This is particularly significant as AAV gene therapy has a solid safety profile, was first approved by the FDA in December 2017 7 and more than 200 clinical trials have been conducted since 1989 8. AAVs can infect dividing and non-dividing cells and result in highly efficient long-term transduction in a broad range of tissues 5, 6. Engineered adeno-associated viruses (AAVs), single-stranded deoxyribonucleic acid (ssDNA) encapsulated within 25-nm protein capsids, have recently shown potential to greatly increase transduction as compared with previous therapeutics 2, 3, 4. The background level of protein/nanotherapeutics reaching the brain is on the order of 0.1 percent injected dose per cubic centimeter (% ID/cc) 1, necessitating more efficient methods of delivery. Therapeutic delivery to the brain has traditionally been limited in volume. The results suggest that novel PET imaging techniques can be applied to inform and optimize capsid design. The PHP.eB capsid brain endothelial receptor affinity is nearly 20-fold greater than that of AAV9. We find that brain accumulation of the PHP.eB capsid 1) exceeds that reported in any previous PET study of brain uptake of targeted therapies and 2) is correlated with optical reporter gene transduction of the brain. To provide the sensitivity required to track AAVs injected at picomolar levels, a unique multichelator construct labeled with a positron emitter (Cu-64, t 1/2 = 12.7 h) is coupled to the viral capsid. Here, we create a non-invasive positron emission tomography (PET) methodology to track viruses. PHP.eB) have been shown to enhance brain delivery in rodents via the LY6A receptor on brain endothelial cells. Recently, tissue-specific AAV capsids (e.g. Nature Communications volume 11, Article number: 2102 ( 2020)Īdeno-associated viruses (AAVs) are typically single-stranded deoxyribonucleic acid (ssDNA) encapsulated within 25-nm protein capsids.
Positron emission tomography imaging of novel AAV capsids maps rapid brain accumulation
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