Safety of Liver Gene Transfer Following Peripheral Intravascular Delivery of Adeno-Associated Virus (AAV)-5 and AAV-6 in a Large Animal Model

Abstract

Intravascular delivery of adeno-associated virus (AAV) vector is commonly used for liver-directed gene therapy. In humans, the high prevalence of neutralizing antibodies to AAV-2 capsid and the wide cross-reactivity with other serotypes hamper vector transduction efficacy. Moreover, the safety of gene-based approaches depends on vector biodistribution, vector dose, and route of administration. Here we sought to characterize the safety of AAV-5 and AAV-6 for liver-mediated human factor IX (hFIX) expression in rabbits at doses of 1Â10 12 or 1Â10 13 viral genomes/kg. Circulating therapeutic levels of FIX were observed in both cohorts of AAV-6-hFIX, whereas for AAV-5-hFIX only the high dose was effective. Long-lasting inhibitory antibodies to hFIX were detected in three of the 10 AAV-6-injected animals but were absent in the AAV-5 group. Overall, vector shedding in the semen was transient and vector dose-dependent. However, the kinetics of clearance were remarkably faster for AAV-5 (3-5 weeks) compared with AAV-6 (10-13 weeks). AAV-6 vector sequences outside the liver were minimal at 20-30 weeks post-injection. In contrast, AAV-5 exhibited relatively high amounts of vector DNA in tissues other than the liver. Together these data are useful to further define the safety and potential for clinical translation of these AAV vectors.

Obstacles and future of gene therapy for hemophilia

“…In male rabbits, vector dissemination depends on the route of vector administration, vector dose and tissue tropism. The kinetics of vector clearance from semen was dose- and time-dependent but serotype-independent for AAV serotypes 2, 6 and 8 [56-58], while AAV5 displayed the shortest duration of vector shedding [58]. In all these studies, no late recurrence of AAV sequences was found in semen over several consecutive cycles of spermatogenesis, suggesting that transduction of an early spermatogenesis precursor exposed to AAV did not occur during hematogenous dissemination to the gonads.…”

Biodistribution of AAV8 Vectors Expressing Human Low-Density Lipoprotein Receptor in a Mouse Model of Homozygous Familial Hypercholesterolemia

“…Subsequent studies in rabbit models following intravascular injection of AAV2 or AAV8 concluded that vector dissemination to the semen is dependent on dose and time course and appears to be transient with no evidence of germ line transmission (Schuettrumpf et al, 2006;Favaro et al, 2009). Furthermore, the kinetics of clearance are also dose dependent and vary between serotypes (Favaro et al, 2011). A separate study in mice indicated that there is no evidence of germ line transmission following AAV gene delivery.…”

Rabbit Biomodels of Human Diseases Developed Using New Genomic Technologies. Crispr/Cas9 (Review)

“…На кроликах проверяли эффективность, безопасность, уровень экспрессии трансгена человеческого фактора IX (hFIX) в зависимости от дозы, серотипа аденоассоциированного вирусного вектора, способного вызывать у человека иммунный ответ [22].…”