RH10 provides superior transgene expression in mice when compared with natural AAV serotypes for neonatal gene therapy
- 1 September 2010
- journal article
- research article
- Published by Wiley in The Journal of Gene Medicine
- Vol. 12 (9), 766-778
- https://doi.org/10.1002/jgm.1496
Abstract
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. Copyright © 2010 John Wiley & Sons, Ltd.Keywords
This publication has 56 references indexed in Scilit:
- Gene Therapy for Leber's Congenital Amaurosis is Safe and Effective Through 1.5 Years After Vector AdministrationMolecular Therapy, 2010
- RETRACTED ARTICLE: Rescue of the spinal muscular atrophy phenotype in a mouse model by early postnatal delivery of SMNNature Biotechnology, 2010
- Systematic Evaluation of AAV Vectors for Liver directed Gene Transfer in Murine ModelsMolecular Therapy, 2010
- Short-term Correction of Arginase Deficiency in a Neonatal Murine Model With a Helper-dependent Adenoviral VectorMolecular Therapy, 2009
- Functional Cystic Fibrosis Transmembrane Conductance Regulator Expression in Cystic Fibrosis Airway Epithelial Cells by AAV6.2-Mediated SegmentalTrans-SplicingHuman Gene Therapy, 2009
- Adeno-Associated Virus (AAV) Serotype 9 Provides Global Cardiac Gene Transfer Superior to AAV1, AAV6, AAV7, and AAV8 in the Mouse and RatHuman Gene Therapy, 2008
- Expanded Repertoire of AAV Vector Serotypes Mediate Unique Patterns of Transduction in Mouse BrainMolecular Therapy, 2008
- Insertional oncogenesis in 4 patients after retrovirus-mediated gene therapy of SCID-X1JCI Insight, 2008
- Evaluation of Gene Promoters for Liver Expression by Hydrodynamic Gene TransferJournal of Surgical Research, 2008
- High-Level Transgene Expression in Nonhuman Primate Liver with Novel Adeno-Associated Virus Serotypes Containing Self-Complementary GenomesJournal of Virology, 2006