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Assessment of toxicity and biodistribution of recombinant AAV8 vector-mediated immunomodulatory gene therapy in mice with Pompe disease.

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Date
2014
Authors
Wang, Gensheng
Young, Sarah P
Bali, Deeksha
Hutt, Julie
Li, Songtao
Benson, Janet
Koeberl, Dwight D
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Abstract
A preclinical safety study was conducted to evaluate the short- and long-term toxicity of a recombinant adeno-associated virus serotype 8 (AAV2/8) vector that has been developed as an immune-modulatory adjunctive therapy to recombinant human acid α-glucosidase (rhGAA, Myozyme) enzyme replacement treatment (ERT) for patients with Pompe disease (AAV2/8-LSPhGAApA). The AAV2/8-LSPhGAApA vector at 1.6 × 10(13) vector particles/kg, after intravenous injection, did not cause significant short- or long-term toxicity. Recruitment of CD4(+) (but not CD8(+)) lymphocytes to the liver was elevated in the vector-dosed male animals at study day (SD) 15, and in group 8 animals at SD 113, in comparison to their respective control animals. Administration of the vector, either prior to or after the one ERT injection, uniformly prevented the hypersensitivity induced by subsequent ERT in males, but not always in female animals. The vector genome was sustained in all tissues through 16-week postdosing, except for in blood with a similar tissue tropism between males and females. Administration of the vector alone, or combined with the ERT, was effective in producing significantly increased GAA activity and consequently decreased glycogen accumulation in multiple tissues, and the urine biomarker, Glc4, was significantly reduced. The efficacy of the vector (or with ERT) was better in males than in females, as demonstrated both by the number of tissues showing significantly effective responses and the extent of response in a given tissue. Given the lack of toxicity for AAV2/8LSPhGAApA, further consideration of clinical translation is warranted in Pompe disease.
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Journal article
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https://hdl.handle.net/10161/11544
Published Version (Please cite this version)
10.1038/mtm.2014.18
Publication Info
Wang, Gensheng; Young, Sarah P; Bali, Deeksha; Hutt, Julie; Li, Songtao; Benson, Janet; & Koeberl, Dwight D (2014). Assessment of toxicity and biodistribution of recombinant AAV8 vector-mediated immunomodulatory gene therapy in mice with Pompe disease. Mol Ther Methods Clin Dev, 1. pp. 14018. 10.1038/mtm.2014.18. Retrieved from https://hdl.handle.net/10161/11544.
This is constructed from limited available data and may be imprecise. To cite this article, please review & use the official citation provided by the journal.
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Scholars@Duke

Bali

Deeksha Sarihyan Bali

Professor of Pediatrics
1)Development of new non-invasive laboratory diagnostic methods using enzymology and molecular diagnostic techniques for Glycogen Storage Diseases (GSDs) and Lysosomal Storage Diseases (LSDs) like Pompe, Fabry, Gaucher, MPS - for early diagnosis and treatment modalities. Exploration of new high throughput diagnostic platforms with an idea of implementation into New born screening (NBS)of these diseases. 2)Clinical research studies associated with Pompe disease with a goal to improve
Koeberl

Dwight D. Koeberl

Professor of Pediatrics
As a physician-scientist practicing clinical and biochemical genetics, I am highly motivated to seek improved therapy for my patients with inherited disorders of metabolism. The focus of our research has been the development of gene therapy with adeno-associated virus (AAV) vectors, most recently by genome editing with CRISPR/Cas9. We have developed gene therapy for inherited disorders of metabolism, especially glycogen storage disease (GSD) and phenylketonuria (PKU).  1) GSD
Young

Sarah Phyllis Young

Professor of Pediatrics
As a clinical biochemical geneticist and a director of the Duke Biochemical Genetics laboratory, my research interests are focused on improving laboratory diagnostics for rare inherited disorders of metabolism. I am actively involved in the development of assays using mass spectrometry and other analytical techniques. My current research on biomarkers for lysosomal storage disorders, such as Fabry and Pompe disease and the mucopolysaccharidoses includes monitoring the response to novel ther
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