Restoring lung tissue regeneration pathways in AATD-related emphysema

touchRESPIRATORY coverage of ATS 2026

What unmet needs exist in the treatment of AATD-related emphysema?

AATD is a hereditary disorder characterized by a single point mutation Pi*Z, E342K in SERPINA1 gene, resulting in low circulating levels of alpha-1 antitrypsin and progressive lung damage, frequently leading to early-onset emphysema, and liver fibrosis, even cirrhosis. A central feature of AATD is the accumulation of Z-AAT polymers, which can lead to cellular stress, inflammation, and tissue damage in the liver and in the lung.²

One of the biggest challenges in AATD-related emphysema is that current AATD therapies focus on slowing disease progression, but they do not promote lung tissue regeneration, leaving AATD individuals at risk of ongoing alveolar loss over time. Even augmentation therapy cannot fully prevent emphysema progression in many individuals, especially if AATD diagnosis and augmentation therapy initiation is delayed by late detection.³ In addition, intracellular accumulation of polymerized Z-AAT remains as an important pathogenic mechanism that is not fully addressed by current approaches, especially in the lung immune and structural cells.^4-7

Polymerized Z-AAT accumulation within the endoplasmic reticulum (ER) lumen triggers unfolded protein response and ER stress which in turn, through IRE1α and ATF6 pathways, causes oxidative stress and mitochondria dysfunction in hepatocytes and lung bronchial epithelial cells.^8-10 Therefore, there is a major need for therapies that can actively promote alveolar repair, while also targeting the AATD-specific underlying mechanisms, e.g. intracellular polymerized Z-AAT driving disease progression.

What was the rationale for investigating lithium treatment in this indication?

We hypothesize that lithium, as a WNT/β-catenin signaling activator, may help restore downstream WNT/β-catenin targets in two murine models of AATD, targets we have previously described as decreased in the lungs and alveolar type 2 (AT2) cells of these animals.¹¹

There is also a wide breadth of published literature that environmental lithium exposure has been associated with reduced hospitalizations for mental health crises, all-cause mortality, suicide mortality, cardiovascular mortality, and neurodegenerative diseases.^12-13 Specifically to lung pathology, lithium treatment has restored WNT/β-catenin signaling and promoted alveolar repair in an elastase induced emphysema model, and in human precision cut lung slices (PCLS) from smoker and COPD individuals.^14-15

Moreover, because lithium reduced pathological β-amyloid aggregation in animal models of Alzheimer disease, we are set to investigate whether in AATD, a disease also marked by polymerized Z-AAT protein accumulation, lithium may reduce intracellular polymerized Z-AAT burden.¹⁶

Could you describe the methodology of your study?

We worked with two AATD murine models and human samples from AATD individuals enrolled in GRADS study. The AATD mouse models were SerpinA1 null mouse which is a knockout mouse for the five SerpinA1 gene copies and does not express mouse AAT (Jackson Laboratory strain #035015); and our novel SerpinA1-null-Z-AAT mouse which expresses the human Z mutated AAT on the SerpinA1-null background (Jackson Laboratory strain #412938). We used lungs, EPCAM+ and FACS-sorted EPCAM+ MHCII+ AT2 cells from these murine models and studied WNT signaling and Z-AAT polymer accumulation using western blot, qPCR, and immunofluorescence using the 2C1 specific antibody against polymerized Z-AAT.

In order to assess AT2 proliferation and differentiation, we cultured primary murine FACS-sorted EPCAM+ MHCII+ AT2 cells with murine fibroblast in Matrigel^® to generate alveolar epithelial organoids and post IgG-panning AT2 cells to derive AT1-like monolayers in 0.4um Corning^® inserts. Ex vivo, AT2 organoids and differentiated AT1-like monolayers were treated with 10mm LiCl in order to evaluate core WNT/β-catenin, cell cycle, and pro-proliferation transcription factors.

For our in-vivo experiments, mice received low-dose lithium (100mg/kg body weight, daily) treatment for 30 days and we analyzed plasma, lung tissue and isolated AT2 cells to evaluate WNT signaling and Z-AAT polymer accumulation. Lastly, we used serum from AATD individuals enrolled in the GRADS study to measure circulating lithium using inductively coupled plasma mass spectroscopy and circulating polymerized Z-AAT using custom-made ELISA using 2C1 specific antibody against polymerized Z-AAT as pull-down antibody.

What were the key findings from the study?

We found that both AATD models displayed impaired canonical WNT/β-catenin signaling in the lung and AT2 cells compared with wild-type, control mice, together with reduced murine AT2 proliferation and differentiation in the organoid and monolayer models. We have previously shown that reduced WNT/β-catenin signaling in these models was associated with chronic neutrophilic inflammation, airspace enlargement, and increased lung compliance recapitulating changes seen in the emphysematous lungs of AATD individuals. In-vivo lithium treatment also increased WNT/β-catenin downstream targets Axin2, Tcf7l2, Cyclin D1 and the WNT receptor FZD5 in the lungs and EPCAM+ AT2 cells of SerpinA1-null-Z-AAT mice.

Ex-vivo lithium treatment decreased GSK3β expression, improved WNT/β catenin signaling, increased expression of regenerative markers, including Axin2, Lef1, Cyclin D1, and improved AT2 organoid growth when assessed by colony forming unit counts. Interestingly, lithium treatment also reduced intracellular Z-AAT polymer accumulation in alveolar organoids and in AT1-like monolayer derived from Z-AAT AT2 cells, suggesting a potential dual mechanism of action for its protective effects on alveolar epithelium in AATD.

Moreover, in AATD individuals we found an inverse correlation between the circulating lithium levels and circulating Z-AAT polymers, suggesting that a higher lithium level may decrease Z-AAT polymer burden. We are actively pursing experiments to elucidate the mechanism of this exciting finding, looking at pathways involving both Z-AAT polymer formation and clearance.

How will these findings support progression into clinical trials?

The pathway to clinical trials for low-dose lithium is short and we partnered with Dr Divay Chandra at University of Pittsburgh to link our basic science findings to the clinical observations noted in AATD and COPD individuals. Some further work is needed to fully characterize the dose response in preclinical models and to confirm the associations we have identified between circulating lithium levels, reduced emphysema, and lower polymer levels in AATD cohorts.

The clinical need is pressing on two fronts. None of the available or upcoming AATD treatments can repair emphysema once it has developed, and there is an equally urgent need for therapies that reduce the toxic AAT polymers that cause liver disease and contribute to emphysema progression. To our knowledge, this is the first time preclinical and translational data have converged to suggest that a single, well-characterized therapeutic can do both.

Low-dose lithium also has a practical regulatory advantage over novel drugs, as it is already widely available. With established safety data and a literature of beneficial effects, including improved survival, the path from positive trial results to patient access is much shorter than for a new molecular entity.