MRI-guided focused ultrasound IVIg immunotherapy for Alzheimer’s disease
University of Toronto, Sunnybrook Research Institute
In patients with Alzheimer’s disease (AD), neurons in the brain degenerate and eventually die, leading to deficits in learning and memory. Our research aims to protect neurons and to help them maintain their function by targeting the accumulated protein amyloid which is toxic in the AD brain. Using a mouse model of AD, we will combine focused ultrasound technology with magnetic resonance imaging (MRI) to allow therapeutics delivered intravenously to reach targeted areas in the brain by altering the blood brain barrier without the need for invasive brain surgery. We will test the efficacy of MRI-guided focused ultrasound technology in conjunction with antibodies targeting amyloid to see whether this therapeutic approach protects neurons and ultimately improves learning and memory.
Relevance to the acceleration of therapeutics for neurodegenerative diseases of aging
If successful, MRI-guided focused ultrasound combined with intravenous therapeutic delivery, such as the use of antibodies, can be rapidly translated to the clinic for AD and other age-related neurodegenerative disorders. The scalability of MRI-guided focused ultrasound applications from mouse to human has been established as high intensity focused ultrasound (HIFU) is used at Sunnybrook to treat essential tremors in patients. At 1% of HIFU’s power, the non-thermal applications proposed in our project modifies rather than destroys the blood-brain barrier in a reversible and controlled manner to allow targeted therapeutic delivery to the brain.
We anticipate that focused ultrasound will allow therapeutics administered intravenously to enter targeted areas of the brain, exert their full potential, act where the pathology is most severe, preserve cellular and vascular integrity, and minimize amyloid toxicity to maintain cognitive function. From this project, we will learn whether therapeutic delivery to the brain using focused ultrasound is more efficient compared to intravenous administration alone. This study also represents a cornerstone in terms of determining the minimal dose of therapeutic required for efficacy using this approach. This dose is expected to be much less than current intravenous administration which is limiting both in terms of cost and safety in clinical trials.
In patients with Alzheimer’s disease (AD), neurons in the brain degenerate and eventually die, leading to deficits in learning and memory. Our research aimed to protect neurons by targeting amyloid beta peptides (Aβ), which are toxic in the AD brain. Using a mouse model of AD, we combined magnetic resonance imaging (MRI) with transcranial focused ultrasound technology (FUS) to disrupt the blood- brain barrier (BBB) and allow human-derived antibodies, injected in the blood, to reach targeted brain areas without the need for invasive surgery. We tested the efficacy of this treatment by measuring neuropathology, cell regeneration and survival, and functions related to learning and memory.
In an animal model of AD, we successfully delivered human-derived antibodies from the blood to targeted brain areas using FUS. This treatment led to the promotion of neuronal regeneration and cognitive functions. These findings have the potential to accelerate the translation of a range of FUS applications for neurodegenerative disorders, including for the delivery of human-derived antibodies to the brain for patients with AD.
The scalability of FUS applications from mouse to human has been established. At Sunnybrook, patients are being treated with high intensity focused ultrasound (HIFU) for essential tremors. At only 1% of HIFU’s power, the non-thermal FUS application used in our study modifies the blood-brain barrier in a reversible and controlled manner, allowing for delivery of therapeutics from the blood to targeted areas of the brain. Such low intensity FUS treatments are planned to enter clinical trials at Sunnybrook for BBB disruption, allowing intravenous chemotherapeutic agents to reach brain tumours in cancer patients. FUS-mediated drug delivery to the brain has the potential to be used in patients with AD and other neurodegenerative disorders in the near future.
Through this work, we evaluated the efficacy of transcranial FUS to mediate the delivery of human- derived antibodies from the blood to the brain, to reduce pathology and to improve neuronal regeneration and functions. We found that FUS-mediated delivery of human-derived antibodies to the brain prevented Aβ accumulation and promoted neuronal regeneration and cognitive functions. The combined treatment (FUS and antibodies) was of greater efficacy then other treatments (e.g. FUS or antibodies alone). This study represents a proof-of-concept in validating the treatment of AD with FUS- mediated delivery of human-derived antibodies from the blood to the brain. Furthermore, our data also provide evidence that only two treatments, over a period of several weeks (i.e. dramatically lowering the total amount of human-derived antibodies typically required), may be sufficient to maintain efficacy. This is relevant and important because human-derived antibodies are a limited resource. It is therefore critical to develop the most cost and resource-effective treatments using FUS and human-derived antibodies, while maximizing clinical improvement in AD.