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Principal Investigator: Alan Koretsky
Organization: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
Fiscal Year: 2020
Award: $1,718,993
Funding agency: National Institute of Neurological Disorders and Stroke
We have made substantial progress towards Aims 1-5 and 8. Specifically:
a) We have determined that 3 nm iron oxide nanoparticles can be reliably fabricated, in collaboration with the NIH image probes development core. These serve as good T1 MRI contrast agents and have strong T2* contrast properties as well. We can now produce these iron oxide nanoparticles independently in our laboratory in the Clinical Center.
b) We have developed several camelid VHH antibody fragment targeting domains for pathological targets relevant to neurological disease, and made specific modifications to enhance the affinity of the targeting domains. Several additional targeting domains are under development, including nanobodies for pathological relevant forms of the tau protein.
c) We have validated the binding specificity of a blood-brain barrier transcytosis functionalization domain. We are creating additional blood-brain barrier transcytosis domains and testing them for optimal transcytosis, including a mouse transferrin receptor binding nanobody for use in mice that are wild-type at the transferrin receptor lcous. We are producing a novel transgenic mouse that expresses the extracellular domain of the human transferrin receptor in place of the homologous mouse domain to test the human specific nanobody that will be used for human studies.
d) We have determined appropriate methods to prevent fouling of nanoparticles in human plasma using PEG coatings.
e) We have successfully assembled nanoparticles using these 4 components, and demonstrated that they retain their properties after assembly.
f) We have determined that MP2RAGE MRI sequences have excellent properties for detecting T1 MRI contrast agents in both mice (at 4.7T and 9.4T) and humans (at 3T). Specifically, the test-retest reliability for MP2RAGE MRI was found to be superior to other T1 methods given similar scan times. Two manuscripts have been submitted for publication.
g) We have optimized method for R2* MRI mapping with very high test retest reliability at 3T and 9.4T. We are in the process of testing these methods in healthy volunteers
h) We have performed initial in vivo experiments in mice, and have refined methods for assessing molecular contrast agent kinetics using infrared tracking. We have constructed detailed mathematical models of the pharmacokinetics in living mice for contrast agents of various sizes.
i), We developed a series of SARS-CoV-2 nanobodies that have potential for use as therapeutics, diagnostics, and laboratory reagents.
Please see the linked preprint
https://www.biorxiv.org/content/10.1101/2020.07.24.219857v3
A manuscript has been submitted for publication.
A provisional patent was filed.
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