Background: Neonatal gene therapy is a promising strategy for treating diseases diagnosed before or shortly after birth. Early and long-term expression of therapeutic proteins may limit the consequences of genetic mutations and result in a potential 'cure'. Adeno-associated viral vectors have shown promise in many areas of adult gene therapy but their properties have not been systematically investigated in the neonate.
Methods: In these studies, using a constitutive promoter expressing luciferase, animals were administered one of ten serotypes of adeno-associated virus (AAV) on the second day of life. Examination of expression, organ growth and vector distribution, maintenance of expression and copy number were measured.
Results: All serotypes demonstrated expression and, in general, transduction of all organs within 3 days, albeit with different biodistribution patterns and expression levels. The highest expression was detected with AAVrh10, whereas the lowest was detected with AAV4. Expression and genomes declined with growth over the first 10 weeks of life; thereafter, to day 100, expression and genomes remained relatively stable. With the highest expressing vectors, whole animal expression at 100 days declined to approximately 10% of that detected on the fifth day. AAVrh10 maintained the highest expression level and copy number throughout these studies.
Conclusions: The impact of tissue and organ growth on the stability of AAV expression will be important if neonatal gene transfer is to be considered as a modality for human gene therapy. Although all vectors did demonstrate expression, rh10 holds the greater promise of the vectors tested to maintain copy number in both mitotic and post-mitotic tissues.