Deficiency of alpha-1 antitrypsin (AAT) is a relatively common genetic disorder, which leads to emphysema in the majority of symptomatic patients. While AAT is normally produced in the liver, and to a lesser extent in monocytes and macrophages, our laboratory has developed a clinical rAAV1-hAAT vector which mediates long-term, ectopic supplementation from muscle, thus avoiding potential for liver toxicity, which may be more likely in the AAT-deficient liver. The current vector has progressed through IM phase 1 and phase 2a trials which have shown dose-related expression persisting for years after 1 IM injection and the presence of regulatory T cells (Tregs) specific for AAV capsid. In the current application, we propose to complete preclinical studies necessary to move to the phase 2b trial, to complete that trial and to develop a method to study and control the Treg response, using novel humanized mouse models. The project is highly interactive with each of the cores and with projects 2, 3 and 4.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL131471-02
Application #
9322548
Study Section
Special Emphasis Panel (ZHL1)
Program Officer
Postow, Lisa
Project Start
Project End
Budget Start
2017-05-01
Budget End
2018-04-30
Support Year
2
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of Massachusetts Medical School Worcester
Department
Genetics
Type
Schools of Medicine
DUNS #
603847393
City
Worcester
State
MA
Country
United States
Zip Code
01655
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
Wang, Dan; Li, Jia; Tran, Karen et al. (2018) Slow Infusion of Recombinant Adeno-Associated Viruses into the Mouse Cerebrospinal Fluid Space. Hum Gene Ther Methods 29:75-85
Yin, Hao; Song, Chun-Qing; Suresh, Sneha et al. (2018) Partial DNA-guided Cas9 enables genome editing with reduced off-target activity. Nat Chem Biol 14:311-316
Keeler, Allison M; Zieger, Marina; Todeasa, Sophia H et al. (2018) Systemic Delivery of AAVB1-GAA Clears Glycogen and Prolongs Survival in a Mouse Model of Pompe Disease. Hum Gene Ther :
Wang, Dan; Li, Shaoyong; Gessler, Dominic J et al. (2018) A Rationally Engineered Capsid Variant of AAV9 for Systemic CNS-Directed and Peripheral Tissue-Detargeted Gene Delivery in Neonates. Mol Ther Methods Clin Dev 9:234-246

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