RNAi therapeutics for diseases involving protein aggregation: fazirsiran for alpha-1 antitrypsin deficiency-associated liver disease

ABSTRACT

Introduction

Therapeutic agents that prevent protein misfolding or promote protein clearance are being studied to treat proteotoxic diseases. Among them, alpha-1 antitrypsin deficiency (AATD) is caused by mutations in the alpha-1 antitrypsin (SERPINA1) gene. Fazirsiran is a small interfering RNA (siRNA) that is intended to address the underlying cause of liver disease associated with AATD through the RNA interference (RNAi) mechanism.

Areas covered

This article describes the role of misfolded proteins and protein aggregates in disease and options for therapeutic approaches. The RNAi mechanism is discussed, along with how the siRNA therapeutic fazirsiran for the treatment of AATD was developed. We also describe the implications of siRNA therapeutics in extrahepatic diseases.

Expert opinion

Using RNAi as a therapeutic approach is well suited to treat disease in conditions where an excess of a protein or the effect of an abnormal mutated protein causes disease. The results observed for the first few siRNA therapeutics that were approved or are in development provide an important promise for the development of future drugs that can address such conditions in a specific and targeted way. Current developments should enable the use of RNAi therapeutics outside the liver, where there are many more possible diseases to address.

Plain Language Summary

When certain proteins in the body are not produced correctly, it can result in disease. Examples of such diseases include alpha-1 antitrypsin deficiency (AATD), hereditary transthyretin amyloidosis (ATTR), amyotrophic lateral sclerosis (ALS), Alzheimer’s disease, and Parkinson’s disease, where misfolded proteins can form harmful aggregates. Research is underway to develop new therapies such as small interfering RNA (siRNA), antisense oligonucleotides, monoclonal antibodies, clustered regularly interspaced short palindromic repeats (CRISPR), and small molecule protein modulators to prevent protein aggregates. An example of an experimental siRNA therapy for patients with AATD is fazirsiran, designed to prevent the production of mutated alpha-1 antitrypsin (Z-AAT) and allows the liver to clear previously accumulated Z-AAT protein, which is believed to be responsible for causing AATD liver disease. This review summarizes the development of fazirsiran and describes how it helps our understanding and treatment of diseases associated with protein aggregation.

KEYWORDS:

• Alpha-1 antitrypsin deficiency
• ARO-AAT
• fazirsiran
• small interfering RNA
• TAK999

Article highlights

• Protein aggregation leading to organ dysfunction has been linked to multiple disorders, such as alpha-1 antitrypsin deficiency (AATD), hereditary transthyretin amyloidosis (ATTR), and common neurodegenerative disorders.

• Therapeutic approaches are being studied to prevent protein misfolding, reduce the synthesis of misfolded proteins, or promote the clearance of protein aggregation. These approaches include the use of small interfering RNA (siRNA), antisense oligonucleotides, monoclonal antibodies, clustered regularly interspaced short palindromic repeats (CRISPR), and small molecule protein modulators.

• An example of a hepatocyte-targeted siRNA is fazirsiran, designed to silence expression of alpha-1 antitrypsin (AAT) messenger RNA (mRNA) in hepatocytes and thus reduce the synthesis of the Z AAT protein, which causes liver disease in patients with AATD.

• Results from an open-label Phase 2 clinical study of fazirsiran in patients with AATD demonstrated a reduction of Z-AAT concentrations in serum and liver and concurrent improvements in liver enzyme concentrations. Fazirsiran was well tolerated with an acceptable safety profile in clinical studies. A placebo-controlled Phase 2 study in patients with AATD is currently ongoing.

• siRNA therapeutics are also being evaluated in targets other than the liver. These targets include muscle, the central nervous system (CNS), eyes, and lungs.

Declaration of interest

Dr. Strnad received grant support and lecture fees from Grifols and CSL Behring, grant support and advisory board fees from Arrowhead Pharmaceuticals and Dicerna Pharmaceuticals, grant support from Vertex Pharmaceuticals, advisory board fees from GSK, Novo Nordisk, Intellia Pharmaceuticals, and Ono Pharmaceuticals, and advisory board fees and lecture fees from Takeda Pharmaceuticals. Dr. San Martin is an employee of Arrowhead Pharmaceuticals, Inc and is an Arrowhead Pharmaceuticals, Inc. shareholder. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This work was supported by the DFG grants STR1095/6-1 and SFB 1382 (ID 403224013).