Falling down and then getting up. Such is the journey that researchers like Prof Adrian Isaacs (UK DRI at UCL) go through to develop new treatment strategies for diseases such as frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). In this article Adrian discusses what he has learned from setbacks, the success of his project harnessing the fruit fly and why the support of the UK DRI has been invaluable to his lab’s development.
This piece is part of our ‘Develop’ series, showcasing the UK DRI's mission to discover the causes of neurodegeneration, develop possible treatments and deliver solutions for healthy ageing.
For Prof Adrian Isaacs, turning to dementia research was “a serendipity”.
During his undergraduate studies, Adrian had the opportunity to spend a year in a laboratory dedicated to the genetics of dementia, run by Prof John Hardy and Dr Mike Hutton, at the Mayo Clinic in Jacksonville (USA). There, he was part of the team that discovered mutations in the MAPT gene, which provides the instructions for production of the protein tau – which, when misfolded, is implicated in neurodegenerative diseases including FTD.
This formative experience opened up a world that Adrian is now immersed in at the UK DRI at UCL.
“We're really trying to understand the genetic and molecular causes of FTD and ALS. After 10 years, now where we're starting to develop potential therapeutics, to translate our studies into improving the lives of people affected,” he says.
A revolutionary fly model to understand FTD and ALS
As a way to understand what lies behind these neurodegenerative diseases, Adrian's lab introduced a new fruit fly model, a project that has not only presented a major challenge, but is also one of his proudest achievements. As he explains, until then no one had succeeded in cloning the expansion of DNA repeats in the C9orf72 gene, which is the most common cause of FTD and ALS.
“We came up with new ways to actually build pieces of DNA to be able to model that repeat expansion in fruit flies for the first time. The insights we gained from that initial study are having important ramifications on the field now,” he explains.
In fact, this fruit fly model has allowed the team to carry out a study on the modulation of lipids in the brain, and bring them a step closer to new treatments for people affected by FTD or ALS.
Lipids or fats are essential for cell function: from membrane formation to intercellular signalling and energy storage, these components play a crucial role. When lipid dysregulation occurs in the brain, it can trigger neurodegenerative diseases.
Efforts to understand how these dysregulations occur and how to address them are encouraging.
“We think this project could have very exciting translational potential,” Adrian says.
The most exciting moments are when you discover something that you realise no one else has seen before.
Group Leader
A supportive framework to develop promising projects
Over the course of his research journey, Adrian has moved from fundamental discovery research, through to translational studies that are moving ever closer to benefitting people affected by neurodegenerative diseases. Adrian has worked closely with the Business & Innovation team at the UK DRI, which guides the institution's technology transfer activities and takes care of procedures and partnerships. He says, the support that the UK DRI has given him has been key during this process.
Additionally, running his lab at the UK DRI has allowed the lab to access intramural funding schemes such as the Translation Award programme, giving him extra support to take his research from the lab to the clinic. Adrian says that these grants have been “absolutely transformative” in enabling his group to deploy a translational project to study small molecules that modulate C9orf72 and other FTD/ALS genes.
“We screened over 100,000 small molecules and we found some really exciting ones. That led to a much bigger major investment in that project and it was really seeded by the initial funding from the UK DRI,” he explains.
Isaacs lab
A path full of learning
On this path to translational research, according to Adrian, one of the main learnings has been to take risks and address new questions: “the safer thing to do would be to jump onto what other people are doing, or confirm other people's findings,” he declares. In fact, he says, the most important work that has come out of his lab has occured when he was encouraged to take a leap of faith into the unknown.
“The most exciting moments are when you discover something that you realise no one else has seen before,” Adrian says.
In 2022, Adrian and his team developed a new biomarker as a way of monitoring harmful changes occurring in FTD and ALS, which would allow scientists to measure the success of therapies targeting the most common genetic causes of the conditions. This innovation was utilised in an early-stage clinical trial to evaluate a new treatment for FTD and ALS.
Unfortunately, the results were not as expected, but Adrian recognises that failure is always an inevitable part of the process that leads to success.
“Even though the trial was negative, it led to a quite clear roadmap now of what we need to do to go forward, so that was an important milestone for us.”
On this path between developing and delivering treatments for people affected by these neurodegenerative diseases, Adrian says it is crucial to never lose sight of the target that drives their work as well as finding the right partners to generate multidisciplinary collaborations. This is how he believes he can get closer to succeeding at delivering treatments.
“Five years from now I'd like to be even further down the translational pathway with two therapeutic modalities we are focused on. Helping to improve quality of life for people with FTD and ALS is the driver of why we all do our work, and it’s truly exciting and gratifying to be getting close to that target,” he concludes.
Banner image: IPSC cells - Credit Rubika Balendra (Isaacs' Lab)
