In response to Fukai Bao, gene therapy has cured several children born with X-SCID. These children would otherwise have died as a matched bone marrow graft could not be found. Four have developed leukaemia but more than a dozen are well. In China, the adenovirus vector, ?Gendicine? has been licensed for head and neck cancer. Results from trials are promising, but perhaps Dr. Bao has a more informed perspective on this.
Adenovirus vectors do not integrate into the host genome (unlike retrovirus and lentivirus vectors) so are unlikely to cause cancer. Indeed, there has been no evidence from preclinical models of cancer caused by adenovirus based vectors. Immune clearance is a major issue with adult gene therapy. For use of adenovirus as an anti-cancer strategy, the possible effects of adenovirus as an immune adjuvant are an advantage rather than a hurdle. For treatment of monogenetic disorders e.g. haemophilia etc. adenovirus is no-longer the vector of choice, being superseded by Adeno-associated virus (AAV) which appears to be less immunogenic. Nevertheless, the most recent clinical trial (carried out by Kathy High?s team in Philadelphia) did find immune response to the AAV capsid (but not transgenic protein). Transient immune suppression may be strategy to overcome this.
In response to Karel Petrak, as I mentioned above ? an accumulation of these tweeks is now producing vectors which have clinical efficacy. Modern vectors, either designed, ?bottom up? e.g. liposome/naked DNA strategies or, ?top down? e.g. AAV vector, are not fully understood and every tweek enables more accurate targeting, greater efficacy etc. Each disease target, whether it be a solid tumour, leukaemia, haemophilia, duchenne muscular dystrophy, cystic fibrosis, hepatitis vaccination, requires its own targeting strategy and calls for a specific vector. There will never be a single revolutionary advance in gene therapy, because the targets are as diverse and complex as life itself.
The paper described in this blog details interaction of adenovirus serotype 5 with coagulation factor X. Until now, there has been little success in stopping adenovirus vector from expressing in the liver; researchers believed that the hepatocyte interaction was down to the fibers and, therefore, their attempts to detarget by fiber mutations were all in vain. However, effort can now be concentrated on hexon mutations to prevent this interaction & therefore unwanted hepatocyte expression (when, for example, adenovirus vector is injected directly into a solid tumour and there is a risk of systemic leakage).
There is also some evidence from meta-analysis of case reports that there is increased prevalence of liver infection by adenovirus serotype 5 in immune-compromised patients. Whether blockage of the fX interaction could improve outcome of adenovirus 5 infection remains to be seen. However, it is important to note that basic gene therapy research is intimately intertwined with all other biological research disciplines and may improve our knowledge of the pathogenesis of the archetypal virus from which the vector was derived.