Alpha-1 Antitrypsin Deficiency: Current Landscape of Detection, Management, and Treatment

Abstract

Alpha-1 antitrypsin deficiency (AATD) is a rare, underdiagnosed genetic disorder characterized by deficient or dysfunctional alpha-1 antitrypsin (AAT), leading to unopposed neutrophil protease activity. This can often lead to progressive lung and liver damage, and in rare cases panniculitis, which can be potentially lethal. Current diagnostic strategies rely on a stepwise approach beginning with serum AAT measurement, followed by phenotyping and genotyping to confirm pathogenic variants. Despite recommendations from major respiratory societies to test all patients with chronic obstructive pulmonary disease (COPD), unexplained liver disease, panniculitis, and vasculitis, delayed recognition persists because of clinical overlap with asthma, COPD, and alcohol- and non-alcohol-related liver disease. Management emphasizes lifestyle modification, avoidance of risk factors, and pharmacological support. Currently, intravenous augmentation therapy is the only disease-modifying option approved for pulmonary disease. Augmentation is expensive and variably available, or reimbursed worldwide. Surgical and interventional approaches, including lung volume reduction techniques and transplantation, provide options for advanced disease, although outcomes vary. Emerging therapies, such as inhaled AAT formulations, recombinant fusion proteins, RNA-editing platforms, and DNA editing using CRISPR-based strategies, aim to correct the protease-antiprotease imbalance and restore endogenous AAT production. The therapeutic landscape is rapidly evolving, but significant challenges remain in improving early detection, broadening access to effective treatments, and optimizing individualized care. Future advances will likely depend on integrating newer therapies with early intervention strategies to preserve organ function and improve long-term prognosis.

Key Summary Points

Alpha-1 antitrypsin deficiency (AATD) continues to be underdiagnosed because of overlapping symptoms and presentation with other common pulmonary and hepatic conditions.

Early diagnosis can influence outcomes, and alpha-1 antitrypsin (AAT) testing is recommended for all high-risk groups, including patients < 45 years old with chronic obstructive pulmonary disease (COPD) and minimal or no smoking history, emphysema on imaging, unexplained bronchiectasis, uncontrolled asthma, and unexplained chronic liver disease.

Continued education about AATD, especially on the avoidance of risk factors such as cigarette smoking, remains an important factor in reducing the risk of early onset and progression of lung disease in these patients.

New treatment for AATD-related lung and liver disease is undergoing significant advancement, with novel small molecules and genetic approaches providing potential for future personalised care and improved prognosis.

Introduction

AATD is a rare genetic disorder characterised by functionally impaired or reduced levels of AAT protein. AAT is a serine protease inhibitor, primarily made in the liver, that regulates neutrophil serine proteases (NSP), in particular neutrophil elastase (NE) and proteinase 3, which are released by activated neutrophils during the inflammatory response. In AATD, unopposed NSP activity degrades elastin and other extracellular matrix components in alveoli, leading to irreversible destruction and development of emphysema and bronchiectasis [1]. Environmental factors, such as smoking and air pollution, cause an increase in NE and accelerate lung damage [2].

Polymerization of misfolded AAT can damage hepatocytes and cause liver fibrosis, cirrhosis, and an increased likelihood of developing hepatocellular carcinoma [3]. AATD is also associated with rare complications such as vasculitis [4] and panniculitis [5].

AATD is inherited in an autosomal co-dominant fashion, and disease severity is determined by phenotype. The normal SERPINA 1 gene, located on chromosome 14 and responsible for encoding AAT protein, has several allelic variants. The normal allele is termed M, and the corresponding homozygous genotype is designated PiMM, with ‘Pi’ denoting protease inhibitor. The most common deficient alleles are S and Z, and PiSZ individuals typically have moderate deficiency, whereas individuals with PiZZ have severe disease [6]. There are many different mutations, including null variants, where there is no functional protein production. Null variants do not cause hepatocyte damage, but respiratory manifestations occur because of protease imbalance. Genetic surveys suggest that PiZZ occurs in approximately 1 out of every 2000–5000 individuals in Northern and Western Europe, where Z allele frequency is estimated to range from 0.014 and 0.02 [7]. The highest frequency for PiS (> 0.14) has been found in southwestern Europe [8]. Given the minimal amount of data available on worldwide estimates of AATD, de Serres used an exploratory study to estimate individuals who may be carriers, homozygous or heterozygous for S and Z variants, in 58 countries [9]. The study concluded that there are potentially > 100 million carriers and > 3 million people with pathological allele combinations representative of moderate or severe disease [9]. A more recent worldwide systematic literature review suggested about 235,000 people worldwide are PiZZ, of whom 50% are in Europe [10].

The aim of this article is to review the current strategies and guidance for detection, management, and treatment of AATD. The main emphasis is on the management and treatment of lung and liver disease as these are the two most common manifestations of the deficiency.

This work is based on previously conducted studies and does not include any new studies involving human participants or animals conducted by any of the authors.

Detection

Given that early management for both hepatic and pulmonary pathologies is usually best supportive care and promoting a healthy lifestyle, there are no newborn screening programmes in place [11]. However, if AATD is diagnosed at birth (due to strong family history or neonatal cholestasis), advice should be given to avoid smoking and excessive alcohol and other hepatotoxic substances. A 1970s study in Sweden showed a significant reduction in smoking in adults identified at birth as having AATD, hence potentially preventing future lung injury [12].

Patients with AATD are variably affected, and providing a diagnosis to families and young children could lead to psychological distress if outcomes are uncertain. Thus, testing is only usually offered to at-risk groups and families of index cases. The American Academy of Paediatrics have called for studies to assess long-term effects of early/newborn screening programmes [11]. Other obstacles to early diagnosis include a lack of awareness and poor availability of specific treatment [13].

AATD is often initially misdiagnosed as asthma or COPD because of an overlap of pulmonary manifestations. Similarly, liver disease may be diagnosed as metabolic-associated steatotic liver disease (MASLD) or another cause of liver fibrosis. International guidance recommends AAT testing for all high-risk groups, specifically all patients with COPD (particularly those < 45 years old and/or with minimal or no smoking history), emphysema on imaging, unexplained bronchiectasis, and uncontrolled asthma despite treatment [14]. AATD screening should also be undertaken in individuals with unexplained liver disease [14], panniculitis, and granulomatosis with polyangiitis [15].

The first line of screening for the at-risk population is serum AAT level [5]. Normal AAT levels are around 100–200 mg/dl, and serum levels ≤ 100 mg/dl warrant further testing in the form of phenotyping or genotyping (Table 1).

Table 1.

AATD common genotypes and clinical manifestations

Common genotype	Serum AAT concentration	Clinical implication
PiZZ	2.5—7 μM (20–45 mg/dl)	High risk of early-onset panacinar emphysema and/or liver disease
PiSZ	8–16 μM (75–120 mg/dl)	Reduced antiprotease protection; increased COPD risk with smoking or environmental exposure
PiMZ	17—33 μM (90–210 mg/dl)	Never smokers do not have an increased risk for COPD
PiMM	20 – 48 μM (150–350 mg/dl)	Wild type; no increased disease risk

Data taken from Stoller & Aboussouan, 2012 [20]; ATS/ERS Statement, 2003 [21]

Phenotyping is usually performed ahead of genotyping and can identify rare alleles [16]. Genotyping of SERPINA1 provides definitive evidence of a mutation. Phenotyping and genotyping are not influenced by the presence of an acute event, whereas serum AAT levels can rise during acute inflammation [17], which could suggest a normal AAT concentration despite the presence of disease. In contrast, gastrointestinal conditions that involve protein-losing enteropathy can lower measured AAT levels [18]. If an index case is identified, family testing should be offered to first-degree relatives together with genetic counselling as per local legislation [19].

Imaging

Chest radiographs and computed tomography (CT) scans can be helpful in diagnosing emphysema [22]. AATD typically exhibits pan-lobular and basal emphysema, and CT scans are recommended at the time of diagnosis to provide baseline information that can be beneficial to track progression and therapeutic effect [14]. Furthermore, it can provide specific details of the type and location of emphysema and the presence of any concurrent bronchiectasis.

Management

Management of AATD has evolved significantly; however, primary treatment guidance has remained unchanged. Smoking cessation slows annual FEV1 decline in patients with longer periods of smoking abstinence [23]. Increased frequency of dust exposure (including occupational exposure to noxious particles) and exacerbations also lead to poorer outcomes and accelerate decline in lung function [23].

Lung Disease

Inhalers play a similar role in AATD as in asthma or COPD. Short-acting β₂ agonists (SABA) act as relievers and all patients with COPD should have a rescue bronchodilator as per Global Initiative for Obstructive Lung Disease (GOLD) guidelines [24]. Long-acting β₂ agonists (LABA) and long-acting muscarinic antagonists (LAMA) are used to reduce exacerbations and as maintenance therapy [24]. The 2025 GOLD report also emphasizes determining eosinophil count to guide inhaled corticosteroid (ICS) prescription; patients found to be eosinophilic are candidates for ICS and other targeted therapies that reduce AECOPD [24]. Consistent with this, use of ICS in patients with PiZZ AATD and eosinophils > 0.2 × 10⁹ showed a reduction in FEV1 decline [25], unlike those with lower counts indicative of differential response. Lung function and symptoms also improved in patients with PiZZ AATD when inhaled ICS was added to salmeterol (LABA) and oxitropium bromide (SAMA) [26]. Patients should also receive influenza and pneumococcal vaccinations and in the event of exacerbations be treated promptly with antibiotics and oral corticosteroids [27]. Self-management plans should also be considered to avoid hospital admissions [28].

Pulmonary rehabilitation improves exercise capacity and breathlessness in patients with AATD/COPD. While evidence remains limited, tailored, high-intensity training has been shown to improve quality of life (QoL) [29, 30], although more recent data suggest benefits are not sustained [31]. Long-term oxygen therapy (LTOT) is recommended for patients with chronic hypoxemia as observational studies suggest it maintains levels during activity and can improve survival [32]. Survival outcomes in AATD patients are generally comparable or slightly better than in patients without AATD/COPD, influenced by lung transplantation eligibility and age [33].

Augmentation Therapy

Intravenous augmentation therapy is the only disease-modifying intervention available for lung manifestations of AATD. Purified AAT is derived from pooled plasma of healthy donors and administered at a recommended weekly dose is 60 mg/kg, which raises serum AAT above the putative protective threshold of 11 µM (≈80 mg/dl) to restore protease-antiprotease balance and slow alveolar destruction due to NE-mediated tissue injury [34–37]. However, reliance on serum thresholds alone to determine clinical risk has been questioned in terms of accuracy for defining disease, and genotypic assessment has been suggested as more reliable for predicting severity and progression [38].

Past iterations of international ATS/ERS guidance recommended augmentation therapy for individuals with severe AATD genotypes (e.g., PiZZ, PiZ/null, or null variants) who have established emphysema and moderate airflow obstruction, as a greater effect was seen in spirometry decline in those with FEV1 approximately 30–65% predicted [21]. Differential response to augmentation based on FEV1 has been proven in multiple studies supported by clinical and imaging endpoints, which led to more recent FEV1-based recommendations from the USA, shown in Table 2 [14]. However, even if emphysema is advanced, there will still be ongoing NE activity, which augmentation therapy can potentially halt, slowing the irreversible decline [39], which provides a rationale for use in lower ranges of lung function. Canadian guidance recognises this, suggesting use in anyone with FEV1 < 80% [40]. European guidance is currently being updated, with scheduled publication late 2026.

Table 2.

Recommendations for provision of intravenous augmentation therapy in AATD

Strong recommendation based on high-quality evidence
Intravenous augmentation therapy recommended for individuals with AATD and FEV₁ within 30–65% predicted	Do not use augmentation therapy for individuals post-liver transplantation
Strong recommendation based on low-quality evidence
For FEV₁ > 65% predicted: discuss augmentation therapy, weighing potential benefits vs. cost and limited evidence	Do not use augmentation therapy for individuals with the MZ genotype who have COPD
Augmentation therapy recommended for individuals with necrotizing panniculitis due to AATD	Do not use augmentation therapy for liver disease due to AATD
Weak recommendation based on low-quality evidence
Augmentation therapy recommended for individuals with FEV₁ < 30% predicted	Do not use augmentation therapy in individuals with AATD-related lung disease who continue to smoke

FEV₁ forced expiratory volume in 1 s

Table derived from Sandhaus RA, Turino G, Brantly ML, et. al. [14]

The RAPID trial was the largest randomised control trial of augmentation conducted to date [41], assigning 180 patients to receive either 60 mg/kg/week of intravenous AAT or placebo for 2 years. The treatment group had a significant reduction in the annual rate of CT lung density loss at total lung capacity (TLC). An open-label extension trial (RAPID-OLE) was performed for another 24 months wherein patients in the placebo group switched to IV AAT therapy while the initial treatment group continued to receive AAT [42]. This demonstrated that delayed starters’ lung density loss decreased significantly from – 2.26 g/l per year to – 1.26 g/l per year [42]. Although a minimum clinically important difference (MCID) for CT density decline has been proposed with values of – 2.04 g/l or – 1.87 g/l/year, linked to clinically relevant changes in FEV1 and health status [43], CT density is not an accepted end point by all regulators internationally (e.g. FDA). This has led to the need for observational data on the more widely accepted outcomes, like FEV1 and quality of life, for which the RAPID RCT was not powered.

Observational studies show that augmentation therapy is associated with a slower decline in lung density on CT imaging, reduced progression of emphysema, and a lower rate of FEV1 decline than seen in untreated individuals. Several large cohorts also report a mortality benefit in patients receiving augmentation therapy [21]. A recent multicentre observational cohort study was conducted using UK and US AATD registry data to compare outcomes among augmentation-naïve and augmentation-treated individuals with severe AATD [44]. Treated patients demonstrated a significantly slower decline in QoL (SGRQ decline of 1.43 points per year; 95% CI 0.47–2.39) and reduced mortality compared with untreated individuals [45]. A similar large multinational registry-based observational analysis also demonstrated a significant reduction in all-cause mortality among patients with severe AATD treated with intravenous augmentation [46]. Using multivariate modelling, this survival benefit persisted after adjusting for baseline FEV1 and its rate of decline, indicating that improved survival is independent of spirometric preservation. The authors also noted that both age and index status, whether diagnosed because of symptomatic lung disease or through screening, strongly influenced outcomes, with younger, lung-index patients deriving the greatest benefit from early intervention [46].

Areas of Uncertainty for Augmentation

There is currently a lack of evidence to suggest that higher doses, such as 120 mg/kg/week, lead to better clinical outcomes; the SPARTA study aims to answer this question [47]. It is also important to consider that a higher dose will increase costs. Treating current smokers with augmentation would be considered counterintuitive as any damage prevented by augmentation would be reversed by smoking, leading to an increased recruitment of NE in the lungs causing further damage. Augmentation should not be considered in the MZ genotype because of lack of efficacy evidence [14].

Lung Volume Reduction Surgery

Surgical management options such as lung volume reduction surgery (LVRS) may also be explored; however, it is generally only considered in highly selected patients. Individuals with severe symptoms including marked hyperinflation and heterogeneous (typically upper lobe predominant) emphysema in whom usual treatments have shown to be inadequate may be candidates for this procedure. LVRS is known to improve QoL and exercise function [48], although Stoller and colleagues showed a higher 2-year mortality rate in 16 AATD individuals who were randomised to LVRS compared with medical treatment [49]. The last relevant systematic review included six small observational and case series studies encompassing approximately 100 patients with AATD/COPD who underwent LVRS. Short-term improvements in physiological parameters and dyspnoea were seen, although these benefits were less pronounced and of shorter duration than those observed in patients with usual COPD. One small randomized controlled trial compared LVRS (n = 10) with medical management (n = 6) and observed a higher 2-year mortality rate in the surgical group (20% vs. 0%), despite concurrent improvements in health related QoL [50]. Most guidelines advise caution in routine LVRS use in AATD [48–50].

Endobronchial Valves and Coils

Bronchoscopic lung volume reduction techniques such as endobronchial coils and endobronchial valves (EBVs) represent minimally invasive techniques for patients with severe emphysema and lung hyperinflation [51]. EBVs are typically offered when no collateral ventilation is present on bronchoscopy or CT [52]. Endobronchial coils may be used even when collateral ventilation is present, as they reduce lung volume through mechanical retensioning rather than lobar occlusion [53]. Typical pan-lobular basal emphysema in AATD is more amenable to endobronchial values as surgical options. A one-way valve is inserted to completely occlude the target lobe to induce atelectasis [52], resulting in only a one-way movement for air and secretions, but it prevents re-entry [53]. This collapses the affected lobe, reducing lung volume, causing redistribution of air to healthier parts of the lung and improving pulmonary function and exercise tolerance [54]. In a multicentre cohort of 53 individuals, of whom 30 had confirmed AATD, EBV therapy resulted in a median FEV₁ gain of 12%, with parallel improvements in exercise capacity and health-related QoL, and no deaths reported at 6 months [55].

Evidence for endobronchial coil therapy in AATD also shows sustained benefit in lung function and exercise tolerance in longer term follow-up cohorts [53]. Endobronchial coils do not need an absence of collateral ventilation or fissure integrity and can be used in homogeneous or heterogeneous emphysema [56]. Clinical trials have demonstrated symptomatic and functional benefits: in the RENEW trial, 315 patients showed significant improvements in FEV₁, 6-min walk distance, and QoL at 12 months [57]. Post hoc analyses in AATD subgroups suggest coils may be safe and beneficial, but sample sizes remain small, and further dedicated trials are warranted [58].

In another study, long-term follow-up in 15 patients with AATD demonstrated sustained benefit, with mean FEV₁ increasing by 54% and functional improvements persisting for up to 4 years; notably, two patients were able to discontinue long-term oxygen therapy [59]. BLVR (EBVs and coils) is generally considered in patients with severe hyperinflation (RV > 150%) who remain symptomatic despite optimal medical therapy and pulmonary rehabilitation [51, 52].

Transplantation

Transplantation remains the only definitive treatment for end-stage lung disease in patients with AATD [60]. This may be considered in patients with COPD and BODE ≥ 8; typically FEV1 and DLCO are < 25% predicted. Compared to patients with usual COPD, individuals with AATD tend to undergo transplantation at a younger age, reflecting both earlier onset and more aggressive progression of emphysema [60]. Factors such as younger age, reduced exposure to tobacco smoke, and minimal co-morbidities in patients with AATD can make them ideal candidates for lung transplant [60, 61].

However, evidence regarding lung transplant in AATD is mixed with some studies reporting clear benefits in QoL and survival while some highlight limited positive outcomes. Data from the Swedish registry demonstrated a median survival of 11 years following transplantation in patients with severe AATD compared with a median survival of 5 years in historical outcomes of non-transplanted cohorts [62]. Fakhro and colleagues reported a 93% (CI 86–99) survival rate after 1 year in transplant patients with AATD compared with 83% (CI 75–93) survival in patients with usual COPD [54]. Fifteen-year survival rate was also better in patients with AATD at 32% (CI 19–55) compared with 22% (CI 12–41) in usual COPD. The study also showed significantly better results in double-lung transplant (DLT) versus single-lung transplant (SLT) at the 10-year post-transplant period [63]. The risk of infections in the native lung are also higher in SLT, further adding to worsening symptoms and in turn QoL.

Conversely, Burton and colleagues noticed no significant difference in survival between patients with COPD and AATD after stratifying for age [64]. Worse early survival rates in SLT have been observed in patients with AATD compared with COPD (adjusted hazard ratio 1.68, CI 1.26–2.23), albeit this was not significant for those who survived beyond the first year [65]. In patients undergoing DLT, there was no mortality difference in AATD, irrespective of duration post-transplant [65 ]. Moreover, Stone and colleagues identified 32 patients with AATD in the UK and demonstrated that while there was a significant improvement in QoL post-transplant, 5-year mortality was similar compared with non-transplanted patients [66]. As the survival benefit of lung transplants in AATD is not clear, the ERS recommends that the main indication should relate to improvement in QoL [19].

Liver Disease

Liver disease is a key systemic manifestation of AATD, resulting from hepatocellular accumulation and polymerisation of misfolded Z-AAT, which leads to cellular injury [67]. Hepatic involvement ranges from isolated biochemical abnormalities to advanced fibrosis, cirrhosis, and hepatocellular carcinoma, reflecting substantial heterogeneity among PiZZ individuals [68]. The natural history of liver disease in patients with AATD is not well understood, but a recent review by Marzi and colleagues focused on new ways of monitoring disease and potential treatments [69]. New consensus guidelines on the assessment and monitoring of liver disease in adults with AATD have also been developed [70]. A group of expert leaders critically reviewed emerging data to propose a diagnostic algorithm and standardise definitions, diagnostic criteria, and staging of liver fibrosis. It is hoped that this guidance will help to improve clinical management and the development of new disease-modifying therapies, which are urgently needed as there are currently no approved treatments for liver disease associated with AATD. Liver transplantation remains the only definitive intervention for advanced disease, restoring normal circulating AAT levels [3].

Emerging AATD Therapies

The treatment landscape for AATD is evolving rapidly, using a range of novel drug strategies (Fig. 1). Several Phase 1 to 3 clinical trials are ongoing with the focus on addressing both lung and liver disease (Table 3). Inhaled AAT therapy seeks to deliver protein directly to the lungs to restore levels over the protective threshold, reduce lung inflammation, and potentially slow the progression of emphysema [71]. Another inhaled therapy, although in Phase 1 trial, is Serpentine-1, which is an inhaled therapy that aims to deliver full-length SERPINA1 genes into the lung via a deficient HSV-1 vector. This aims to re-establish healthy AAT production in the lungs [72]

Fig. 1.

Main therapeutic targets in AATD. Created in BioRender. Pye, A (2025) https://BioRender.com

Table 3.

Current clinical trials of investigational medicinal products for AATD treatment

Intervention	Delivery method	Mode of action	Target	Development stage
SPARTA SPARTA-OLE	Weekly IV infusion of Alpha1-proteinase inhibitor (prolastin-C) at 60 mg/kg or 120 mg/kg versus placebo 2-year open0label extension following 3-year double-blind phase	Increase serum levels of alpha1 proteinase inhibitor to re-establish anti-neutrophil elastase protection for lower respiratory tract	Lung Aim: slow progression of emphysematous lung disease	Phase 3 NCT01983241 NCT02796937
Kamada-AAT for inhalation InnovAATe	Once daily inhalation of Kamada-AAT for inhalation or placebo Double-blind plus open-label extension	Increase AAT levels in epithelial lining fluid to provide antiprotease activity and reduce inflammation	Lung Aim: prevent or slow the progression of lung damage	Phase 3 NCT04204252
Fazirsiran Redwood study	Subcutaneous injection of multiple dose 200 mg/ml fazirsiran or placebo Double-blind	Synthetic, double-stranded, N-acetyl galactosamie (GalNAc)-conjugated RNA interference (RNAi) trigger to target mRNA and decrease production of wild-type or Z-alpha-1 antitrypsin (Z-AAT)	Liver Aim: decrease synthesis of mutant Z-AAT protein in the liver to reduce protein polymer accumulation, portal inflammation, and fibrosis	Phase 3 NCT05677971 NCT06165341
SAR447537 (INBRX-101) ElevAATe- OLE	IV infusion Open-label extension	Recombinant, bivalent Fc human AAT fusion protein	Lung Aim: raise serum functional AAT to normal physiological levels	Phase 2 NCT05897424
Alpha-1 15%	Subcutaneous infusion of single and weekly dose of alpha-1 15%, 72 mg/kg, and 180 mg/kg	Human alpha1-proteinase inhibitor to raise AAT levels above protective threshold	Lung Aim: raise serum AAT levels	Phase 1/ 2 NCT04722887
BEAM-302		Lipid nanoparticle (LNP)-based therapy Base-editing DNA	Liver and lung Aim: correct PiZ gene and produce normal AAT protein in the liver, which will circulate to the lungs	Phase 1/2 NCT06389877
WVE-006 RestorAATion-2	Subcutaneous injection of single (SAD) and multiple ascending dose (MAD) Open-label	RNA editing of SERPINA1-Z mRNA back to wild type (M)	Liver and lung Aim: reduce AAT protein aggregation in Liver and restore circulating functional AAT	Phase 1b/2a NCT06405633
KB408 Serpentine-1	Inhalation of single-dose escalation Open label	Herpes simplex virus type 1 (HSV-1-derived vector to deliver function human SERPINA1	Lung Aim: raise serum functional AAT levels	Phase 1 NCT06049082

IV intravenous infusion, AAT alpha-1 antitrypsin, RNA ribonucleic acid, mRNA messenger RNA, Fc fragment crystallizable, SAD single ascending dose, MAD multiple ascending dose, LNP lipid nanoparticle, DNA deoxyribonucleic acid, SERPINA serine protease inhibitor, HSV-1 herpes simplex virus type 1

INBRX-101 is a genetically engineered form of AAT made by fusion of 2 AAT molecules that is attached to the Fc region on the IgG4 [73], again working to increase AAT levels in the lung to protect against NE. Theoretically, this will require less frequent dosing than human derived AAT augmentation, with consequent reduction in the treatment's impact on lifestyle, potentially making it attractive to patients. A recent press release regarding the ElevAATe phase 2 study indicates promising results from human trials [74].

Genetic approaches currently being explored include both RNA and DNA editing. WVE-006 uses RNA editing of SERPINA1 Z mRNA. The pathological variant in AATD is a single base mutation, and WVE 006 aims to edit this to enable M-AAT production from the liver [75]. The trial is still in its early stages, but stage 1 showed > 60% of AAT post-treatment was wild-type M in two patients [76]. Other RNA-editing programmes include KRRO-110, being developed by Korro Bio, a proprietary RNA-editing oligonucleotide delivered to liver cells using a nanoparticle (LNP) delivery system and a Phase 1 study of AIR-001 by AiRNA Corp., which aims to start trials in early 2026.

BEAM Therapeutics Inc. are trialling CRISPR-based editing technology to create an A:T to G:C base pair substitution to correct the PiZ variant in the SERPINA1 gene [77]. Current studies are looking at safety and efficacy and optimal doses of the respective treatments. Alpha-1 15% is the first in-human study of a subcutaneous approach to treatment of AATD. It is being conducted by Grifols and is compared with standard intravenous therapy. If the trial proves successful, then this could give patients added flexibility and convenience when receiving ongoing treatment at home.

Previous trials have also looked at oral products, including a NE inhibitor [Alvelestat (MLP966), NCT03636347] taken twice daily to address the protease/anti-protease imbalance in AATD lung disease, which has shown promising results at Phase 2 [78]. Compounds developed by Vertex Pharmaceuticals, including VX-668 (NCT05727800), VX-864 (NCT05643495, NCT04474197), and VX-634 (NCT05579431) in single and multiple doses, have also been trialled in early phase double-blind studies that aimed to increase functional AAT serum levels. These compounds have not currently been taken forward because of the lack of clinical efficacy, but other small molecules such as BMN 349 (NCT06738017) are currently being explored at Phase 1.

Despite promising early results, all the above approaches remain experimental, and significant uncertainties persist regarding long-term safety, durability of effect, and feasibility of large-scale clinical use. Most studies involve small cohorts and short follow-up, and larger controlled trials will be essential before these therapies can be integrated into routine care.

Conclusion

AATD continues to be underdiagnosed because of its overlapping presentation with common pulmonary and hepatic conditions. Improving clinician education along with public and patient awareness holds the key to reduce the underdiagnosis of the condition. Phenotyping and genotyping remain the gold standards for diagnosis, while management should prioritize lifestyle modifications, avoidance of environmental risk factors, and vaccination, alongside pharmacological interventions such as inhalers and augmentation therapy. Surgical approaches, including lung volume reduction and transplantation, provide options for advanced disease. The therapeutic landscape is rapidly evolving, with novel strategies including inhaled AAT formulations, gene-based therapies, recombinant fusion proteins, and RNA-editing therapies now entering clinical development. Although these innovations show promise, substantial uncertainties remain regarding long-term safety, durability of benefit, and real-world applicability. Despite these advances, challenges remain in early detection, access to therapies, and optimizing individualized management. Continued research, strengthened registry data, and targeted interventions will be essential to improve outcomes and QoL for individuals living with AAT.

Author Contribution

Raunak Mawani and Anita Pye contributed to writing the review. Alice Turner formulated the content and edited the manuscript. All authors approved and reviewed the final manuscript.

Funding

No funding or sponsorship was received for the writing or publication of this article.

Data Availability

Data sharing is not applicable to this review article as no datasets were generated or analysed.

Declarations

Conflict of Interest

Raunak Mawani and Anita Pye have nothing to disclose. Alice Turner has received grants or honoraria from AstraZeneca, GlaxoSmithKline, CSL Behring, Takeda, Vertex, Sanofi, Beam, AiRNA, Korrobio, Tessera, and Grifols Biotherapeutics.

Ethical Approval

This review article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.