Treating hereditary transthyretin amyloidosis: Present & future challenges

Area of Science:

• Genetics
• Pharmacology
• Neurology

Background:

• Hereditary transthyretin amyloidosis (ATTRv) is a rare, lethal, autosomal dominant adult-onset genetic disorder.
• Caused by mutations in the TTR gene, leading to a gain-of-function (GOF).
• Limited therapeutic options historically, primarily liver transplantation and TTR-stabilizers.

Purpose of the Study:

• To review recent therapeutic breakthroughs in ATTRv treatment.
• To highlight the impact of novel gene-silencing therapies.
• To discuss the potential of these therapies for other genetic disorders.

Main Methods:

• Review of recent clinical trials and commercially available treatments for ATTRv.
• Focus on small interfering RNA (siRNA) and antisense oligonucleotide (ASO) therapies targeting TTR mRNA.
• Evaluation of emerging treatments like CRISPR-Cas9 gene editing.

Main Results:

• Significant advancements in ATTRv treatment with the development of effective siRNA and ASO therapies.
• Commercially available treatments (patisiran, inotersen) have dramatically improved neurological outcomes.
• Ongoing trials for vutrisiran, eplontersen, and CRISPR-Cas9 show promising results.

Conclusions:

• Recent therapeutic developments represent a paradigm shift for ATTRv, transforming it from a lethal to a treatable disorder.
• siRNA, ASO, and CRISPR-Cas9 therapies offer new hope for ATTRv patients.
• These approaches provide a proof-of-concept for treating other gain-of-function genetic disorders.