Editing approaches to treat Alpha-1 Antitrypsin Deficiency (AATD).

Abstract

TOPIC IMPORTANCE Alpha-1 antitrypsin (AAT) deficiency (AATD) is a genetic disorder most commonly due to a single G to A point mutation, leading to debilitating lung and/or liver disorders and is associated with increased mortality. The E342K point mutation causes a conformational change of the AAT protein resulting in its retention in liver hepatocytes. This reduces AAT secretion into the serum resulting in higher protease activities due to the lack of inhibition from AAT, causing damage to healthy lung tissue. The current standard of care for lung manifestations involves weekly intravenous augmentation therapy and is considered sub-optimal for these patients. Furthermore, there is currently no approved treatment for liver manifestations. The unmet medical need for AATD patients remains high and new treatment options are needed to treat the underlying disease etiology. REVIEW FINDINGS Advances in genomic medicines may enable treatment by editing the DNA or RNA sequence to produce wild-type AAT instead of the mutated AAT caused by the E342K mutation. One approach can be achieved by directing endogenous Adenosine Deaminases that act on RNA (ADARs) to the E342K RNA site, where they catalyze adenosine to inosine conversion through a process known as RNA editing. The A-I RNA change will be read as a G during protein translation, resulting in an altered amino acid and restoration of wild-type AAT secretion and function. SUMMARY In this review, we will discuss the pathophysiology of AATD and emerging treatment options with particular focus on RNA editing as a disnd have stock options in ease-modifying treatment for both liver and lung disease.