Nerve Growth Factor Delivery into the Brain – focus on therapeutic potential in Alzheimer’s disease and In Vivo Evaluation via PET

Alzheimer’s disease (AD) is a neurodegenerative disease affecting the aged population and is projected to increase 3-fold in the next 30-years.

Treatment options in AD are limited due to complex pathological processes and the blood-brain barrier (BBB), which restrict entry molecules into the brain. A finding in AD is the loss of cholinergic neurons.

Tropomyosin receptor kinase A (TrkA) and its substrate, the nerve growth factor (NGF), are involved in neuronal survival and have been evaluated in small clinical trials as a therapeutic intervention in AD.

Advances in BBB shuttling methods, in which antibodies and enzymes can be transported over the BBB, make NGF a possible treatment option in AD.Within this proposal, I will develop novel methods for the delivery of NGF into the brain. Two different approaches for BBB delivery of NGF will improve the success rate.

In one approach, NGF will be delivered into the brain by transferrin receptor (TfR)-mediated transcytosis.

NGF will be chemically conjugated to a TfR binding antibody using a linker that selectively and quantifiably can release NGF in its native form in the brain, ensuring retained biological activity. An alternative approach, BBB will be opened with focused ultrasounds allowing passage of NGF into the brain.

Positron emission tomography occupancy studies with [18F]TRACK, a TrkA selective tracer, will be used to evaluate in vivo binding of NGF to TrkA. The above-described BBB transport methods for NGF will be evaluated in long-term therapeutic study using 5xFAD mice.

Pharmacodynamic readouts will be changes in brain amyloid-beta levels, neuroinflammation parameters and improved memory and cognitive functions.

In this project, I will expand my knowledge in BBB delivery of macromolecules, learn new radiolabeling techniques from a world-leading radiochemist, and novel develop the necessary skills to take my career to the next level.