Researchers at the University of Essex have used artificial intelligence to design microscopic antibody fragments that can work inside human cells, opening a new route for studying and potentially treating neurodegenerative diseases such as Alzheimer's, Parkinson's, and motor neurone disease (MND).
The redesigned molecules, called intrabodies, are engineered to remain stable within cells, where they can attach to proteins associated with disease. Ordinary antibodies generally function outside cells, which has limited their use against conditions that develop through intracellular processes.
The research, funded by the MND Association and led by Dr. Caitlin O'Shea and Dr. Gareth Wright from the School of Life Sciences, was published in Nature Communications. The team converted 672 different antibodies into intrabodies capable of targeting disease-related proteins.
Electrical charge holds the key
The researchers discovered that electrical charge determines whether antibody fragments can survive and function inside cells. Antibodies typically carry the wrong charge to exist inside cells without sticking together, so the team used AI-powered protein redesign software to adjust them.
"We looked at the properties of millions of antibodies and compared them with human proteins found inside the cell," said lead author Dr. O'Shea, who specializes in MND and Parkinson's disease. "From this we figured out that antibodies usually have the wrong charge to exist inside cells without sticking together."
"We used software developed by Nobel Prize winner David Baker and his group to redesign our antibody fragments, so they had the right charge and are super stable."
The redesigned molecules will be made freely available to other scientists following publication.
Repurposing existing antibodies
The findings could allow researchers to find new uses for millions of antibodies developed during decades of biomedical research. Rather than starting from scratch, existing antibodies may be adaptable for use as laboratory tools and, potentially, as the foundation for future treatments aimed at disease-causing proteins.
Dr. Wright, who directed the research, said the approach could have major implications for diseases that affect tens of millions of people worldwide.
"We've made intracellular antibodies that stick to proteins that cause neurodegenerative diseases such as Alzheimer's, Parkinson's, Huntington's and motor neurone disease," said Dr. Wright. "These diseases can lead to cognitive impairment, forgetfulness, loss of muscle control and death. They affect over one million people in the UK alone, so they are a big public health concern."
"There are no cures for these diseases and finding molecules that interact with the proteins that cause them in their native environment is a major challenge in the medicine discovery process,"
Potential path to new therapies
The MND Association welcomed the findings and highlighted their potential importance for future treatments. Chief Scientist Dr. Brian Dickie said the work overcomes a key barrier in antibody development for neurodegenerative diseases.
"Dr. Wright and his colleagues have made a significant advance in overcoming one of the key challenges that has impeded the development of antibodies as treatments for neurodegenerative diseases, such as MND," said Dr. Dickie. "Their research findings provide optimism that a combination of this novel 'intrabody' science with emerging gene therapy techniques may lead to new therapeutic strategies that can hit specific molecular targets within neurones."
Why this matters for science and research professionals
For researchers working in drug discovery, this approach demonstrates a practical use of AI for protein engineering that goes beyond prediction. The team's method of analyzing millions of antibodies and redesigning them for intracellular stability offers a template for tackling other diseases where intracellular proteins are the target.
The open availability of the redesigned molecules means laboratories can test them against their own targets without licensing barriers. For scientists studying protein misfolding or aggregation, these intrabodies could become standard laboratory tools for probing disease mechanisms inside living cells.
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