Positron emission tomography imaging of novel AAV capsids maps rapid brain accumulation

Abstract

Adeno-associated viruses (AAVs) are typically single-stranded deoxyribonucleic acid (ssDNA) encapsulated within 25-nm protein capsids. Recently, tissue-specific AAV capsids (e.g. PHP.eB) have been shown to enhance brain delivery in rodents via the LY6A receptor on brain endothelial cells. Here, we create a non-invasive positron emission tomography (PET) methodology to track viruses. 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. 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. The PHP. eB capsid brain endothelial receptor affinity is nearly 20-fold greater than that of AAV9. The results suggest that novel PET imaging techniques can be applied to inform and optimize capsid design.

RETRACTED ARTICLE: Mesenchymal stem cell-derived exosome miR-542-3p suppresses inflammation and prevents cerebral infarction

“…Adeno-associated virus vector is a safe, durable, and efficient gene manipulation tool, which has been widely used in the field of neurobiology [ 46 ]. The AAV9 subtype is a common type of brain tissue infection [ 47 ]. And in the present study, miR-542-3p level in brain tissues was prominently increased after AAV9-miR-542-3p injection.…”

Radiolabelling of nanomaterials for medical imaging and therapy

“…In particular, Seo et al developed a method to radiolabel AAV capsids using multimeric NO2A bioconjugate platforms. 373 The multichelator systems contained eight NO2A rings attached to with either a transcyclooctene (TCO) or maleimide to allow conjugation through either a tetrazinemodified amine group or cysteine residue on the AAV surface (Fig. 26B and C).…”

Direct capsid labeling of infectious HIV-1 by genetic code expansion allows detection of largely complete nuclear capsids and suggests nuclear entry of HIV-1 complexes via common routes

“…Its potential for virus imaging has not been exploited, however, presumably because this method is still challenging in eukaryotic cells. While GCE has been explored in virology for the generation of conditionally replication-competent live attenuated vaccines (Yuan et al 2017; Si et al 2020; Wang et al 2014), the combination of GCE and click labeling for the purpose of capsid imaging has only been successfully applied for the non-enveloped adeno-associated virus (AAV) (Zhang et al 2018; Seo et al 2020; Katrekar et al 2018; Rubino et al 2012). Unlike HIV-1 CA, the AAV capsid protein has also been shown to tolerate modifications by peptide insertions (Asokan, Schaffer, and Samulski 2012; Kotterman and Schaffer 2014; Thadani et al 2018; Börner et al 2020; Grimm and Zolotukhin 2015).…”