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A - Viral Vector Development -> AAV Vectors – Clinical/Non-Human Primate Studies

77: Monitoring Fetal and Infant Somatic Cell Genome Editing in Rhesus Monkeys with Total-Body PET

Type: Oral Abstract Session

Presentation Details
Session Title: AAV Vectors: Clinical and Non-Human Primate Studies
Location: Room 411
Start Time: 5/17/2023 16:30
End Time: 5/17/2023 16:45

Key issues for translational somatic cell genome editing are to understand the extent of editing in the body at a given time, the specificity of editing for the desired genomic target, if edited cells persist, the impact of editing on the immune system, and the potential for adverse events. Addressing these and related questions substantially benefits from a noninvasive approach that can identify edited cells in vivo. Positron emission tomography (PET) can provide three-dimensional quantitative images deep inside the body of radiotracers at subnanomolar concentrations. New, transformative total-body PET can image the entire body simultaneously. The goal of these studies was to use total-body PET to identify gene editing in vivo in fetal and infant rhesus monkeys. Time-mated dams were identified as pregnant by ultrasound then screened (seronegative for AAV9 and SaCas9) and selected for the study. Fetuses (N=12) were administered the imaging vector (AAV9/SaCas9/HSV-sr39TK) in utero using an intrahepatic (IH) ultrasound-guided approach in the late first or early second trimester (10e12 vector genomes [vg]/fetus). After administration of [18]F-FHBG intravenously to the dams (3 mCi/kg), imaging of fetuses in utero was performed in the second and third trimesters and consistently showed editing in the fetal liver, which was sustained across gestation. Findings were confirmed at the tissue level near term with 8-12% editing in the liver, and with no evidence of adverse effects. The AAV9 imaging vector was also administered in a separate study to infants at ~3 months of age (N=16, 10e13 vg/kg; IV or IH under ultrasound guidance). All infants remained healthy and robust during the study period (up to 3 months post-vector administration). Hematology and clinical chemistry panels were all within normal limits and no adverse events were detected. Infants were administered [18]F-FHBG IV (0.3 mCi/kg) for PET imaging at two weeks post-administration then monthly during the study period. Similar to fetal studies, extensive evaluation of the liver at tissue collection showed high levels of transduction and an editing outcome of ~7-12% in the liver. These studies have shown for the first time that total-body PET can noninvasively provide insights on gene-edited cells in vivo and with high sensitivity and reproducibility.

Alice F. Tarantal1, Michele Martinez1, Charles Lee2, Lionel Sanz1, Henriette O'Geen3, Dennis J. Hartigan-O'Connor4, David J. Segal5

1Pediatrics, Cell Biology and Human Anatomy, and California National Primate Research Center, University of California, Davis, Davis, CA,2Cell Biology and Human Anatomy and California National Primate Research Center, University of California, Davis, Davis, CA,3Genome Center, University of California, Davis, Davis, CA,4Medical Microbiology and Immunology, and California National Primate Research Center, University of California, Davis, Davis, CA,5Biochemistry and Molecular Medicine, and Genome Center, University of California, Davis, Davis, CA
 A.F. Tarantal: None.

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