A Preliminary Evaluation of Recombinant Adeno-Associated Virus Biodistribution in Rhesus Monkeys After Intrahepatic InoculationIn Utero

Abstract

The ability to deliver genes to fetuses in utero may prove crucial for those genetic diseases that are associated with severe fetal morbidity and for which there is no effective postnatal therapy. In utero therapy may be especially useful in diseases that affect the central nervous system because the immature blood-brain barrier may facilitate gene delivery to neural target cells. We investigated whether in utero inoculation of recombinant adeno-associated virus (rAAV) into rhesus monkey fetuses would be a useful method of gene delivery, especially to the central nervous system. When the monkeys were sacrificed after birth, we found vector genomes distributed in many tissues, including the brain and peripheral blood. Pericapillary astrocytes expressing transgene products were detected by immunohistochemistry. In addition, we occasionally found vector genomes in the maternal blood. No adverse clinical or pathologic effects were observed in the inoculated monkeys. We concluded that (1) in utero intrahepatic inoculation of rAAV is a potentially safe and useful method of delivering genes to many fetal tissues; (2) astrocytes may be the cell type most easily targeted in the central nervous system (CNS) after systemic administration; and (3) the potential of inadvertent gene transfer to the mother must be considered.

HIV-1-derived lentiviral vectors and fetal route of administration on transgene biodistribution and expression in rhesus monkeys

“…delivery of viral vectors in a variety of species. 17,[25][26][27][28] In addition, it is possible that random cell and tissue transduction may occur; further work is needed to address these possibilities.…”

Longevity of rAAV vector and plasmid DNA in blood after intramuscular injection in nonhuman primates: implications for gene doping

“…3,4 The type of vector, the delivery method, injection schedule, route of administration and administrated dose are the main variables to affect biodistribution and shedding. [5][6][7][8][9] Intramuscular (IM) injection is a convenient method owing to physical accessibility, mass of the tissue and access to the vasculature. [10][11][12] Moreover, recombinant adeno-associated viral (rAAV) vectors and naked plasmid are two different gene transfer systems used for IM delivery in animal models [13][14][15][16][17] and in humans.…”

Gene transfer vector biodistribution: pivotal safety studies in clinical gene therapy development

“…Some authors have undertaken biodistribution studies in nonhuman primates on the sole ground that they are the most 'similar' to humans. 17,40 In our opinion, species models should be used in well-defined cases like aotus or marmosets for HSV, 18,59,60 or cotton-rat for AdV. 70 Regarding biodistribution, big species can be justified as well when addressing problems that cannot find solution in smaller mammals (like special administration routes, which Techniques for gene transfer vectors biodistribution P Gonin and C Gaillard S105 cannot be modeled correctly in rodents).…”

“…Some authors also used an internal control, which is often a competitive piece of DNA used in the same reaction tube. 12,15,[17][18][19][20] The advantage of this technique is a precise control of inhibition in the same tube, the inconvenience being the sensitivity decrease because of competition. We would recommend qPCR in triplicate, with spiking of one of the reaction tubes with a low DNA amount (as in Hanke et al 13 ).…”