Periodic Reporting for period 1 - Beyond the BBB (Nerve Growth Factor Delivery into the Brain – focus on therapeutic potential in Alzheimer’s disease and In Vivo Evaluation via PET)
Période du rapport: 2023-04-01 au 2025-03-31
Diseases of the brain, including Alzheimer’s disease and other neurodegenerative disorders, remain some of the most difficult to treat. One of the major obstacles is the blood-brain barrier (BBB)—a natural defence system that protects the brain but also blocks the entry of most drugs into the brain. While biologics (such as antibodies and neurotrophic factors) hold great promise for brain therapy, delivering them effectively and monitoring their impact remains a significant challenge in neuroscience and drug development.
This project addressed this issue by developing a non-invasive strategy to deliver biologics into the brain and visualising their engagement with disease-relevant targets using PET imaging (Positron Emission Tomography). The original approach involved modifying nerve growth factor (NGF) for brain delivery, targeting its receptor (TrkA), and assessing successful targeting binding using a newly designed PET tracer. However, due to technical challenges with NGF production, the project pivoted to a more flexible and robust strategy: developing a pretargeted PET imaging platform based on bioorthogonal click chemistry (specifically, TCO–tetrazine ligation). This approach decouples the therapeutic molecule from the radiotracer, offering a safer, more modular way to monitor drug delivery to the brain in real time. To support this strategy, the project also implemented a focused ultrasound (FUS) technique that allows temporary opening of the BBB in animal models. This combination of technologies was designed to significantly improve the precision of brain-targeted delivery and the ability to measure whether therapeutic agents reach their intended targets.
This research solves a bottleneck in brain drug development: the lack of practical tools to assess whether large biologics reach the brain and bind to their intended targets. The imaging method developed during this fellowship offers the potential to:
- Accelerate the development of brain-targeted drugs by providing quantitative imaging of drug-target engagement
- Improve diagnostic and therapeutic precision for neurodegenerative diseases.
While the original scientific approach was revised, the project maintained its overall objectives and adapted to technical challenges, yielding promising results.
This project addressed this issue by developing a non-invasive strategy to deliver biologics into the brain and visualising their engagement with disease-relevant targets using PET imaging (Positron Emission Tomography). The original approach involved modifying nerve growth factor (NGF) for brain delivery, targeting its receptor (TrkA), and assessing successful targeting binding using a newly designed PET tracer. However, due to technical challenges with NGF production, the project pivoted to a more flexible and robust strategy: developing a pretargeted PET imaging platform based on bioorthogonal click chemistry (specifically, TCO–tetrazine ligation). This approach decouples the therapeutic molecule from the radiotracer, offering a safer, more modular way to monitor drug delivery to the brain in real time. To support this strategy, the project also implemented a focused ultrasound (FUS) technique that allows temporary opening of the BBB in animal models. This combination of technologies was designed to significantly improve the precision of brain-targeted delivery and the ability to measure whether therapeutic agents reach their intended targets.
This research solves a bottleneck in brain drug development: the lack of practical tools to assess whether large biologics reach the brain and bind to their intended targets. The imaging method developed during this fellowship offers the potential to:
- Accelerate the development of brain-targeted drugs by providing quantitative imaging of drug-target engagement
- Improve diagnostic and therapeutic precision for neurodegenerative diseases.
While the original scientific approach was revised, the project maintained its overall objectives and adapted to technical challenges, yielding promising results.
The project's original approach involved delivering NGF constructs across the BBB and by using a TrkA PET tracer, [¹⁸F]TRACK, to assess NGF´s binding to its receptor, TrkA. Due to technical difficulties in NGF construct production, the research plan was revised, and the scientific focus shifted to an alternative brain target and targeting vector using a pretargeted PET imaging strategy based on bioorthogonal click chemistry (TCO–tetrazine) to quantify target engagement in the brain.
Scientific achievements include:
- Successful radiosynthesis of [¹⁸F]TRACK
- Establish and optimise a focused ultrasound (FUS) protocol for temporary BBB opening in rodents.
- Development and application of a pretargeting strategy for PET imaging in the brain, decoupling the pharmacokinetics of antibodies and radiotracers to improve imaging precision and safety.
- Proof-of-concept experiments evaluating target engagement of an anti-amyloid-beta antibody in an amyloid-beta mouse model using the newly implemented pretargeting platform.
Scientific achievements include:
- Successful radiosynthesis of [¹⁸F]TRACK
- Establish and optimise a focused ultrasound (FUS) protocol for temporary BBB opening in rodents.
- Development and application of a pretargeting strategy for PET imaging in the brain, decoupling the pharmacokinetics of antibodies and radiotracers to improve imaging precision and safety.
- Proof-of-concept experiments evaluating target engagement of an anti-amyloid-beta antibody in an amyloid-beta mouse model using the newly implemented pretargeting platform.
This project explored new ways to deliver and track biological medicines (such as antibodies) in the brain, a significant challenge in treating brain diseases like Alzheimer’s. A key barrier is the blood-brain barrier (BBB), a protective layer that blocks most drugs from entering the brain. In addition, it is difficult to measure whether these medicines reach their target once inside the brain.
To address these challenges, the project developed and tested a new imaging strategy — pretargeted PET imaging — a method that separates the drug from the radioactive imaging agent, using a precise “click chemistry” reaction in the body to link them at the right time and place. This approach improves safety, flexibility, and image clarity.
Although the original plan to test NGF treatment could not be completed, the project successfully:
- Established FUS platform for use in small animal models.
- Implemented a new radioactive tracer ([¹⁸F]TRACK) that can image NGFs target receptor in the brain.
- Tested pretargeted imaging method to measure how well an antibody against Alzheimer’s disease binds in the brain.
However, to take these results further, additional research will be needed to optimise dosing, the timing interval between antibody and tetrazine injection, brain uptake and clearance of the tetrazine, and safety studies. To meet these needs, new industry and academic partnerships and securing additional funding will be essential.
To address these challenges, the project developed and tested a new imaging strategy — pretargeted PET imaging — a method that separates the drug from the radioactive imaging agent, using a precise “click chemistry” reaction in the body to link them at the right time and place. This approach improves safety, flexibility, and image clarity.
Although the original plan to test NGF treatment could not be completed, the project successfully:
- Established FUS platform for use in small animal models.
- Implemented a new radioactive tracer ([¹⁸F]TRACK) that can image NGFs target receptor in the brain.
- Tested pretargeted imaging method to measure how well an antibody against Alzheimer’s disease binds in the brain.
However, to take these results further, additional research will be needed to optimise dosing, the timing interval between antibody and tetrazine injection, brain uptake and clearance of the tetrazine, and safety studies. To meet these needs, new industry and academic partnerships and securing additional funding will be essential.