RNAi Therapies Offer New Hope for Patients With Hereditary Transthyretin Amyloidosis

RNA interference (RNAi)-based treatments for hereditary transthyretin amyloidosis (ATTR) have shown remarkable promise, offering new hope for patients with this rare but devastating genetic disorder, according to a study published in Cureus.

Recent advancements in RNAi technology have led to the development of several groundbreaking treatments for ATTR, a condition characterized by the buildup of abnormal protein deposits in various organs. Four FDA-approved RNAi medications—patisiran, vutrisiran, inotersen, and eplontersen—have demonstrated significant efficacy in clinical trials, potentially transforming the landscape of ATTR treatment.

“Overall data demonstrate the safety and efficacy of these RNAi medications; however, a thorough understanding of each drug is essential for appropriate clinical application,” wrote Prashil Dave, MD, Internal Medicine, State University of New York Downstate Health Sciences University in New York, USA, and coauthors.

Patisiran, the first siRNA drug approved for ATTR, has shown impressive results in reducing transthyretin (TTR) protein levels and improving neurological symptoms. In the APOLLO trial, patisiran-treated patients experienced substantial improvements in neuropathy and quality of life compared to placebo. Vutrisiran, a newer subcutaneous treatment, has also demonstrated potent and sustained TTR reduction with a favorable safety profile.

Inotersen and eplontersen, both antisense oligonucleotides, have shown similar promise. The NEURO-TTR trial for inotersen reported significant improvements in neurological function and quality of life measures. Eplontersen, in the NEURO-TTRansform trial, not only reduced serum TTR levels but also showed potential benefits for patients with ATTR cardiomyopathy.

These RNAi-based treatments represent a paradigm shift from purely symptomatic management to targeted therapy that addresses the root cause of ATTR. By reducing the production of both wild-type and variant TTR proteins, these medications offer a more comprehensive approach to treating the disease.

Looking ahead, researchers are exploring even more innovative approaches. CRISPR-based gene-editing therapies and novel antibody treatments aimed at removing existing amyloid deposits are currently in development, potentially offering additional options for patients with ATTR.

As research continues, the combination of TTR stabilizers, gene-silencing therapies, and anti-seeding inhibitors may provide a multi-pronged approach to halting disease progression and improving outcomes for those affected by this challenging condition.

“These new FDA-approved drugs for ATTR, known for their reasonable safety profile and efficacy, expand the boundaries of ATTR management,” the study authors concluded.

Reference

Dave P, Anand P, Kothawala A, et al. RNA interference therapeutics for hereditary amyloidosis: a narrative review of clinical trial outcomes and future directions. Cureus. 2024;16(6):e62981. doi:10.7759/cureus.62981