Inclusion of the Woodchuck Hepatitis Virus Posttranscriptional Regulatory Element
Enhances AAV2-Driven Transduction of Mouse and Human Retina
#MMPMID28325286
Patrício MI
; Barnard AR
; Orlans HO
; McClements ME
; MacLaren RE
Mol Ther Nucleic Acids
2017[Mar]; 6
(?): 198-208
PMID28325286
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The woodchuck hepatitis virus posttranscriptional regulatory element (WPRE) has
been included in the transgene cassette of adeno-associated virus (AAV) in
several gene therapy clinical trials, including those for inherited retinal
diseases. However, the extent to which WPRE increases transgene expression in the
retina is still unclear. To address this question, AAV2 vectors containing a
reporter gene with and without WPRE were initially compared in vitro and
subsequently in vivo by subretinal delivery in mice. In both instances, the
presence of WPRE led to significantly higher levels of transgene expression as
measured by fundus fluorescence, western blot, and immunohistochemistry. The two
vectors were further compared in human retinal explants derived from patients
undergoing clinically indicated retinectomy, where again the presence of WPRE
resulted in an enhancement of reporter gene expression. Finally, an analogous
approach using a transgene currently employed in a clinical trial for
choroideremia delivered similar results both in vitro and in vivo, confirming
that the WPRE effect is transgene independent. Our data fully support the
inclusion of WPRE in ongoing and future AAV retinal gene therapy trials, where it
may allow a therapeutic effect to be achieved at an overall lower dose of vector.
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