Correction of Hyperbilirubinemia in Gunn Rats Using Clinically Relevant Low Doses of Helper-Dependent Adenoviral Vectors
| العنوان: | Correction of Hyperbilirubinemia in Gunn Rats Using Clinically Relevant Low Doses of Helper-Dependent Adenoviral Vectors |
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| المؤلفون: | Donna Palmer, David Dimmock, Nicola Brunetti-Pierri, Arthur L. Beaudet, Philip Ng |
| المساهمون: | Dimmock, D, BRUNETTI PIERRI, Nicola, Palmer, Dj, Beaudet, Al, Ng, P. |
| المصدر: | Human Gene Therapy. 22:483-488 |
| بيانات النشر: | Mary Ann Liebert Inc, 2011. |
| سنة النشر: | 2011 |
| مصطلحات موضوعية: | Crigler–Najjar syndrome, Bilirubin, Genetic enhancement, Genetic Vectors, Rats, Gunn, Pharmacology, Biology, medicine.disease_cause, digestive system, Adenoviridae, chemistry.chemical_compound, Transduction, Genetic, Gene Order, Genetics, medicine, Animals, Molecular Biology, Crigler-Najjar Syndrome, Hyperbilirubinemia, Unconjugated hyperbilirubinemia, Genetic Therapy, medicine.disease, Gunn rat, Uridine, Rats, Disease Models, Animal, Phenotype, Liver, chemistry, Injections, Intravenous, Immunology, Hydrodynamics, Molecular Medicine, Female, Brief Reports, Expression cassette |
| الوصف: | Crigler-Najjar syndrome type I is a severe inborn error of bilirubin metabolism caused by a complete deficiency of uridine diphospho-glucuronosyl transferase 1A1 (UGT1A1) and results in life-threatening unconjugated hyperbilirubinemia. Lifelong correction of hyperbilirubinemia by liver-directed gene therapy using a helper-dependent adenoviral (HDAd) vector has been previously reported in the Gunn rat, a model of Crigler-Najjar syndrome, but was only achieved using high doses (≥ 3 × 10(12) viral particles [vp]/kg), which are likely to elicit a severe toxic response in humans. Therefore, in this study, we investigate strategies to achieve correction of hyperbilirubinemia in the Gunn rat using clinically relevant low HDAd doses. We have found that correction of hyperbilirubinemia in the Gunn rat can be achieved with a low dose of 5 × 10(11) vp/kg by using an HDAd vector bearing a more potent UGT1A1 expression cassette. Furthermore, by using hydrodynamic injection of the improved HDAd vector, correction of hyperbilirubinemia in the Gunn rat can be achieved using an even lower dose of 5 × 10(10) vp/kg. Although hydrodynamic injection as performed in rats is not acceptable in humans, clinically attractive, minimally invasive methods have been successfully developed to mimic hydrodynamic injection of HDAd vector in non-human primates. Therefore, using an improved expression cassette combined with a more efficient method of vector delivery permits correction of hyperbilirubinemia in the Gunn rat using clinically relevant low HDAd doses and may thus pave the way to clinical application of HDAd vectors for Crigler-Najjar syndrome gene therapy. |
| تدمد: | 1557-7422 1043-0342 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::9adba95e6344486ee51b790b4cf6bdc5Test https://doi.org/10.1089/hum.2010.167Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....9adba95e6344486ee51b790b4cf6bdc5 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15577422 10430342 |
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