Clade F AAVHSCs cross the blood brain barrier and transduce the central nervous system in addition to peripheral tissues following intravenous administration in nonhuman primates

• DOI: 10.1371/journal.pone.0225582
• Publication Date: 2019-11-26T13:30:03Z
• Authors: Jeff L. Ellsworth; Jacinthe Gingras; Laura J. Smith; Hillard Rubin; Tania A. Seabrook; Kruti Patel; Nicole Zapata; Kevin Olivieri; Michael O’Callaghan; Elizabeth Chlipala; Pablo Morales; Albert Seymour
• Keywords: Central Nervous System; Neurons; 0301 basic medicine; Science; Q; Genetic Vectors; Green Fluorescent Proteins; R; Genetic Therapy; Dependovirus; Immunohistochemistry; 3. Good health; 03 medical and health sciences; HEK293 Cells; Blood-Brain Barrier; Ganglia, Spinal; Medicine; Animals; Humans; Macaca; Administration, Intravenous; Tissue Distribution; Neuroglia; Research Article

The biodistribution of AAVHSC7, AAVHSC15, and AAVHSC17 following systemic delivery was assessed in cynomolgus macaques (Macaca fascicularis). Animals received a single intravenous (IV) injection self-complementary AAVHSC-enhanced green fluorescent protein (eGFP) vector tissues were harvested at two weeks post-dose for anti-eGFP immunohistochemistry genome analyses. IV AAVHSC vectors produced widespread distribution eGFP staining glial cells throughout the central nervous system, with highest levels seen pons lateral geniculate nuclei (LGN). eGFP-positive neurons also observed peripheral systems all three including brain, spinal cord, dorsal root ganglia (DRG) evident neuronal cell bodies, axons dendritic arborizations. Co-labeling sections from DRG antibodies cell-specific markers confirmed eGFP-staining glia, protoplasmic fibrous astrocytes oligodendrocytes. For capsids tested, 50 to 70% (S100-β+) on average 8% (NeuroTrace+) LGN positive expression. In DRG, 45 62% 8 12% satellite tested. abundant hepatocytes, skeletal- cardio-myocytes acinar pancreas. Biodistribution genomes organs generally correlated liver These data demonstrate that AAVHSCs have broad tissue tropism cross blood-nerve blood-brain-barriers nonhuman primates, making them suitable gene editing or transfer therapeutic application human genetic diseases.