The secretion of alpha-1 antitrypsin (AAT) appears to be dependent on cell type, according to a study published in the Proceedings of the National Academy of Sciences (PNAS), which could affect the efficacy of gene therapy for AAT deficiency (AATD).

In the study, it was found that cultured hepatocytes, the cell type which natively produces AAT, were the most efficient at secreting the protein, while myoblasts and myotubes were the least efficient. This finding could pose issues for intramuscular delivery of gene therapy in patients with AATD.

Treatment with suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, was shown to augment AAT secretion in myoblasts and myotubes. The use of proteostasis regulators could be a potentially useful strategy for the optimization of protein expression with a number of therapeutics, according to the authors.

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“Our study sheds light on a possible mechanism to enhance the efficacy of gene therapy approaches for AAT and, moreover, may have implications for the production of proteins from mRNA vaccines, which rely on the expression of viral glycoproteins in nonnative host cells upon intramuscular injection,” the study’s authors said.

Read more about experimental AATD therapies

To investigate the suitability of a variety of cells as hosts for the expression of exogenous AAT, Huh-7 hepatocytes, Chinese hamster ovaries (CHO), and C2C12 myoblasts were transfected with myc-tagged wild-type AAT (AAT-M). A pulse-chase metabolic labeling experiment was then performed to monitor the production and secretion of the AAT-M from the different cell types.

The Huh-7 cells achieved a maximum of 88% secretion after 2 hours of chase while the CHO cells reached 75% and the C2C12 cells only reached 55%. Treatment of the C2C12 cells was found to increase AAT-M secretion by 75%.

Since gene therapy often targets mature myotubes rather than myoblasts, C2C12 cells were differentiated and then treated with AAV capsids containing AAT-M cDNA. SAHA was also found to increase the secretion of AAT-M in these cells by 40%, supporting its possible use in future gene therapy trials.


Ke H, Guay KP, Flotte TR, Gierasch LM, Gershenson A, Hebert DN. Secretion of functional α1-antitrypsin is cell type dependent: Implications for intramuscular delivery for gene therapy. Proc Natl Acad Sci. 2022;119(31):e2206103119. doi:10.1073/pnas.2206103119