‘Transformative': the UK lab working on a way to halt genetic type of dementia

Yahoo

2 days ago

Behind the gleaming glass facade of an office block in east London's Docklands, Dr Martina Esposito Soccoio is pipetting ribonucleic acid into test tubes.
Here, not far from Canary Wharf's multinational banks, a British university spinout is working on a breakthrough treatment for a form of dementia that affects millions of people worldwide.
There is no cure for dementia at present, but scientists at AviadoBio hope their clinical studies can stop the progression of a particular genetic type of frontotemporal dementia (FTD).
'It may be one of the first dementias to have a definitive treatment, a cure if you like, a really transformative treatment that allows people to live much longer and much more normal lives,' says Prof James Rowe, a consultant neurologist at Cambridge's Addenbrooke's hospital who is involved in the UK trial.
FTD mainly affects the front and sides of the brain and, unlike Alzheimer's disease, does not begin with memory loss, which tends to occur later. It is characterised by progressive loss of language and changes in personality and behaviour.
Most cases are diagnosed in people aged 45 to 65, but it can affect those in their 20s and 30s. There are an estimated 20,000 to 40,000 people living with FTD in the UK, and between 1 million and 2 million in the world.
Rowe says: 'It's a double-edged sword: the young onset, the high genetic burden and rapid illness are also features that perhaps make it more tractable to treat.'
The Die Hard and Pulp Fiction actor Bruce Willis, who recently celebrated his 70th birthday, was diagnosed two years ago with FTD, which his family described as a 'cruel disease'. They have not said whether he has a genetic form of FTD.
The gene therapy developed by AviadoBio, which was spun out of Prof Christopher Shaw's research lab at King's College London in 2021, targets a type of FTD known as FTD-GRN. This is caused by mutations of a gene that lead to a deficiency of progranulin (GRN), a protein that is essential for maintaining healthy brain cells.
AviadoBio, which employs 60 people, signed an exclusive licence agreement with the Japanese pharmaceutical firm Astellas last October to develop the therapy. It is now recruiting patients for its clinical trial in the UK, as well as the US, Poland, Spain, Sweden and the Netherlands.
The infusion was administered in Warsaw in March 2024 in one of six patients who have had the treatment so far, in Poland and the US. All patients will be followed for up to five years as part of the trial. AviadoBio expects to publish the first data next year.
Three years ago, Jessica Crawford, from Beverley in East Yorkshire, lost her mother, Julia, to FTD, caused by mutations of another gene, C9orf72. In 2014, when Julia was 58, her behaviour changed; the family suspected depression. Previously very sociable, she stopped going out and started playing games such as Candy Crush or watching TV shows 'over and over', her daughter recounts.
Her mother initially did not want to see a doctor, and was only diagnosed with FTD in February 2019. By this time she was so confused she once put raw chicken in a sandwich. 'Getting the diagnosis wasn't easy because FTD wasn't well known; my mum was acing in the memory tests,' Jessica says.
Julia became increasingly confused and lost the ability to speak, and then to communicate at all. Jessica became her full-time carer in 2020, but her mother deteriorated so much that she had to enter a care home in late 2021, and died the following year.
Jessica, 33, found out she also carries the gene mutation, and with her husband decided to conceive through IVF with a pre-implantation genetic diagnosis. When their five embryos were screened, four had the gene mutation, and the fifth resulted in the birth of their son. The couple donated their other four embryos to science and she takes part in GENFI – a long-running UK-led global study of families with FTD across 40 sites.
AviadoBio itself was born out of the research done at King's by Shaw, a neurologist who has focused on FTD and amyotrophic lateral sclerosis (ALS) for more than three decades, and Dr Youn Bok Lee and Dr Do Young Lee from the UK Dementia Research Institute's centre based at King's. ALS, the most common form of motor neurone disease, has also been linked to mutations of the GRN gene and leads to muscle weakness, paralysis and eventually death.
Shaw acts as the company's chief scientific and clinical adviser, and while the Lees are no longer involved in the firm's research, all three remain shareholders.
David Cooper, AviadoBio's chief medical officer, says: 'It was something that hit me when I first joined the company, [when] you look at the MRI scans of patients with a GRN mutation, the frontal and temporal parts of their brain are just melting away … So we really need earlier treatment, an earlier diagnosis and a more organised healthcare approach to deal with it.'
AviadoBio's lead product, AVB-101, is infused directly into the brain by a neurosurgeon using a cannula as thin as a strand of angel hair pasta, during a 90-minute procedure guided by MRI. It delivers a functional copy of the progranulin gene to restore appropriate levels of the protein to affected areas of the brain. It is a one-off treatment, and no immunosuppressant drugs are needed afterwards.
'The patients who have FTD are born with almost half of the progranulin levels that you and I might have,' says the chief executive, Lisa Deschamps. 'Our goal in the study is to supplement the GRN gene and restore as much progranulin in these individuals as possible to normal levels to reduce the neurodegeneration effect.'
Other medications in development around the world include two gene therapies, from Philadelphia-based Passage Bio and Eli Lilly-owned Prevail Therapeutics, but they do not target the thalamus, the 'relay station' in the brain. Passage Bio's therapies are delivered directly to the cerebrospinal fluid in a single treatment. Denmark's Vesper Bio has developed an oral capsule, designed to act on the GRN gene, that is being trialled at University College London hospital.
AviadoBio, whose investors include Johnson & Johnson's innovation arm and the UK not-for-profit LifeArc Ventures, is part of a growing life science cluster in Canary Wharf. At its labs, scientists – assisted by robotics – research how to target a particular gene.
'The UK has real strengths in this area,' says Rowe, pointing to the international GENFI study, run since 2011 by Prof Jonathan Rohrer, a neurologist from UCL Queen Square Institute of Neurology who also sits on AviadoBio's scientific advisory board. 'It's a real win for the UK.'