What is happening in the AATD investigation?

The DAAT web portal contains DAAT news and we summarize the following points of interest

Alpha-1 antitrypsin deficiency (AATD) is a rare entity that is associated with the development of chronic obstructive pulmonary disease (COPD) and pulmonary emphysema in adults and liver disease and panniculitis in children and adults.

Research into rare diseases requires the development of patient registries that include a large number of cases to find out their characteristics and natural history. Without research, there is no cure.

The EARCO registry is an initiative of the EARCO Clinical Research Collaboration (CRC) of the European Respiratory Society (ERS). This is an international, observational and multicenter study whose main objectives are:

  • Generate high-quality clinical data from AATD patients in a longitudinal and long-term manner.
  • Understand the nature and prognosis of individuals with AATD.
  • Investigate the effect of AAT replacement therapy and other therapies on the progression of the disease.
  • Expand knowledge about the course of the disease in patients with severe AATD with genotypes other than Pi*ZZ.

News of the knowledge of AATD mutational variants

Alpha 1 antitrypsin deficiency is a mutation-sensitive disease

This is because AAT is a protein that has conformational flexibility with several regions involved in a large structural rearrangement necessary for its protease inhibitory function.

This protein is susceptible to mutations that cause misfolding, inactivation, or intracellular accumulation of polymers that cause liver damage.

Rare variants may be more frequent than expected and therefore, in discordant cases, standardized detection of the S and Z alleles needs to be complemented by gene sequencing and structural approaches.

Structural characterization of novel pathogenic SERPINA1 mutations encoding circulating AAT could provide new insights into the mechanisms of AAT misfolding in liver and lung diseases.

This could have important implications for molecular diagnostics and therapeutic development.

The authors discuss the utility of computational modeling in providing supporting evidence for the pathogenicity of rare single nucleotide variations.

Five variants, four of them previously unknown, of the SERPINA1 gene are characterized, defining new alleles that contribute to AATD.

Author of the commentary: Dr. Carlota Rodríguez García. Pneumology Service. University Hospital Complex of Santiago de Compostela, Galicia.

Resource: PubMed National Library of Medicine

News of AATD Treatments

Treatments for AATD patients

Patients with chronic obstructive pulmonary disease (COPD) and severe alpha-1 antitrypsin (AATD) deficiency who meet criteria for this may benefit from intravenous (iv) AAT replacement therapy with weekly infusions of purified human AAT. .

Inhaled route

A non-invasive treatment strategy is the administration of human AAT by the inhaled route, either by nebulization or dry powder inhalers (DPIs). Both methods have advantages and disadvantages.

In the case of liquid aerosols, penetration of the particles into the respiratory tract, a key requirement for therapeutic effect, may be a potential problem.

Additionally, during nebulization, proteins can be denatured and inactivated by oxidation or aggregation at the air-liquid interface or by mechanical stress and thermal degradation.

On the other hand, the production of DPIs is frequently carried out by processes, such as freeze-drying or spray-drying, which can expose the protein to thermal and physical-chemical stress, causing a reduction in its activity.

However, the use of dry powder inhalers is more accepted, with greater adherence to treatment by patients.

On the other hand, it improves the quality of life with respect to the use of nebulizers, since the time needed for administration is drastically reduced compared to nebulization.

The authors of this article investigate an alternative treatment strategy of recombinant AAT (rAAT) replacement of Escherichia coli in dry powder produced by spray drying, delivered by inhalation via DPI.

Resource: PubMED

Results of the research

Since the spray-drying process can be a source of stress leading to protein degradation or denaturation.

Researchers have paid special attention to the effect of formulation parameters on protein stability, as well as possible mechanisms. of degradation.

In this way, purified, active and endotoxin-free rAAT was produced.

In the formula using L-leucine and mannitol as excipients after identifying the compromise conditions for protein activity and good aerodynamic performance.

Parenteral infusion replacement therapy aims to achieve a serum concentration of at least 11 µM, which is estimated to correspond to a pulmonary epithelial fluid concentration of 1.7 M (8.8 mg/dL).

To achieve this concentration, about 50 mg of powder should be administered (2 capsules of 25 mg of the formulation).

These authors present a novel and innovative research paper on replacement therapy with rAAT of Escherichia coli administered by inhalation via DPI.

This work could represent an alternative to current AATD treatments, avoiding its weekly parenteral administration, generally in day hospitals.

Author of the comment: Dr. Francisco Casas Maldonado. Pneumology Service. San Cecilio Clinical University Hospital of Granada.

Resource: PubMed National Library of Medicine

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