Rezai AR, Ranjan M, D'Haese PF, Haut MW, Carpenter J, Najib U, Mehta RI, Chazen JL, Zibly Z, Yates JR, Hodder SL, Kaplitt M. Noninvasive hippocampal blood-brain barrier opening in Alzheimer's disease with focused ultrasound. Proc Natl Acad Sci U S A. 2020 Apr 28;117(17):9180-9182. Epub 2020 Apr 13 PubMed.
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The University of Queensland
A major challenge in treating brain diseases is presented by the blood-brain barrier (BBB), which constitutes an efficient barrier not only for toxins but also a wide range of therapeutic agents. In overcoming this impediment, ultrasound in combination with intravenously injected microbubbles has emerged as a powerful technology that allows for the selective brain uptake of blood-borne factors and therapeutic agents by transiently opening the BBB. Given that ultrasound parameters are highly tunable, the technique has been safely applied to achieve BBB opening in a range of species including mice, dogs, sheep, and macaques.
Extending these findings to humans, Lipsman and colleagues have shown in a proof-of-concept Phase 1 study that safe BBB opening can be achieved in a limited non-eloquent white-matter area of the dorsolateral prefrontal cortex (Lipsman et al., 2018). Extending this work, the Kaplitt team now reports data from an ongoing multicenter Phase 2 trial demonstrating that a large volume of the BBB in the deep structure of the hippocampus and entorhinal cortex (14 percent to 71 percent, average 29 percent, of hippocampal volume) can be safely, reversibly, and repeatedly opened. Additional laboratories have either initiated clinical trials or are getting ready to embark on such a journey. The strategies vary and also include implanted ultrasound transducers (Carpentier et al., 2016).
Several questions remain. The first is whether opening of the BBB by itself is sufficient to clear any Alzheimer's pathology. We have shown that BBB opening is required for amyloid to be cleared (Leinenga et al., 2019), and our work further showed that dormant microglia become activated, presumably by unidentified blood-borne factors that enter the brain, with interstitial amyloid being taken up into microglial lysosomes (Leinenga et al., 2019; Leinenga and Götz, 2015). The mechanism by which pathological tau is cleared differs. Here, neuronal autophagy is induced by therapeutic ultrasound (Pandit et al., 2019). Whether this approach will be sufficient in a human setting, or whether a combination therapy, such as with a tau antibody as pursued by us, is warranted, requires further study (Nisbet et al., 2017).
A second question relates to the treatment envelope and how this is linked to cognitive improvements. One could argue that one needs to target a brain area where neurodegeneration is initiated and assume that mitigates more widespread pathology that can be traced back to such a brain area. This is, in all likelihood, a too-simplistic viewpoint. It is more reasonable to assume that larger brain areas need to be targeted and that several treatment sessions will be required. Currently, however, the available technology does not allow for that.
Having said that, it is exciting to see more and more data that ultrasound as a tunable modality can be applied safely to the brain, even in such a crucial brain area as the hippocampus with its fundamental role in memory functions.
References:
Lipsman N, Meng Y, Bethune AJ, Huang Y, Lam B, Masellis M, Herrmann N, Heyn C, Aubert I, Boutet A, Smith GS, Hynynen K, Black SE. Blood-brain barrier opening in Alzheimer's disease using MR-guided focused ultrasound. Nat Commun. 2018 Jul 25;9(1):2336. PubMed.
Carpentier A, Canney M, Vignot A, Reina V, Beccaria K, Horodyckid C, Karachi C, Leclercq D, Lafon C, Chapelon JY, Capelle L, Cornu P, Sanson M, Hoang-Xuan K, Delattre JY, Idbaih A. Clinical trial of blood-brain barrier disruption by pulsed ultrasound. Sci Transl Med. 2016 Jun 15;8(343):343re2. PubMed.
Leinenga G, Koh WK, Götz J. Scanning ultrasound in the absence of blood-brain barrier opening is not sufficient to clear β-amyloid plaques in the APP23 mouse model of Alzheimer's disease. Brain Res Bull. 2019 Nov;153:8-14. Epub 2019 Aug 7 PubMed.
Leinenga G, Götz J. Scanning ultrasound removes amyloid-β and restores memory in an Alzheimer's disease mouse model. Sci Transl Med. 2015 Mar 11;7(278):278ra33. PubMed.
Pandit R, Leinenga G, Götz J. Repeated ultrasound treatment of tau transgenic mice clears neuronal tau by autophagy and improves behavioral functions. Theranostics. 2019;9(13):3754-3767. Epub 2019 May 31 PubMed.
Nisbet RM, Van der Jeugd A, Leinenga G, Evans HT, Janowicz PW, Götz J. Combined effects of scanning ultrasound and a tau-specific single chain antibody in a tau transgenic mouse model. Brain. 2017 Mar 4; PubMed.
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