In a mouse model of alpha-1 antitrypsin deficiency (AATD), the efficacy of transient receptor potential mucolipin 1 (TRPML1) in decreasing the toxic burden of Z-alpha-1 antitrypsin (ATZ) and fibrosis has been demonstrated, according to findings from a study conducted in 6-week-old PiZ mice and published in the journal Molecular Therapy.

The development of AATD is linked to pathogenic variants in the SERPINA1 gene that encode an acute-phase plasma glycoprotein and serine-proteinase inhibitor, which are synthesized mainly in the liver. AAV-mediated gene transfer of SERPINA1 into muscles is associated with sustained expression of AAT among individuals with AATD.

Although the delivery of the SERPINA1 gene to the liver or muscle is a long-term solution for lung disease in individuals with AATD, it does not impact hepatic disease. To treat both lung and liver disease in individuals with the condition, hepatic knockout or downregulation of the mutant SERPINA1 gene is required to eliminate expression of toxic ATZ protein, along with providing the wild-type SERPINA1 gene.

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Quelling expression of the mutant SERPINA1 gene with concomitant expression of the wild-type SERPINA1 is being researched as a way to achieve this goal. This approach has been realized in preclinical analyses by AAV vectors that deliver microRNA sequences targeting the SERPINA1 gene while, at the same time, driving expression of the microRNA-resistant wild-type SERPINA1 gene, thus attaining “concomitant ATZ knockdown in the liver and increased expression of AAT.” Such a strategy is still in the preclinical stages of development, but a siRNA-based therapy that decreases expression of ATZ might become clinically available in the near future.

Read more about experimental therapies for AATD

The researchers in this study sought to evaluate TRPML1 as a candidate target to treat liver disease generated by ATZ by using hepatic gene transfer or pharmacologic activation. For their investigation, they administered intravenous (IV) injections of a serotype 8 adeno-associated virus (AAV8) vector that expressed the human TRPML1 in 6-week-old PiZ mice, thus recapitulating the hepatic pathology of human AATD.

Gender- and age-matched PiZ mice received IV injections of AAV expressing transcription factor EB (TFEB) as a positive control (AAV-TFEB) or AAV expressing the reporter green fluorescent protein (GFP) as a negative control (AAV-GFP). Real-time polymerase chain reaction was used to verify hepatic AAV-mediated delivery of the TRPML1 gene in the livers of the PiZ mice, which revealed expression of human TRPML1 mRNA in AAV-TRPML1-injected mice.

Based on the use of liver immunofluorescence, transgene expression (ie, TRPML1, GFP, or TFEB) was demonstrated in around 70% of hepatocytes in PiZ mice. In comparison with the AAV-GFP-injected controls, the livers of the PiZ mice that received injections of AAV-TRPML1 exhibited a significant decrease in periodic-acid-Schiff with diastase-positive globules—the pathologic hallmark of hepatic disease due to ATZ, which is lacking in wild-type mice.

According to the researchers, “In conclusion, we found that TRPML1-mediated lysosomal exocytosis is a druggable pathway for treatment of the liver disease due to ATZ that can be added to therapeutic strategies based on downregulation of ATZ expression by siRNA and activation of intracellular degradation pathways, such as the proteasome and autophagy.”


Pastore N, Annunziata F, Colonna R, et al. Increased expression or activation of TRPML1 reduces hepatic storage of toxic Z alpha-1 antitrypsin. Mol Ther. Published online July 1, 2023. doi:10.1016/j.ymthe.2023.06.018