Robust systemic transduction with AAV9 vectors in mice: efficient global cardiac gene transfer superior to that of AAV8

Abstract

It has been recently shown that recombinant adeno-associated virus serotype 8 (rAAV8) is a robust alternative serotype vector that overcomes many of the limitations of rAAV2 and transduces various tissues efficiently and globally through systemic vector administration. AAV9 is a serotype newly isolated from human tissues, but our knowledge of the biology of rAAV9 in vivo is currently limited. Here, we demonstrate by a series of comprehensive side-by-side experiments with rAAV8 and 9 vectors delivered via different routes or at various doses in mice that rAAV9 vectors share the robustness of rAAV8, i.e., (1) very high liver transduction efficiency irrespective of whether vectors are administered intravascularly or extravascularly and (2) substantial transduction in the heart, skeletal muscle, and pancreas by peripheral vein injection. Importantly, rAAV9 transduced myocardium 5- to 10-fold higher than rAAV8, resulting in over 80% cardiomyocyte transduction following tail vein injection of as low as 1.0 x 10(11) particles per mouse. Thus rAAV9, as well as rAAV8, is a robust vector for gene therapy applications and rAAV9 is superior to rAAV8 specifically for cardiac gene delivery by systemic vector administration.

Heart-targeted adeno-associated viral vectors selected by in vivo biopanning of a random viral display peptide library

“…39 We observed that both, the targeted capsid selected here and the wt AAV9 capsid, mediated a comparable cardiac gene transfer upon co-injection (Figures 3b [6] and c [6]). However, while the wt AAV9 capsid enabled a wide-spread gene transfer with high levels of vg in the liver, pancreas, kidney and muscle, the peptide PSVSPRP-modified capsid provided a more specific targeting to the heart with low levels of detectable virus in other organs.…”

“…Although some earlier studies reported higher vg in the liver than in the heart with AAV9 vectors, 39,47,48 another publication found a better transduction of the heart than the liver of neonatal-injected animals. 45 These variations in biodistribution between different studies might be explained by different experimental conditions such as vector dose, mouse strain, gender of the mice and time point of tissue harvesting.…”

“…40 Tissue directed in vivo gene transfer has also been attempted by systemic application of pseudotyped AAV6, AAV8 or AAV9 vectors. 38,39,[42][43][44][45] Besides the fact that there is only a limited number of vector serotypes available, by far lower than the variety of potential tissue targets, these serotype-based targeted vectors also have limited or no specificity for the tissue of interest. In congruence with this assumption, our data showed that the library-derived vectors presented here were more specific than AAV serotype 9 (at least with respect to biodistribution of the genomes), which is known to confer efficient transduction of heart tissue.…”

“…In congruence with this assumption, our data showed that the library-derived vectors presented here were more specific than AAV serotype 9 (at least with respect to biodistribution of the genomes), which is known to confer efficient transduction of heart tissue. 39,45 Compared with phage-based vectors that have also been described for in vivo gene transfer recently, 46 the vectors presented here have higher target cell transduction efficiency and decreased liver homing.…”

Transgene and islet cell delivery systems using nano-sized carriers for the treatment of diabetes mellitus

“…The transduction efficiency of transgenes with viral vectors in the pancreas via intravenous administration was reported to improve under conditions of reduced blood flow to the liver, such as with a liver bypass or transient blockade of liver circulation [44,52]. However, other studies have reported that intravenous administration of AAV-8 or AAV-9 substantially delivered transgenes to the pancreas [40,53]. There is, therefore, room for debate on suitable administration routes of transgenes with viral vectors to the pancreas.…”