α1-antitrypsin (AAT) is a protein produced in the liver that protects the body from the enzymes released by white blood cells which can otherwise damage cells. Mutations in SERPINA1 – the gene that encodes AAT – can cause insufficient or defective production of AAT. AAT deficiency can cause lung and liver damage, and affected people require lifelong regular infusions of AAT protein. Researchers from the University of Massachusetts are trying to develop a gene therapy for the condition.
'Our ultimate goal is to provide an easy shot that could cure a very difficult, potentially devastating genetic disorder,' said study author Professor Lila Gierasch.
The researchers wanted to develop a gene therapy where AAT is produced by muscle cells, as it is much easier to inject a gene therapy into muscle tissue. Using a harmless adeno-associated virus (AAV) as a delivery vehicle, the researchers tried to introduce a functional copy of SERPINA1 to various cell types. Their findings showed that liver cells were the most effective in secreting the AAT protein followed by ovary cells then muscle cells.
Muscle cells are not very efficient at producing and secreting the AAT protein, but the researchers were able to use a specific regulator that made muscle cells produce and secrete more of the functional AAT protein in necessary amounts that could potentially treat AAT deficiency.
The researchers believe their approach combining gene therapy with other regulators could enhance the effectiveness of gene therapy treatments for various genetic diseases.
As well as producing the peptide chain that makes up the protein, it needs to fold in a specific way to have a certain three-dimensional shape in order to be functional. This may be partly why previous clinical trials were less effective than researchers had hoped.
'We have completed three clinical trials in which we inject AAV containing the normal version of the AAT gene into muscle to create a "sustained release" of the protein in AAT deficient patients,' said co-author Professor Terence Flotte. 'But until now we did not understand how well the AAT protein was processed within the muscle at biochemical level.'
The authors, who published their findings in the Proceedings of the National Academy of Science, hope their findings have broad implications in developing gene therapies that can treat a wide range of other genetic diseases but could also help improve the effectiveness of other muscle-injected drug types including mRNA vaccines.