Progress with Recombinant Adeno-Associated Virus Vectors for Gene Therapy of Alpha-1 Antitrypsin Deficiency

Gruntman, Alisha M.; Flotte, Terence R.

doi:10.1089/hgtb.2015.086

Cited by 13 publications

(3 citation statements)

References 43 publications

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“…They determined the long-term (up to 49 weeks) expression of LacZ in mice, with better outcomes being recorded when employing the CMV promoter. Despite the different gene therapy studies carried out in primates, most of them [ 136 , 137 ] have employed viral vectors to transfer genes to skeletal muscle and liver. However, the ethical implications, the lack of clinical response (possibly limited by viral particle size) and the difficulty of working with this animal model have limited its use and researchers have focused especially on pigs.…”

Section: Translation Of the Hydrodynamic Method: From Mouse To Larmentioning

confidence: 99%

Translational Advances of Hydrofection by Hydrodynamic Injection

Sendra

Herrero

Aliño

2018

Genes

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Hydrodynamic gene delivery has proven to be a safe and efficient procedure for gene transfer, able to mediate, in murine model, therapeutic levels of proteins encoded by the transfected gene. In different disease models and targeting distinct organs, it has been demonstrated to revert the pathologic symptoms and signs. The therapeutic potential of hydrofection led different groups to work on the clinical translation of the procedure. In order to prevent the hemodynamic side effects derived from the rapid injection of a large volume, the conditions had to be moderated to make them compatible with its use in mid-size animal models such as rat, hamster and rabbit and large animals as dog, pig and primates. Despite the different approaches performed to adapt the conditions of gene delivery, the results obtained in any of these mid-size and large animals have been poorer than those obtained in murine model. Among these different strategies to reduce the volume employed, the most effective one has been to exclude the vasculature of the target organ and inject the solution directly. This procedure has permitted, by catheterization and surgical procedures in large animals, achieving protein expression levels in tissue close to those achieved in gold standard models. These promising results and the possibility of employing these strategies to transfer gene constructs able to edit genes, such as CRISPR, have renewed the clinical interest of this procedure of gene transfer. In order to translate the hydrodynamic gene delivery to human use, it is demanding the standardization of the procedure conditions and the molecular parameters of evaluation in order to be able to compare the results and establish a homogeneous manner of expressing the data obtained, as ‘classic’ drugs.

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Section: Translation Of the Hydrodynamic Method: From Mouse To Larmentioning

confidence: 99%

Translational Advances of Hydrofection by Hydrodynamic Injection

Sendra

Herrero

Aliño

2018

Genes

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“…13,24 Thus, Rec2 vector provides an alternative route for systemic gene therapy of genetic diseases currently targeting liver such as hemophilia B, α-1 antitrypsin deficiency, ornithine transcarbamylase deficiency, phenylketonuria, and lysosomal storage disorders. [25][26][27][28][29][30][31][32] Hepatic-restricted expression can be achieved by using liver-specific promoters, e.g., a minimal promoter region of α-1antitrypsin coupled with the enhancer element of the ApoE gene. 33…”

Section: Discussionmentioning

confidence: 99%

Genetic Manipulation of Brown Fat Via Oral Administration of an Engineered Recombinant Adeno-associated Viral Serotype Vector

et al. 2016

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Recombinant adeno-associated virus (rAAV) vectors are attractive vehicles for gene therapy. Gene delivery to the adipose tissue using naturally occurring AAV serotypes is less successful compared to liver and muscle. Here, we demonstrate that oral administration of an engineered serotype Rec2 led to preferential transduction of brown fat with absence of transduction in the gastrointestinal track. Among the six natural and engineered serotypes being compared, Rec2 was the most efficient serotype achieving high level transduction at a dose 1~2 orders lower than reported doses for systemic administration. Overexpressing vascular endothelial growth factor (VEGF) in brown fat via oral administration of Rec2-VEGF vector increased the brown fat mass and enhanced thermogenesis. In contrast, knockdown VEGF in brown fat of VEGF (loxP) mice via Rec2-Cre vector hampered cold response and decreased brown fat mass. Oral administration of Rec2 vector provides a novel tool to genetically manipulate brown fat for research and therapeutic applications.

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“…Researchers have investigated several methods to reduce liver damage caused by the misfolding and aggregation of α1ATZ. These methods include gene therapy with artificial microRNA to suppress transcription of α1ATZ [ 7 , 8 ], induction of autophagy to remove aggregated proteins [ 9 , 10 ] and use of small molecules to block the polymerization of the mutant protein [ 11 , 12 ]. Another interesting strategy to reduce liver toxicity is to reduce the synthesis of α1ATZ by inhibiting its translation, though there has been little focus on utilizing this approach.…”

Section: Introductionmentioning

confidence: 99%

Post-Transcriptional Regulation of Alpha One Antitrypsin by a Proteasome Inhibitor

Rao

Reineke

et al. 2020

IJMS

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Alpha one antitrypsin (α1AT), a serine proteinase inhibitor primarily produced by the liver, protects pulmonary tissue from neutrophil elastase digestion. Mutations of the SERPINA1 gene results in a misfolded α1AT protein which aggregates inside hepatocytes causing cellular damage. Therefore, inhibition of mutant α1AT production is one practical strategy to alleviate liver damage. Here we show that proteasome inhibitors can selectively downregulate α1AT expression in human hepatocytes by suppressing the translation of α1AT. Translational suppression of α1AT is mediated by phosphorylation of eukaryotic translation initiation factor 2α and increased association of RNA binding proteins, especially stress granule protein Ras GAP SH3 binding protein (G3BP1), with α1AT mRNA. Treatment of human-induced pluripotent stem cell-derived hepatocytes with a proteasome inhibitor also results in translational inhibition of mutant α1AT in a similar manner. Together we revealed a previously undocumented role of proteasome inhibitors in the regulation of α1AT translation.

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Progress with Recombinant Adeno-Associated Virus Vectors for Gene Therapy of Alpha-1 Antitrypsin Deficiency

Cited by 13 publications

References 43 publications

Translational Advances of Hydrofection by Hydrodynamic Injection

Translational Advances of Hydrofection by Hydrodynamic Injection

Genetic Manipulation of Brown Fat Via Oral Administration of an Engineered Recombinant Adeno-associated Viral Serotype Vector

Post-Transcriptional Regulation of Alpha One Antitrypsin by a Proteasome Inhibitor

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