Real-time MR imaging of adeno-associated viral vector delivery to the primate brain

Abstract

We are developing a method for real-time magnetic resonance imaging (MRI) visualization of convection-enhanced delivery (CED) of adeno-associated viral vectors (AAV) to the primate brain. By including gadolinium-loaded liposomes (GDL) with AAV, we can track the convective movement of viral particles by continuous monitoring of distribution of surrogate GDL. In order to validate this approach, we infused two AAV (AAV1-GFP and AAV2-hAADC) into three different regions of non-human primate brain (corona radiata, putamen, and thalamus). The procedure was tolerated well by all three animals in the study. The distribution of GFP determined by immunohistochemistry in both brain regions correlated closely with distribution of GDL determined by MRI. Co-distribution was weaker with AAV2-hAADC, although in vivo PET scanning with FMT for AADC activity correlated well with immunohistochemistry of AADC. Although this is a relatively small study, it appears that AAV1 correlates better with MRI-monitored delivery than does AAV2. It seems likely that the difference in distribution may be due to differences in tissue specificity of the two serotypes.

Magnetic Resonance Imaging-Guided Delivery of Adeno-Associated Virus Type 2 to the Primate Brain for the Treatment of Lysosomal Storage Disorders

“…5; Table 2). We have reported similar findings with other transgenes delivered into NHP putamen (Fiandaca et al, 2008b;Fiandaca et al, 2009). In the brainstem, infusions of AAV2-hASM-HA resulted in a 17% greater area of transduction than was predicted by MRI.…”

Efficient gene therapy-based method for the delivery of therapeutics to primate cortex

“…They also highlight the need for intraoperative imaging of gene delivery vector infusions, to ensure correct infusion of the vector into the target structure (36)(37)(38). Leakage during vector infusion into nonthalamic areas, such as the internal capsule and lateral ventricle, was observed in 2 of the 4 monkeys.…”

Evaluation and optimization of the administration of a selectively replicating herpes simplex viral vector to the brain by convection-enhanced delivery

“…As such, a number of T1 and T2 contrast agents have been developed to act as surrogate markers of vector distribution. 53,54 However, co-infusion of vector with a surrogate marker adds significant complexity and regulatory hurdles to the clinical administration of gene therapy vectors to the brain. In this study, T2-weighted MR imaging was undertaken in an attempt to visualize infusion-related edema.…”