What novel therapies are being investigated for the treatment of alpha1-antitrypsin deficiency (AATD)?

Updated: Sep 11, 2020
  • Author: Dora E Izaguirre Anariba, MD, MPH; Chief Editor: John J Oppenheimer, MD  more...
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Several manufacturers are testing alternative routes of administration of current augmentation medications. Although IV replacement therapy shows promise in delaying progression the disease, it has the disadvantage that only 2% of the administered drug reaches the lungs. In addition, IV replacement requires weekly visits for treatment. Testing is now underway to investigate direct application of Prolastin in the lungs by inhalation. With commercial inhalation devices and deep slow inhalation, peripheral deposition of approximately 60% of aerosolized drug can be achieved. Further randomized, blinded, controlled efficacy studies are needed, though the small doses and ease of administration make inhalation therapy an attractive option.

Some manufacturers are investigating alternative sources of augmentation therapy particularly given concerns related to the limited supply of the pooled human plasma and the potential for transmission of infectious agents. Transgenic production of human alpha1-antitrypsin protein has been accomplished in sheep and goats. Recombinant technology has also been used to produce human alpha1-antitrypsin in yeast. Unfortunately, because of differences in the glycosylation of the alpha1-antitrypsin protein in the different species, these proteins are cleared rapidly from human circulation; therefore, IV administration is difficult. However, such transgenic or recombinant sources may prove useful in inhalation devices.

Other investigations have targeted the emphysematous changes in the lungs. Studies with elastase induced emphysema in rats suggested that administration of all-trans retinoic acid (ATRA) caused reversal of the emphysematous changes due to stimulation of growth of new alveoli by ATRA. Other trials are testing hyaluronic acid as individuals with emphysema have been noted to have reduced levels of hyaluronic acid in their lungs. Last, investigators are considering antioxidants, such as vitamins A, C and/or E, as potential treatments for emphysema.

The most common alpha1-antitrypsin genetic defects prevent release of the protein from hepatocytes because of inappropriate polymerization and folding. Some investigators are testing processes or medications that could promote release from the liver cells. Synthetic chaperones, such a 4-phenyl-butyric acid (4-PBA), have been used in cystic fibrosis and are being studied in alpha1-antitrypsin deficiency. Initial results show modest increases in serum alpha1-antitrypsin levels, but GI adverse effects can be dose limiting. Work is being done on molecular interventions, such as the introduction of small peptides that fit into the abnormal alpha1-antitrypsin molecule at the site where abnormal folding begins. Other approaches are to replace specific amino-acid targets in the folding site to prevent abnormal folding.

Insertion of a normal human alpha1-antitrypsin gene has been performed in muscle and liver cells. Gene-repair technologies are also being studied, as are attempts to turn off production of the abnormal gene product.


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