Alpha-1 antitrypsin (AAT) is the second most abundant serum protein with circulating levels of 570-1500 mcg/ml. It is a multi-functional anti-protease and anti-inflammatory protein whose prototypic function is to neutralize neutrophil elastase, protecting the interstitial elastin in the lung parenchyma from degradation. This was first described as a genetic syndrome of emphysema associated with the deficiency of AAT five decades ago. The glu342lys (PiZ) mutation of AAT is remarkably common in Northern Europe, with a carrier frequency in several of those nations exceeding 5%. In North America the carrier frequency is approximately 4%, making AAT deficiency among the most common genetic disorders. In the homozygous state (PiZZ), AAT deficiency is also associated with a liver disease that appears to be due to retention of Z-AAT polymers and aggregates within hepatocytes, which are the cells responsible for the production of the bulk of AAT in the serum. Animal models play an important role in the understanding of the pathogenesis of chronic obstructive pulmonary disease (COPD) and alpha-1 antitrypsin deficiency (AATD). The latter being served by the PIZ mouse that accumulates AAT globules in the liver and goes on to develop liver disease. There are many abundant examples in the literature of transgenic mice that have contributed to the understanding of COPD, but none so far has been able to model lung disease as a consequence of AATD. Previous gene-targeting studies aimed at the serpina1 gene and its isoforms in mice have failed. This failure is mainly due to the complexity of the locus, in which a gene amplification event in mice results in 6 highly conserved isoforms of the gene, of which, depending on the stain, 3 to 5 copies are expressed. To the best of our knowledge our laboratory has created the first complete mouse knockout of alpha-1 antitrypsin. The core will make these mice available to the various projects of this grant along with an un-paralleled variety of other mouse models of which 3 are unique to this core. The core will also be phenotyping and creating new mouse lines. This will be accomplished in the following three aims.
Aim 1 will characterize the biochemical and physiological phenotype of the AAT knockout mice and their utility to predict gene augmentation efficacy.
Aim 2 will focus on generating a more physiologically relevant mouse models for testing genome editing of Z-AAT alleles as well as an AAT KO mouse in which to investigate immune responses to rAAV-AAT augmentation vectors. Finally, aim 3 will optimize the PiZ-NSG mouse for human liver xeno-engraftment.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
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University of Massachusetts Medical School Worcester
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Ibraheim, Raed; Song, Chun-Qing; Mir, Aamir et al. (2018) All-in-one adeno-associated virus delivery and genome editing by Neisseria meningitidis Cas9 in vivo. Genome Biol 19:137
Wang, Dan; Li, Jia; Song, Chun-Qing et al. (2018) Cas9-mediated allelic exchange repairs compound heterozygous recessive mutations in mice. Nat Biotechnol 36:839-842
Smith, Jordan L; Mou, Haiwei; Xue, Wen (2018) Understanding and repurposing CRISPR-mediated alternative splicing. Genome Biol 19:184
Yoon, Yeonsoo; Wang, Dan; Tai, Phillip W L et al. (2018) Streamlined ex vivo and in vivo genome editing in mouse embryos using recombinant adeno-associated viruses. Nat Commun 9:412
Song, Chun-Qing; Xue, Wen (2018) CRISPR-Cas-related technologies in basic and translational liver research. Nat Rev Gastroenterol Hepatol 15:251-252
Zhang, Wei; Li, Linjing; Su, Qin et al. (2018) Gene Therapy Using a miniCEP290 Fragment Delays Photoreceptor Degeneration in a Mouse Model of Leber Congenital Amaurosis. Hum Gene Ther 29:42-50
Tai, Phillip W L; Xie, Jun; Fong, Kaiyuen et al. (2018) Adeno-associated Virus Genome Population Sequencing Achieves Full Vector Genome Resolution and Reveals Human-Vector Chimeras. Mol Ther Methods Clin Dev 9:130-141
Borel, Florie; Sun, Huaming; Zieger, Marina et al. (2018) Editing out five Serpina1 paralogs to create a mouse model of genetic emphysema. Proc Natl Acad Sci U S A 115:2788-2793
Zhang, Xiao-Ou; Fu, Yu; Mou, Haiwei et al. (2018) The temporal landscape of recursive splicing during Pol II transcription elongation in human cells. PLoS Genet 14:e1007579
Wang, Dan; Gao, Guangping (2018) Taking a Hint from Structural Biology: To Better Understand AAV Transport across the BBB. Mol Ther 26:336-338

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