- An Australian research team has published a study on the intricacies of ultrasound-assisted drug delivery for Alzheimer’s disease.
- They hypothesized that ultrasound in combination with an antibody would produce a greater therapeutic effect than either therapy alone.
- Combination treatment increased antibody delivery to the brain but did not further reduce disease pathology.
The research team led by Jürgen Götz, PhD, and Rebecca Nisbet, PhD, at the Queensland Brain Institute (QBI) in Australia recently published a study that provides new clues on how ultrasound-assisted antibody delivery across the blood-brain barrier (BBB) may or may not help treat Alzheimer’s disease.
The group’s preclinical research tested whether using scanning ultrasound plus microbubbles (SUS+MB) to open the BBB and deliver a tau-specific monoclonal antibody, “RNF5,” in a mouse model of Alzheimer’s disease would reduce the amount of tau beyond reductions observed when administering RNF5 alone or SUS+MB alone. RNF5 is a proprietary antibody that was generated at QBI and validated in QBI’s Alzheimer’s model. In a previous study, SUS delivery of a different (single chain) tau antibody enhanced brain and neuronal uptake, reduced tau pathology, and improved behavioral outcomes (see Nisbet et al. Brain 2017). Delivering RNF5 alone, or using SUS+MB alone, also reduced tau pathology; therefore, they hypothesized that the combination approach would produce an even greater effect than using either alone.
The combination of SUS+MB and RNF5 did increase antibody localization in the brain, but it did not further reduce the tau pathology when compared with RNF5 alone. In fact, after the treatment, RNF5 heavily accumulated in off-target cells.
“Adding to the complexity, when we combined SUS+MB with an analogue of Aducanumab (anti-Abeta antibody) in an earlier study (Leinenga et al. Alz Res Ther 2021), this led to improved spatial memory and histopathological outcome,” said Prof. Götz. “But in assessing the uptake of the fluorescently labelled antibody (spiked to the last treatment), the analysis focused on plaque and microglial co-localisation (amyloid being an extracellular target) and cellular accumulation of the antibody (if it had occurred) may have been masked by the large plaques.”
Prof. Nisbet added, “Our study highlights that getting therapeutics into the brain is only half the challenge. Ensuring that the therapeutic then reaches its target, especially targets localized within neurons such as tau, is a significant additional hurdle.”
The article concluded that antibody delivery appeared to be a considerably complex scientific problem requiring further study.
“This study has implications beyond Alzheimer’s disease,” said Kelsie Timbie, PhD, the Foundation’s Scientific Programs Manger. “It could alter the perception of focused ultrasound as a drug-agnostic delivery platform.”
Investigator Profile: Q&A with Jürgen Götz, PhD October 2015