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Transgene expression from the liver following recombinant adeno-associated viral vector (rAAV) gene transfer is mediated mainly by episomally maintained genomes. For chronic disorders such as haemophilia this raises concerns that transgene expression will decline to subtherapeutic levels over time with the natural turnover of hepatocytes in humans. Neutralising antibodies that develop at the time of primary vector administration will however prevent readministration of the same serotype. Therefore strategies that allow repeated administration of the optimal vector system may be required to maintain transgene expression at therapeutic levels. We have used a non-depleting CD4 antibody (NDCD4) in conjunction with other immunosuppressive agents in an attempt to attenuate the primary immune response to AAV. Cohorts of male C57BL/6 mice (n= 7-8) were treated with NDCD4 (0.5mg/mouse) alone, or in combination with cyclosporine (CyA) 25mg/kg or mycophenolate mofetil (MMF) 20mg/kg on days −1, 0, +1, 3, 6, 8 after tail vein administration of a pseudotype 8 vector encoding human factor IX. Additional cohorts received CyA or MMF alone and one group received no treatment. CD4 T lymphocyte analysis by FACs with an antibody against CD4 epitope B over 56 days, showed a moderate decline in the NDCD4 treated cohorts (34%) compared to naïve mice (sham treated). At day 98 anti-AAV8 antibody titers were reduced in cohorts receiving NDCD4 alone (11.3±3.5) or in combination with MMF (12.3±5.5). However, the humoral response in CyA+NDCD4 was undetectable. Secondary challenge with a low titer (5×1010) of AAV8 encoding human β interferon (hβIFN) resulted in serum hβIFN levels of 7.3±3.9 ng/mL in the CyA+NDCD4 cohort. These levels were comparable (9.0±5.2 ng/mL) to those in animals receiving only AAV8 hβIFN. Hence treatment with NDCD4 antibody and cyclosporine at the time of vector administration can substantially attenuate the immune response to primary immunisation with AAV, enabling repeat administration and efficient transduction with vectors based on the same serotype. Unlike previously used strategies our approach offers significant safety advances and will have widespread appeal.Molecular Therapy (2006) 13, S190–S190; doi: 10.1016/j.ymthe.2006.08.560 [ABSTRACT FROM AUTHOR]

An abstract of the article "Treatment of Acute Myeloid Leukemia by rAAV 8 Vector Mediated Human Interferon-β Gene Transfer," by Reuben Benjamin,1 Andrew M. Davidoff, Nalini Singh, Asim Khwaja, Jenny McIntosh, Cathy C. Y. Ng, Tony Meager, Meenu Wadhwa and Amit C. Nathwani is presented.