The following questions were submitted by members of the Alpha-1 community and were answered by Dr. Robert A. Sandhaus, MD, PhD, FCCP, AlphaNet Medical Director.
If an individual has a genotype of ZZ, is the alpha-1 antitrypsin that escapes the liver able to protect the lungs at all since the protein is misfolded?
The Z alpha-1 antitrypsin protein functions very well as an inhibitor of neutrophil elastase, the protein that is thought to cause the lung disease of Alpha-1. Out of the 394 amino acids that make up the alpha-1 antitrypsin molecule, there is only one amino acid that is different in the Z protein compared with the M protein (normal alpha-1 antitrypsin). That one amino acid difference does allow the molecules of the Z protein to stick together inside the liver cells, but the Z protein that makes it into the circulation seems to work quite well. That’s why some people with ZZ Alpha-1 never get any lung disease at all.
Since the body makes small amounts of alpha-1 antitrypsin in places other than the liver, why not target those places for making more of the protein when trying gene therapy?
The vast majority of the alpha-1 antitrypsin in the circulation and the tissues comes from the liver. That’s why, when an individual with Alpha-1 gets a liver transplant, their blood will have normal amounts of alpha-1 antitrypsin in their circulation. There is good evidence that the cells that have been shown to make alpha-1 antitrypsin get clogged with abnormal protein just like the cells in the liver. Having said all this, it is interesting to note that some past gene therapy studies in Alpha-1 aimed to turn muscle cells into alpha-1 antitrypsin secreting cells.