have a functioning nervous system and are a good experimental model for screening drugs to be used on the nervous system and then in mammalian cells. This revealed a number of suitable candidate compounds that could then be tested in mouse models of prion disease and a form of familial tauopathy (frontotemporal dementia - FTD), both of which had been protected by the experimental - but toxic - compounds in the team’s previous studies.

̽��ֱ��researchers identified two drugs that restored protein production rates in mice – trazodone hydrochloride, a licensed antidepressant, and dibenzoylmethane, a compound being trialled as an anti-cancer drug. Both drugs prevented the emergence of signs of brain cell damage in most of the prion-diseased mice and restored memory in the FTD mice. In both mouse models, the drugs reduced brain shrinkage which is a feature of neurodegenerative disease.

Professor Giovanna Mallucci, who led the team from the Medical Research Council’s (MRC) Toxicology Unit in Leicester and is now based at the ̽��ֱ�� of Cambridge, was today announced as one of the five associate directors of the UK Dementia Research Institute. She said: “We know that trazodone is safe to use in humans, so a clinical trial is now possible to test whether the protective effects of the drug we see on brain cells in mice with neurodegeneration also applies to people in the early stages of Alzheimer’s disease and other dementias. We could know in 2-3 years whether this approach can slow down disease progression, which would be a very exciting first step in treating these disorders.

“Interestingly, trazodone has been used to treat the symptoms of patients in later stages of dementia, so we know it is safe for this group. We now need to find out whether giving the drug to patients at an early stage could help arrest or slow down the disease through its effects on this pathway.”

̽��ֱ��research was funded by the MRC and Professor Mallucci was also funded by a grant from Alzheimer’s Society and Alzheimer’s Drug Discovery Foundation.

Dr Rob Buckle, Chief Science Officer at the MRC, said: “This study builds on previous work by this team and is a great example of how really innovative discovery science can quite quickly translate into the possibility of real drugs to treat disease.”

Dr Doug Brown, Director of Research and Development at the Alzheimer's Society, said: “We’re excited by the potential of these findings. They show that a treatment approach originally discovered in mice with prion disease might also work to prevent the death of brain cells in some forms of dementia. This research is at a very early stage and has not yet been tested in people - but as one of the drugs is already available as a treatment for depression, the time taken to get from the lab to the pharmacy could be dramatically reduced.”

Reference
Halliday, M et al. Repurposed drugs targeting eIF2α-P-mediated translational repression prevent neurodegeneration in mice. Brain; 20 April 2017; DOI: 10.1093/brain/awx074

Adapted from a press release by the Medical Research Council

A team of scientists who a few years ago identified a major pathway that leads to brain cell death in mice, have now found two drugs that block the pathway and prevent neurodegeneration. ̽��ֱ��drugs caused minimal side effects in the mice and one is already licensed for use in humans, so is ready for clinical trials.

We could know in 2-3 years whether this approach can slow down disease progression, which would be a very exciting first step in treating [Alzheimer’s disease and other dementias]

Giovanna Mallucci

US National Institute on Aging, Alzheimer's Disease Education and Referral Center

PET scan of a human brain with Alzheimer's disease

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Cambridge named as a centre for the UK Dementia Research Institute

cjb250 — Wed, 19 Apr 2017 23:57:50 +0000

̽��ֱ��UK DRI is a joint £250 million investment into dementia research led by the Medical Research Council (MRC) alongside founding charity partners Alzheimer’s Society and Alzheimer’s Research UK. Established in response to the Government’s 2020 Challenge on Dementia, the DRI’s mission is to find new ways to diagnose, treat and prevent and care for people with dementias, a group of neurodegenerative disorders which include Alzheimer’s, Parkinson’s and Huntington’s disease.

̽��ֱ��selection of the UK DRI centres marks a significant investment for the institute, with total funding for the foundation programmes and resources awarded to the centres reaching £55 million, which the centres will supplement with over £20m worth of co-investment.

Bringing together world-leading expertise across the spectrum of dementia research, and maximising the benefit of cutting-edge facilities and skills, the newly announced centres join ̽��ֱ�� College London (UCL) which was the first centre to be announced as the location of the DRI headquarters in December 2016, alongside the announcement of UK DRI Director, Professor Bart De Strooper.

Each centre will be led by an associate director and up to four programme leaders who will lead the centre’s foundation programmes. ̽��ֱ��centres have been awarded a total of 20 professorships and seven fellowships in the foundation phase, to build momentum in the institute. ̽��ֱ��centres have a biomedical focus, and care research will also be integrated into the institute next year.

̽��ֱ��Cambridge centre will be led by Professor Giovanna Mallucci, who added: “We are very excited about the opportunity for Cambridge to be part of the UK DRI. Our centre on the Cambridge Biomedical Campus will focus on interdisciplinary science, building on our ̽��ֱ��’s strengths across research areas from chemistry and biophysics through to cell biology of neurodegeneration.”

Professor Bart De Strooper, Director of the UK DRI, said: “ ̽��ֱ��shared vision between the centres will be at the heart of the DRI’s success, and this creativity at the borders will lead us to truly understand dementias and how they progress. We selected the centres based on innovative, excellent science, evidence of strong leadership, the alignment of goals with the DRI as a whole, and the ability to grow and collaborate as the institute gathers pace.

“An overarching theme from the ̽��ֱ�� of Cambridge was the excellence of its science. Professor Mallucci’s energy and commitment to the cause was clear and I am confident she will drive successful interactions not only between her team’s programmes but with the wider DRI.”

Science Minister Jo Johnson said: “Dementia affects millions of people around the world, but through greater understanding we can make significant steps forward to improve lives.

“Today’s announcement of the institute’s centre locations demonstrates the UK’s existing wealth of knowledge and research expertise, and the leadership role we can take in developing new treatments to tackle this disease. This is exactly the type of project our Industrial Strategy will build on to ensure the UK remains at the forefront of global science.”

Following the announcement of the centres and their foundation programmes, recruitment will soon begin to establish a number of a core programmes. ̽��ֱ��institute is seeking talented researchers from around the world, from a wide variety of fields, to fill knowledge gaps in dementias and enrich expertise. Visit the UK DRI website here for more information.

Adapted from a press release by the Medical Research Council

̽��ֱ�� ̽��ֱ�� of Cambridge has been announced as one of the centres that will form the UK Dementia Research Institute (UK DRI) alongside Cardiff ̽��ֱ��, the ̽��ֱ�� of Edinburgh, Imperial College London and King’s College London.

Our centre on the Cambridge Biomedical Campus will focus on interdisciplinary science, building on our ̽��ֱ��’s strengths across research areas from chemistry and biophysics through to cell biology of neurodegeneration

Giovanna Mallucci

Dementia: Catching the memory thief

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