Respiratory Diseases

Alpha1 anti-trypsin deficiency is genetic disease associated with mutations within the SERPINA1 gene which presents with symptoms of emphysema, chronic obstructive pulmonary disease (COPD), and occasionally chronic liver disease.  This gene encodes a secreted protein which is expressed in the liver but it is responsible for neutralizing neutrophil elastase particularly in the lungs. Neutrophil Elastase is important in fighting infections, but if not tightly controlled by alpha1 antitrypsin it can destroy tissues particularly the lungs.  The severity of alpha1 anti-trypsin deficiency is variable.  People who carry one normal allele and one null allele have no symptoms and express about one third (35%) of the normal level of alpha1 anti-trypsin.  One mutation (PiZ) creates low expression of mutant alpha 1 antitrypsin that is significantly lower than the amount of Alpha1 anti-trypsin in people with the normal allele. This variant of the alpha1 anti-trypsin protein folds in an abnormal manner and this altered structure prevents its release from liver cells, which can cause liver cell death.  However, mutations that create a null allele and therefore do not produce any alpha1 anti-trypsin protein, increase the risk for emphysema, but causes no liver disease as there is no protein to over-accumulate. This creates a unique dilemma for scientist creating therapies for alpha1 anti-trypsin disease, as the disease can have two aspects a loss of function of the alpha1 anti-trypsin’s ability to regulate neutrophil elastase, as well as in the case of Z mutants a toxic gain of function which can lead to liver diseases.

Scientists face similar challenges in designing the ideal vector for the long term expression of alpha1 anti-trypsin as cystic fibrosis. However, because alpha1 anti-trypsin is a secreted protein, the site for delivery of the gene therapy vector can be an alternate site to the liver or lungs, such as using the muscle to express alpha1 anti-trypsin.  A phase II trial is assessing the safety profile and efficacy of intramuscularly administering an AAV1 vector that carries the alpha1 anti-trypsin gene to patients with alpha1 anti-trypsin deficiency. The results from this and previous trials are helping to develop a gene therapy treatment for patients with severe alpha1 anti-trypsin deficiency. Ongoing new therapeutics aim to simultaneously to knock-down expression of mutant PiZ expression while augmenting expression of normal alpha1 antitrypsin.

A combined gene and cell therapy strategy is also being explored for treatment of cystic fibrosis and alpha1 anti-trypsin deficiency in animal models. The concept of such a therapy is as follows. Basically, the stem cells from the patient would be treated with a gene therapy agent that will allow the expression of a normal copy of the mutated gene. The cells would then be allowed to grow in number and transferred back into the patient. To meet these goals, ongoing scientific research is identifying the relevant stem cells, developing methods for their successful harvest or maturation, engineering vectors with the appropriate characteristics to maintain long term expression of this gene, and reduce detection of the corrected cells by the immune and inflammatory cells that could potentially eliminate them. After appropriate testing in tissue and animals, these studies can eventually lead to combined gene and cell therapy strategies for the treatment of cystic fibrosis and alpha1 anti-trypsin deficiency.

22nd Annual Meeting
April 29 – May 2 | Washington D.C.