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 US 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 utilising 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 polymerisation in the liver, and subsequent liver disease.[93] ARO-AAT, an RNA interference trigger, has received fast-track designation from the US 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]