Alpha-1-antitrypsin Deficiency

1. Disease Summary:

Alpha-1-antitrypsin deficiency (AATD) is a genetic disorder caused by mutations in the SERPINA1 gene, leading to insufficient production of the protein alpha-1 antitrypsin (AAT). This protein plays a crucial role in protecting the lungs and liver from damage caused by enzymes released by white blood cells. AATD can result in serious lung diseases, such as emphysema and chronic obstructive pulmonary disease (COPD), as well as liver diseases, including cirrhosis and liver failure. The condition is inherited in an autosomal co-dominant manner, meaning that individuals can have varying levels of AAT based on their genetic makeup.

2. Global Prevalence and Disease Burden:

AATD is estimated to affect approximately 1 in 2,000 individuals in Western Europe, but it is believed to be underdiagnosed, with many cases going unrecognized. Globally, it is estimated that around 3.4 million people have deficiency alleles, with a significant number of carriers (approximately 116 million) who may not exhibit symptoms but are at risk for developing related diseases (de Serres, 2003, PMID: 14654440). The disease burden is substantial, as individuals with AATD often experience a reduced quality of life, increased healthcare costs, and a higher incidence of comorbidities, including cardiovascular diseases and respiratory infections. The economic impact of AATD is significant, with increased healthcare resource utilization due to hospitalizations and treatments for associated complications (Herrera et al., 2021, PMID: 34036848).

3. Unmet Medical Need:

Despite the existence of treatment options, there are several unmet medical needs for patients with AATD:

Liver Disease Treatment: Currently, there are no approved therapies specifically targeting liver manifestations of AATD. The only management option for severe liver disease is liver transplantation, which is not feasible for all patients and carries its own risks and complications (Pires Ferreira et al., 2023, PMID: 36825473).
Efficacy of Current Treatments: The standard treatment for lung disease associated with AATD is intravenous augmentation therapy, which involves infusing AAT derived from human plasma. However, this therapy is considered suboptimal as it does not address the underlying genetic defect and may not provide sufficient protection against lung damage (McElvaney et al., 2023, PMID: 36896570).
Awareness and Diagnosis: AATD is often underdiagnosed or misdiagnosed as asthma or COPD, leading to delays in appropriate treatment. Increased awareness and better diagnostic tools are needed to identify affected individuals earlier in their disease course (Greene et al., 2016, PMID: 27465791).
Access to Care: There are disparities in access to treatment across different regions, particularly in low- and middle-income countries, where patients may not have access to augmentation therapy or genetic testing (Wilkens, 2021, PMID: 34295404).

4. Current Treatment Options:

The current treatment landscape for AATD includes:

Intravenous Augmentation Therapy: This is the primary treatment for lung disease associated with AATD. It involves regular infusions of AAT to increase serum levels and provide some protection against lung damage. However, it does not correct the underlying genetic defect and may not be effective for all patients (Greene et al., 2016, PMID: 27465791).
Supportive Care: Patients are often treated with standard therapies for COPD, including bronchodilators, corticosteroids, and oxygen therapy. However, these treatments do not address the root cause of AATD and may have limited efficacy (McElvaney et al., 2023, PMID: 36896570).
Liver Transplantation: For patients with severe liver disease, transplantation may be the only option, but it is limited by donor availability and the risks associated with surgery (Pires Ferreira et al., 2023, PMID: 36825473).

5. Current Clinical Trials:

Several clinical trials are currently investigating new treatment options for AATD:

Gene Therapy: Trials are exploring gene editing techniques to correct the underlying genetic defect in AATD. For example, BEAM-302 is an investigational gene therapy that aims to restore normal AAT production (Beam Therapeutics, 2025).
RNA Interference Therapies: Fazirsiran is an RNA interference therapeutic being evaluated for its efficacy in reducing liver Z-AAT concentrations and improving liver function in patients with AATD-related liver disease (Strnad et al., 2022, PMID: 35748699).
New Augmentation Therapies: Ongoing studies are assessing the safety and efficacy of new formulations of AAT and alternative delivery methods to improve patient outcomes (McElvaney et al., 2023, PMID: 36896570).

6. Additional Context:

The landscape of AATD treatment is evolving, with promising new therapies on the horizon. However, significant gaps remain in the management of liver disease and the overall awareness of AATD among healthcare providers. Addressing these unmet needs will require collaborative efforts among researchers, clinicians, and patient advocacy groups to improve diagnosis, access to care, and the development of effective treatments.