Neurological efficacy and safety of RNA therapeutics in hereditary transthyretin amyloidosis: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND

Hereditary transthyretin amyloidosis (hATTR) is caused by mutations in the transthyretin (TTR) gene, which lead to the aggregation of misfolded TTR protein and amyloid accumulation in the peripheral nerves, heart, and gastrointestinal tract. Recently, RNA therapeutics, including small interfering RNAs (siRNAs) and antisense oligonucleotides (ASOs), have been approved for treating patients with hATTR.

OBJECTIVES

To assess the neurological efficacy and safety of RNA therapeutics in hATTR patients.

DESIGN

Systematic review and meta-analysis.

DATA SOURCES AND

METHODS

A systematic literature search was conducted on PubMed, Cochrane, and ClinicalTrials.gov from inception to August 14, 2024. Outcomes included changes from baseline in the Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QOL-DN) score and the modified Neuropathy Impairment Score +7 (mNIS + 7), modified body mass index (mBMI), adverse effects, serious adverse events, and all-cause mortality.

RESULTS

Our study included four RCTs with 842 patients (568 in the RNA therapeutics group and 274 in the placebo group). RNA therapeutics significantly improved Norfolk QoL-DN (mean difference (MD), -18.79; 95% CI, -22.32 to -15.25; p < 0.00001; I2 = 28%) and mNIS + 7 scores (MD, -26.90; 95% CI, -31.67 to -22.13; p < 0.00001; I2 = 61%), with significant preservation of mBMI (MD, 114.98; 95% CI, 90.64-139.32; p < 0.00001; I2 = 59%) compared to placebo. There were no significant differences between the two groups regarding the risk of adverse effects (risk ratio (RR), 0.89; 95% CI, 0.69-1.15; p = 0.36; I2 = 34%), serious adverse effects (RR, 0.70; 95% CI, 0.31-1.58; p = 0.39; I2 = 20%), and all-cause mortality (RR, 0.70; 95% CI, 0.31 to 1.58; p = 0.39; I2 = 20%).

CONCLUSION

RNA therapeutics are effective and well-tolerated in patients with hATTR, significantly improving quality of life and the progression of neurological impairment. siRNAs demonstrate better outcomes compared to ASOs.

TRIAL REGISTRATION: PROSPERO (CRD42024568346).