Editing Approaches to Treat Alpha-1 Antitrypsin Deficiency

Area of Science:

• Genetics and Molecular Biology
• Genomic Medicine
• RNA Therapeutics

Background:

• Alpha-1 antitrypsin (AAT) deficiency is a genetic disorder caused by the E342K mutation, leading to severe lung and liver disease.
• The E342K mutation causes misfolded AAT protein retention in hepatocytes, reducing serum AAT levels and impairing protease inhibition, thus damaging lung tissue.
• Current treatments for lung manifestations are suboptimal, and no treatments exist for liver issues, highlighting a significant unmet medical need.

Purpose of the Study:

• To review the pathophysiology of AAT deficiency.
• To discuss emerging therapeutic strategies for AAT deficiency.
• To focus on RNA editing as a potential disease-modifying treatment.

Main Methods:

• Exploration of genomic medicine advancements for treating genetic disorders.
• Focus on RNA editing technology utilizing endogenous adenosine deaminases that act on RNA (ADARs).
• Mechanism involves directing ADARs to the E342K mutation site for adenosine to inosine conversion.

Main Results:

• RNA editing can correct the E342K mutation at the RNA level.
• The adenosine to inosine change is translated as guanine, restoring the wild-type amino acid sequence.
• This process is expected to restore AAT secretion and function, potentially treating both liver and lung disease.

Conclusions:

• RNA editing represents a promising disease-modifying therapeutic approach for Alpha-1 antitrypsin deficiency.
• This technology has the potential to address the underlying cause of both hepatic and pulmonary manifestations.
• Further development of RNA editing could significantly improve outcomes for patients with AAT deficiency.