Assessment of toxicity and biodistribution of recombinant AAV8 vector-mediated immunomodulatory gene therapy in mice with Pompe disease.
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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https://hdl.handle.net/10161/11544Published Version (Please cite this version)
10.1038/mtm.2014.18Publication 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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Show full item recordScholars@Duke
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
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
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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