Alpha-1 antitrypsin deficiency - Emerging treatments

Inhaled AAT augmentation therapy

Initial studies indicate that inhaled AAT augmentation therapy may provide sufficient AAT to reach normal concentrations in the lung fluid.[84] Difficulties of using this modality include poor equality of distribution in lung tissue, and penetration of AAT into interstitial tissue.[85][86]

Recombinant AAT augmentation/leukoprotease inhibitors

Recombinant AAT has been developed and seems efficacious in vitro.[87] Research evaluating the effectiveness of INBRX-101 (a recombinant human AAT-Fc fusion protein) was completed in one phase 1 trial with encouraging data regarding safety and tolerability as well as maintaining normal levels of AAT in the plasma.[88] Larger studies are starting now in the US and Europe.[87] INBRX-101 has been granted orphan drug designation in the US. Orally bioavailable synthetic inhibitors of neutrophil elastase (e.g., alvelestat) have also been developed and studies are under way.[89][90] Alvelestat has received fast-track designation by the Food and Drug Administration (FDA).

Gene therapy

Cytomegalovirus vectors have been used to transduce AAT DNA into muscle cells with sustained AAT production for 15 weeks; retroviral transfection of AAT cDNA to lung epithelium has yielded subtherapeutic AAT levels.[91][92] Multiple other modalities to alter genetic sequences are being explored in early works. More work is needed in this area, especially given the mutagenic risks with some viral vectors.

Post-transcription message modification (mRNA editing)

Several companies are utilizing technology to alter the transcribed Z DNA messenger RNA into the correct M message to be translated by the normal protein manufacturing mechanisms.

Post-transcriptional gene silencing

RNA interference mediated via small interfering RNA (siRNA) is being examined to prevent the AAT polymerization in the liver, and subsequent liver disease.[93] ARO-AAT, an RNA interference trigger, has received fast-track designation from the FDA and is currently undergoing phase 2/3 trials.[94]

Lung volume reduction surgery (LVRS)

In small studies those managed medically have better outcomes than those undergoing surgery.[95] LVRS is more effective in those with emphysema who are not AAT-deficient; further studies in patients with AAT deficiency are needed.[10][38]

Endobronchial valves

In the US, two endobronchial valves have been approved for emphysema. The EMPROVE study had a sub-study of 20 AAT patients who had similar results as non-AAT deficient patients.[96][97][98] The European Respiratory Society statement states that endobronchial valves may be considered in select patients with AAT deficiency, but further studies are needed.[8] The Thoracic Society of Australia and New Zealand position statement does not recommend their use outside of clinical trials.[10]