Observed incidence of tumorigenesis in long-term rodent studies of rAAV vectors

Abstract

Gene therapy using recombinant adeno-associated virus vectors (rAAV) is generally considered safe. During the course of a study designed to determine the long-term efficacy of rAAV-mediated gene therapy initiated in newbornRecombinant adeno-associated virus (rAAV) vectors are generally considered safe. No side-effects have been reported in the many in vivo studies designed to assess the efficacy of rAAV vectors.1 Wild-type AAV (wtAAV) is not associated with any disease and the virus integrates with high frequency into a single site on human chromosome 19. However, the site specificity is lost in rAAV vectors and they have been shown to either persist as episomes or to integrate randomly into the host genome. 2-5Therefore, the potential for rAAV to have adverse sideeffects due to insertional mutagenesis may exist.In this issue of Gene Therapy, Daly et al 6 report on the long-term (1 year) efficacy of intravenous neonatal rAAV treatment for murine mucopolysaccharidosis type VII (MPSVII). Following submission of the paper, three of five rAAV-treated MPSVII mice that were part of a longevity study were killed at approximately 18 months of age for histochemical, biochemical, and histopathological analyses. All of the animals appeared healthy and the three animals killed were chosen at random. Interest-

Absence of ocular malignant transformation after sub-retinal delivery of rAAV2/2 or integrating lentiviral vectors in p53-deficient mice

“…In mucopolysaccharidosis type VII mice, Donsanto et al 5,7 discovered an increased incidence of liver tumours after systemic administration of rAAV vectors, a finding supported by specific rAAV genomic integration analyses, and concluded that administration of rAAV could lead to malignant transformation. On the other hand, Bell et al 6 looked at tumour incidence in an ornithine transcarbamylase-deficient mouse model with and without rAAV gene therapy.…”

“…4 Concerns have also been raised by several in vivo studies regarding the possibility of pro-oncogenic events arising from recombinant adeno-associated virus (rAAV) vectormediated gene transfer to hepatocytes, concerns that are supported by vector integration site analyses. [5][6][7][8] Insertional mutagenesis (IM) is a risk associated with the transposition of genetic material. The ectopic integration of DNA arising from the use of integrating viral vectors may disrupt chromatin or gene structure, thereby altering gene transcription, regulation and/or coding sequences.…”

Immunity to adeno-associated virus serotype 2 delivered transgenes imparted by genetic predisposition to autoimmunity

“…7 Concerns surrounding the latter findings have been allayed, in part, by attribution of the abnormal pathology to the long-term survival of a mouse model normally subject to early mortality in the absence of AAV-mediated therapeutic gene delivery. 8 Immune responses against AAV, although mild and noninflammatory, have been documented. Of the known AAV serotypes, antibodies against serotype 2 appear at the highest frequencies (ie, 30-90% of human populations), while those against serotypes 1 and 5 are observed less often.…”

AAV for pain: steps towards clinical translation

“…31 Vector integration in tumors was shown. In at least some of the cases, integration occurred in a microRNA locus on mouse chromosome 12.…”