Disease relevance of Serpina1a

• 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 [1].
• Phase I trial of intramuscular injection of a recombinant adeno-associated virus alpha 1-antitrypsin (rAAV2-CB-hAAT) gene vector to AAT-deficient adults [2].
• Optimal therapy for AAT deficiency will require a high percentage of hepatocyte transduction to be effective for liver and lung disease [3].
• 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 [4].
• Spi-1/PU.1 transgenic mice develop multistep erythroleukemias [5].

High impact information on Serpina1a

• The PU.1 transcription factor is the product of the putative oncogene Spi-1 [6].
• The p53 and Spi-1 genes were frequently aberrant in transplanted tumors and cell lines derived from them, but were not in primary leukemic spleens [7].
• Using peritoneal infiltration models, we demonstrate that AAT decreases allogeneic fibroblast-elicited natural-killer-cell influx by 89%, CD3-positive cell influx by 44%, and thioglycolate-elicited neutrophil emigration by 66% [8].
• 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 [1].
• 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 [1].

Chemical compound and disease context of Serpina1a

• The rates of rearrangement of the Spi-1 (PU.1 ) oncogene by provirus integration and alteration of the p53 tumor-suppressor gene were the same in leukemia cell lines derived from folate-deficient mice as they were in cell lines from control mice [9].
• In contrast to the results described for mouse erythroleukemia cells, DMSO did not markedly decrease the level of the Spi-1/PU.1 transcription factor [10].
• Activities of the cytoplasmic and mitochondrial isozymes of aspartate aminotransferase (aspartate:2-oxoglutarate aminotransferase, EC 2.6.1.1, AAT) in transplantable mouse hepatomas BW7756 and H-4 are reduced when compared to normal adult liver [11].

Biological context of Serpina1a

• Mice express at least seven closely related alpha(1)-PI isoforms, encoded by a family of genes clustered at the Spi1 locus on chromosome 12 [12].
• The Mus musculus alpha 1-protease inhibitor gene cluster encodes five highly related proteins [13].
• Adoptive transfer experiments demonstrated that AAT gene therapy attenuated cellular immunity associated with beta cell destruction [14].
• Safety parameters will be measurement of changes in serum chemistries and hematology, urinalysis, pulmonary function testing, semen assay for vector genomes, immunologic response to AAT, and AAV, as well as reported subject history of any symptoms [2].
• 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 [14].

Anatomical context of Serpina1a

• 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 [15].
• T cell receptor spectratyping indicated that AAT gene therapy altered T cell repertoire diversity in splenocytes from NOD mice [14].
• 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 [16].
• The peripheral components of PI1 and PI2 appear to be localized at nuclear pores and the nuclear envelope, respectively [17].
• Thin sections of mouse 3T3 fibroblast nuclei labelled by immunoperoxidase with anti-nuclear antibodies I1, PI1, PI2, anti-peripherin, -lamin, and -centromere have been examined in the electron microscope [17].

Associations of Serpina1a with chemical compounds

• 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 [18].
• The most common escape mutation was an amino acid change of asparagine (AAT) to aspartic acid (GAT) at position 280; an additional mutation was glycine (GGT) to aspartic acid (GAT) at position 282 [19].
• After induction of MEL cell differentiation by treatment with dimethylsulfoxide (DMSO), expression of the PU.1/Spi-1 gene decreased before induction of beta-globin gene expression [20].
• alpha 1-Antitrypsin (alpha 1-protease inhibitor), an essential plasma protein, is synthesized predominantly in the liver of all mammals [21].
• Tyrosine phosphorylation and calcium mobilization induced by BCR engagement is diminished in Spi1+/- SpiB-/- B lymphocytes, although many key BCR signaling proteins are expressed, suggesting that Spi-1 and Spi-B regulate expression of additional, unidentified signaling molecules [22].

Other interactions of Serpina1a

• The internal component of PI1 staining consisted of irregular patches and strands in the nucleoplasm, closely resembling snRNP staining as reported by others [17].
• Now Kosmider et al report the acquisition of Kit mutations in 86% of late-stage eryhtroleukemias in Spi-1/PU.1 transgenic mice [23].
• We demonstrate that these values are a consequence of a decreased concentration of the alpha 1-protease inhibitor for elastase [PI(E)], which is the major serum inhibitor of elastase and cathepsin G [24].
• The primary structure of each of the three proteins has about 70% homology with that of mouse contrapsin, in contrast to 43-46% homology with that of rat alpha 1-protease inhibitor [25].
• Detection of alpha 2-macroglobulin, alpha 1-protease inhibitor, and neutral protease-antiprotease complexes within liver granulomas of Schistosoma mansoni-infected mice [26].

Analytical, diagnostic and therapeutic context of Serpina1a

• In light of the established safety record and the nondiabetogenic potential of AAT, these data suggest that AAT may be beneficial as adjunctive therapy in patients undergoing islet transplantation [8].
• 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 [15].
• These results strongly suggest that rAAV1-mediated AAT gene therapy may be useful as a novel approach to prevent type 1 diabetes [14].
• 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 [18].
• Electrophoretic mobility shift assays and DNase I protection analyses revealed that FP I was bound by the transcription factor PU.1/Spi-1 [27].

References