Gene Therapy Strategies for Alpha-One Antitrypsin Deficiency

Dr. Terence Flotte and Dr. Chris Mueller from the Horae Gene Therapy Center are conducting research and developing therapeutic strategies for rare inherited diseases such as the Huntington's disease.


What is alpha-one antitrypsin deficiency?  

Alpha-one antitrypsin (AAT) deficiency is a common (although often unrecognized) genetic disease, with up to 4% of the population carrying an abnormal AAT gene. Patients can suffer from either a lung disease, which is caused by a loss of the normal AAT action, or from a liver disease, which is caused by build-up of the abnormal mutant protein (called Z-AAT) within the liver cells.

AAT deficiency occurs worldwide, but the prevalence is variable depending on regions. It is a rare disease in Europe and in the US. It affects between 1:1500 and 1:3500 in people of European descent. It is the 2nd most common genetic disorder in Ireland, where 1:25 people carry the mutant gene. It is rare in Asians. 


Dr. Terence Flotte, MD

A leading researcher for the alpha-one antitrypsin deficiency

Terence R. Flotte, MD, is the Celia and Isaac Haidak Professor of Medical Education, executive deputy chancellor, provost and dean of the School of Medicine at UMass Medical School. In 1995, he was the PI of the first human use of rAAV, in a cystic fibrosis (CF) clinical trial. Since then, his lab has conducted several Phase 1 clinical trials for AAT and CF as well as a Phase 2 clinical trial in AAT with vectors developed in his lab. He has received numerous awards, including the 2005 Society for Pediatric Research’s E. Mead Johnson Award for Outstanding Scientific Contributions.

He currently serves as Editor-in-Chief of Human Gene Therapy (and its associated periodicals Human Gene Therapy Methods and Human Gene Therapy Clinical Development) and as the Chair of the Advisory Council of the American Society of Cell and Gene Therapy setting policy and goals for promoting gene therapy research through public education, scientific meetings and scientific committees. Flotte is the author of more than 230 scholarly papers. His research has been funded continuously by the NIH for 22 years. 

Dr. Flotte's gene therapy strategy on AAT Deficiency 

Flotte's lab currently focuses on systematically developing RNAi-based approaches to Z-AAT down-regulation within hepatocytes and devising appropriate strategies that might allow this to be combined with M-AAT gene augmentation.

Dr. Flotte and his lab members have successfully developed two different investigational clinical gene therapy products for gene augmentation of AAT as a potential therapy for the lung disease (rAAV2-AAT and rAAV1-AAT), and a third vector in development that is much more efficient for delivery of wild-type (M) AAT to hepatocytes (rAAV8-AAT). 

 Dr. Terence Flotte from the Flotte Lab (Horae Gene Therapy Center) is conducting research and developing therapeutic strategies for rare inherited diseases such as the Alpha-one antitrypsin (AAT) deficiency

Terence R. Flotte, MD

Celia and Isaac Haidak Professor of Medical Education, Executive Deputy Chancellor, Provost and Dean, School of Medicine

View Publications Contact Dr. Flotte


Dr. Chris Mueller, PhD

A leading researcher for alpha-one antitrypsin deficiency

Chris Mueller, PhD, is an Associate Professor of Pediatrics and a faculty member of the Horae Gene Therapy Center. Dr. Mueller received his PhD from the University of Florida and later became an independent investigator at UMass where he established his lab in 2011. Alpha-one antitrypsin has always remained his primary line of research. Dr. Mueller was recently awarded the 2016 Shillelagh Award from the Alpha-1 Foundation, which rewards outstanding Alpha-1 researchers and clinicians.   

Dr. Mueller's gene therapy strategy on AAT Deficiency  

The Mueller Lab for Gene Therapy has developed a novel, proprietary gene therapy platform and applied it to develop a gene therapy treatment for alpha-one antitrypsin deficiency. This platform is named “dual-function vectors” and designates AAV vectors that combine two functions: gene expression and gene silencing.

When the clinical trial revealed that targeting the muscle for AAT augmentation was only leading to sub-therapeutic serum levels, the liver was next considered. However, because the liver of most AAT deficiency patients (ZZ) carries a heavy burden due to the production and accumulation of Z-AAT polymers, it was hypothesized that liver-directed AAT augmentation may be unsafe. Preclinical studies revealed that indeed, there could be a risk, and from there the use of a dual-function vector became the obvious choice.

In the case of alpha-one antitrypsin deficiency, the dual-function vector silences endogenous AAT (including Z-AAT and M-AAT) and expresses a de-targeted AAT. The sequence of the de-targeted AAT is slightly modified to avoid silencing, but retains fully its biological function.

Extensive preclinical studies in mice have documented the safety and efficacy of this approach, and further studies in non-human primates will be next.

Other research interests

Currently Dr. Mueller is also developing gene therapy strategies on Amyotrophic Lateral Sclerosis (ALS)Cystic Fibrosis and Huntington's Disease.


Dr. Mueller's goal is to improve the effectiveness of this strategy in mice 

with the long term goal of developing these methods into therapy

for treating AAT deficient patients. 


 Dr. Chris Mueller from the Mueller Lab (Horae Gene Therapy Center) is conducting research and developing therapeutic strategies for rare inherited diseases such as the Alpha-one antitrypsin (AAT) deficiency

Chris Mueller, PhD

Associate Professor, Department of Pediatrics and Horae Gene Therapy Center

View Publications Visit Lab Website


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