Disease relevance of Serpina3n

• Efficient hepatic delivery and expression from a recombinant adeno-associated virus 8 pseudotyped alpha1-antitrypsin vector [1].
• A single injection of an EBV/genomic SERPINA1 vector provided >300 microg/ml of AAT, which approached normal plasma levels and persisted for the >9-month duration of the experiment [2].
• Optimal therapy for AAT deficiency will require a high percentage of hepatocyte transduction to be effective for liver and lung disease [1].
• IL-10 modestly attenuated neutrophilic leukocytosis and neutrophil degranulation (plasma concentrations of elastase/alpha1-antitrypsin complexes) (both p < 0.05) [3].
• Transiently expressed mutant and WT AAT variants underwent rapid destabilization in response to an artificially elevated ERManI concentration in the murine hepatoma cell line, Hepa1a [4].

Psychiatry related information on Serpina3n

• In three brain regions obtained post-mortem from Huntington's disease patients, alpha1-antitrypsin expression was also altered [5].

High impact information on Serpina3n

• The transcription rate of genes like albumin and alpha1-antitrypsin is reduced, while the gene coding for phenylalanine hydroxylase is totally silent, giving rise to phenylketonuria [6].
• For newly synthesized alpha1-antitrypsin (AAT), the modification of its asparagine-linked oligosaccharides by a slow-acting mannosidase partitions the misfolded monomer into the proteasomal degradation pathway [4].
• Herein, we asked whether, and how, modification by endoplasmic reticulum mannosidase I (ERManI) contributes to the preferential selection of the misfolded AAT monomer for proteasomal degradation [4].
• The human alpha1-antitrypsin promoter was chosen to direct expression because it was the most efficient of several tested in yielding expression of alpha1-antitrypsin protein from a retroviral vector in hepatocytes in vivo [7].
• FTF binding sites are found in the promoters of other liver-expressed genes, some encoding liver transcription factors; FTF, liver alpha1-antitrypsin promoter factor LFB2, and HNF-3beta promoter factor UF2-H3beta are probably the same factor [8].

Biological context of Serpina3n

• The efficacy of this same vector for expression of AAT in vivo in the nondividing cells of mouse liver was determined by hydrodynamic injection of naked plasmid DNA by means of the tail vein [2].
• AAV2 and pseudotyped vectors for serotypes 1, 5, and 8 carrying the human AAT transgene were injected at 1 x 10(10) particle doses into C57Bl/6 mice [1].
• Adoptive transfer experiments demonstrated that AAT gene therapy attenuated cellular immunity associated with beta cell destruction [9].
• This study demonstrates that AAT gene therapy attenuates cell-mediated autoimmunity, alters the T cell receptor repertoire, and efficiently prevents type 1 diabetes in the NOD mouse model [9].
• This is a novel model for studying in vivo the effects of CS oxidative stress on human protease inhibitors with antitrypsin activity [10].

Anatomical context of Serpina3n

• Therefore, pseudotyped AAV8 provides a vehicle to infect a high percentage of hepatocytes stably and thereby express therapeutic molecules to modify AAT PiZ transcripts [1].
• Changes of endoplasmic reticulum chaperone complexes, redox state, and impaired protein disulfide reductase activity in misfolding alpha1-antitrypsin transgenic mice [11].
• In addition, staining of endothelial cells with ATZ11 antibody in both M- and Z-AAT individuals shows that AAT attached to endothelial cells is in a polymerized form [12].
• T cell receptor spectratyping indicated that AAT gene therapy altered T cell repertoire diversity in splenocytes from NOD mice [9].
• Retinoic acid does not affect the angiogenic capacity of the VYS mesenchyme but destroys lysosomes, which release hydrolytic enzymes, leading to degradation of AAT in the endodermal cells and then digestion of endocytosed bFGF [13].

Associations of Serpina3n with chemical compounds

• We have shown recently that the serine proteinase inhibitor (serpin)-enzyme complex receptor (SEC-R), a receptor initially identified for binding of alpha1-antitrypsin (alpha1-AT) and other serine protease inhibitors, also recognizes the amyloid-beta 25-35 domain [14].
• The sequence analyses of these cDNAs and NH2-terminal peptides of the purified proteins revealed that both isoforms of alpha 1-antiproteinase consist of 405 amino acid residues including a signal peptide of 24 residues and that contrapsin consists of 410 amino acid residues with the same length of the signal peptide [15].
• Suppression of cholesterol 7alpha-hydroxylase transcription and bile acid synthesis by an alpha1-antitrypsin peptide via interaction with alpha1-fetoprotein transcription factor [16].
• The pTG7101 plasmid, containing the full-length human AAT gene, was encapsulated in small liposomes bearing 10% of negatively (phosphatidylserine, PS) or positively (DOTAP) charged lipids [17].
• Long-term expression of the human alpha1-antitrypsin gene in mice employing anionic and cationic liposome vectors [17].

Analytical, diagnostic and therapeutic context of Serpina3n

• Alpha1-antitrypsin monotherapy prolongs islet allograft survival in mice [18].
• Using electrophoresis, Western blotting, and ELISA procedures, we have shown in the present study that this monoclonal antibody specifically detects a conformation-dependent neoepitope on both polymerized and elastase-complexed molecular forms of AAT [12].
• These results strongly suggest that rAAV1-mediated AAT gene therapy may be useful as a novel approach to prevent type 1 diabetes [9].
• The efficiency of both anionic and cationic liposomes as vectors for in vivo human alpha1-antitrypsin (AAT) gene transfer was studied in mice with and without an associated partial hepatectomy [17].
• Western blot analysis with antitrypsin antibody showed that 26 and 24 kDa proteins were highly detected in S4 conditioned medium (CM) in comparison to R3 CM [19].

References