Adenoviral vector-mediated gene replacement therapy for inborn errors involving hepatocyte metabolism has been hindered by toxicity, limited duration of transgene expression, and restrictions on vector cloning capacity. These obstacles are due in part to the viral sequences within the vector and to a combination of both humoral and cell mediate immune responses of the host against products of viral transcripts and the therapeutic transgene. The recent development of helper-dependent adenoviral vectors (HDV) devoid of all coding viral sequences holds great promise for circumventing these obstacles. However, much remains to be done regarding the understanding of factors including liver-specific gene expression and nature a transgene product in modifying host-vector interactions. These will ultimately impact on efforts to obtain high-level prolonged expression of a therapeutic transgene for correction of a metabolic deficiency. A model of one such enzymatic deficiency of hepatocyte metabolism is citrullinemia, a defect in human argininosuccinate synthetase (hASS). This urea cycle disorder is characterized by severe neurologic morbidity associated with hyperammonemia which may present in both neonates, children, and adults. Moreover, the development of gene replacement intervention in this model is appropriate given the inadequacy of current treatments, the availability of both bovine and murine disease models, and the development of in viva isotopic measures of clinical efficacy of treatment. This group of disorders are an important model for developing liver directed gene replacement of diseases whose pathogenesis require high level gene expression of intracellular proteins and efficient transduction of hepatocytes. We propose to 1) elucidate the effects of liver-specific vs. ubiquitous expression of a therapeutic, eukaryotic intacellular transgene (hASS) on host cell mediated immune response (specifically cytotoxic T lymphocytes), duration of expression, and liver toxicity using a HDV, 2) determine whether prolonged transgene expression mediated by liver-specific expression is due to induction of tolerance or modification of antigen presenting cell function using hASS and/or ovalbumin, and 3) develop helper-dependent adenoviral vectors expressing hASS from an optimal liver-specific promoters to achieve prolonged clinical correction in a murine models of citrullinemia. The data from these studies would be widely applicable to gene replacement therapy in a host of intrinsic disorders of liver metabolism as well as deficiencies of secretory proteins.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK056787-04
Application #
6722800
Study Section
Medical Biochemistry Study Section (MEDB)
Program Officer
Mckeon, Catherine T
Project Start
2001-04-15
Project End
2006-01-31
Budget Start
2004-02-01
Budget End
2005-01-31
Support Year
4
Fiscal Year
2004
Total Cost
$248,325
Indirect Cost
Name
Baylor College of Medicine
Department
Genetics
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
Ruan, Merry Z C; Erez, Ayelet; Guse, Kilian et al. (2013) Proteoglycan 4 expression protects against the development of osteoarthritis. Sci Transl Med 5:176ra34
Sule, Gautam; Suzuki, Masataka; Guse, Kilian et al. (2012) Cytokine-conditioned dendritic cells induce humoral tolerance to protein therapy in mice. Hum Gene Ther 23:769-80
Suzuki, Masataka; Cela, Racel; Bertin, Terry K et al. (2011) NOD2 signaling contributes to the innate immune response against helper-dependent adenovirus vectors independently of MyD88 in vivo. Hum Gene Ther 22:1071-82
Suzuki, Masataka; Cela, Racel; Clarke, Christian et al. (2010) Large-scale production of high-quality helper-dependent adenoviral vectors using adherent cells in cell factories. Hum Gene Ther 21:120-6
Suzuki, Masataka; Cerullo, Vincenzo; Bertin, Terry K et al. (2010) MyD88-dependent silencing of transgene expression during the innate and adaptive immune response to helper-dependent adenovirus. Hum Gene Ther 21:325-36
Brunetti-Pierri, Nicola; Clarke, Christian; Mane, Viraj et al. (2008) Phenotypic correction of ornithine transcarbamylase deficiency using low dose helper-dependent adenoviral vectors. J Gene Med 10:890-6
Cerullo, Vincenzo; Seiler, Michael P; Mane, Viraj et al. (2007) Correction of murine hemophilia A and immunological differences of factor VIII variants delivered by helper-dependent adenoviral vectors. Mol Ther 15:2080-7
Cerullo, V; McCormack, W; Seiler, M et al. (2007) Antigen-specific tolerance of human alpha1-antitrypsin induced by helper-dependent adenovirus. Hum Gene Ther 18:1215-24
Seiler, Michael P; Cerullo, Vincenzo; Lee, Brendan (2007) Immune response to helper dependent adenoviral mediated liver gene therapy: challenges and prospects. Curr Gene Ther 7:297-305
Cerullo, Vincenzo; Seiler, Michael P; Mane, Viraj et al. (2007) Toll-like receptor 9 triggers an innate immune response to helper-dependent adenoviral vectors. Mol Ther 15:378-85

Showing the most recent 10 out of 19 publications