RNA Interference Therapeutics for Hereditary Transthyretin-Mediated Amyloidosis with Neuropathy: A Systematic Review
Authors: Dave Prashil , Opeyemi Yakubu Aliu , Irfan Sohaib , Shastri Dipsa 
Published: December 2024

Introduction: Hereditary transthyretin amyloidosis (ATTRv) is a rare and rapidly progressing disease caused by autosomal dominant mutations in transthyretin (TTR) gene variants leading to the deposition of transthyretin in various organs leading to peripheral and autonomic neuropathy, cardiomyopathy, and nephropathy leading to progressive dysfunction and decline in quality of life. Currently, limited treatment options are available for ATTRv, which include orthotopic liver transplantation and transthyretin tetramer stabilizers (tafamidis or diflunisal). However, the continued deposition of wild-type transthyretin amyloid after transplantation remains challenging and limits its effectiveness. RNA interference (RNAi) inhibits hepatic TTR synthesis and stabilizes TTR tetramer configuration, preventing the release of amyloid monomers and leading to reduced formation of TTR amyloid. This systematic review focuses on the efficacy and safety of various RNAi medications in ATTRv with polyneuropathy.
Methods: An extensive literature search using PubMed, Cochrane, and ClinicalTrials.gov with the keywords “RNA interference” OR “RNA therapeutics” AND “amyloidosis” OR “hereditary amyloidosis” OR “amyloid neuropathy” was conducted. Clinical trials, abstracts, and cohort studies available as of February 2024 resulted. Four clinical trials met our inclusion criteria, which required participants to be over 18 years old, have associated neuropathy, and studies that reported a Modified Neuropathy Impairment Score +7 (mNIS+7) composite score. Demographic, efficacy, and safety data for the drugs under study was extracted. Descriptive statistics were used to compare the four drugs using R statistical software.
Results: A total of 765 patients who had diabetic neuropathy were included in this systematic review. 69.5% of the patients were male (n= 532/765). The median age of the included patients ranged from 56.25 to 60 years. 78.5% of the patients were white. 62.7% of the patients had ambulatory status as disease stage (n= 377/601). The median time to diagnosis ranged from 1.4 to 4.25 years. The median mNIS+7 composite score was 77.67 (67.6-78.05). The median Norfolk Quality of Life-Diabetic Neuropathy (QOL-DN) total score was 49.85 (46.4-57.55). Coelho et al. reported a difference in mNIS+7 and a difference in Norfolk QOL-DN score after the use of Eplontersen -24.8 (-31 to -18.6, p &lt; 0.001) and-19.7 (-25.6 to -13.8, p &lt; 0.001) respectively at 66 weeks. Benson et al. reported at 66 weeks -19.7 (-26.4 to -13, p &lt; 0.001) for the difference in mNIS+7 and -11.7 (-18.3 to -5.1, p &lt; 0.001) after the use of Inotersen. Adams et al. reported the use of Vutrisiran led to a difference of -28.6 (-34 to -23.1, p &lt; 0.001) for the mNIS+7 composite score and a difference of -21 (-27.1 to -14.9, p &lt; 0.001) for Norfolk QQL-DN score at 18 months. Duarte et al. reported the use of Patisiran caused a difference of -34 (-39.9 to -28.1, p &lt; 0.001) for the mNIS+7 composite score and a difference of -21.1 (-27.2 to -15.0, p &lt; 0.001) for Norfolk QQL-DN at 18 months. The highest serious adverse effects were reported by Benson et al. for Inotersen at 99.8% (n= 171/172). Diarrhea was the most common reported side by all four studies at 14%. The most common cause of death reported was cardiac failure.
Conclusion: RNA interference therapies, including Eplontersen, Inotersen, Vutrisiran, and Patisiran, have demonstrated significant benefits in enhancing the quality of life for patients with ATTRv and associated polyneuropathy. These treatments have shown promise in reducing neurological impairment and stabilizing disease progression, providing reassurance and confidence in their efficacy. However, careful monitoring is essential due to potential adverse effects such as diarrhea, thrombocytopenia, and glomerulonephritis. While RNAi therapies offer substantial symptomatic relief, vigilant surveillance for side effects is crucial to optimize patient outcomes and ensure safety. Further studies, including comparative studies, are essential to establish therapeutic protocols and ensure improved quality of life for patients with ATTRv.