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SUMMARY:Recombinant adeno-associated virus for therapeutic gene delivery: 
 30 million years in the making. - Dr Grant Logan\, Research Fellow in the 
 Gene Therapy Research Unit at the Children's Medical Research Institute\, 
 Sydney Australia
DTSTART:20160509T150000Z
DTEND:20160509T160000Z
UID:TALK65906@talks.cam.ac.uk
CONTACT:Fiona Roby
DESCRIPTION:Our laboratory is focused on the translation of gene therapies
  to treat metabolic liver disease in the paediatric setting using recombin
 ant adeno-associated virus (AAV)\, which is emerging as an effective in vi
 vo vector platform for new modalities of disease treatments. The laborator
 y research program encompasses a bench-to-bedside approach and includes "v
 iral palaeontology" in Australian marsupials to discover new vector capsid
 s as well as the design and testing of vectors in preclinical models. Reco
 mbinant AAV is based on a human parvovirus from the Dependoviridae family 
 which has long been an appealing virus for vectorisation due to (i) its re
 latively simple structure with only two known genes encoded on the sense s
 trand of the genome\, (ii) requirement for helper virus to complete virus 
 cycle and (iii) non-pathogenic status. However\, this latter feature has b
 een recently called into question by a study implicating AAV insertional m
 utagenesis in hepatocellular carcinoma (Nault et al. Nature Genetics 2015)
 . Conclusions drawn from the report have caused contention with one point 
 of concern the relatively small size of the integrated AAV genome fragment
  (201-1975 bp) and how this might be responsible for driving oncogenesis. 
 In the course of our studies\, we have discovered a novel promoter/enhance
 r element in the anti-sense genome of the virus\, which is common to 10/11
  AAV genome fragments implicated in the HCC study. The element is compact\
 , operates in a cell restricted manner largely in cells of hepatic origin 
 and appears to be conserved across phylogenetically-related AAV. Our findi
 ngs provide an underlying mechanism to account for the dysregulation of ge
 ne expression at the site of AAV integration in human HCC and indicate pot
 ential biological function for the anti-sense genome.\n
LOCATION:Lecture Theatre 2\, Department of Veterinary Medicine
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