Efficacy and Safety of RNA Interference Therapies/Protein Stabilizers for Transthyretin Amyloidosis with Polyneuropathy: A Systematic Review and Meta-analysis
Fahad Amin1, Rohama Rehman1, Fatima Rasool1, Hafiza Maheen Fatima1
1King Edward Medical University
Objective:
This systematic review and meta-analysis aimed to evaluate and compare the efficacy and safety of RNA interference (RNAi) therapies and protein stabilizers in patients with transthyretin amyloidosis with polyneuropathy (ATTR-PN), synthesizing evidence from randomized controlled trials to inform clinical decision-making and identify differences between these two therapeutic mechanisms.
Background:
Transthyretin amyloidosis with polyneuropathy (ATTR-PN) is a progressive hereditary disorder caused by misfolded transthyretin deposition, leading to severe neuropathy and multisystem failure. Two therapeutic strategies exist: RNA interference therapies suppressing transthyretin production and stabilizers preventing tetramer dissociation. Comprehensive comparative evidence across clinical outcomes remains limited, necessitating systematic synthesis to inform treatment selection.
Design/Methods:
This systematic review followed PRISMA 2020 guidelines. Four electronic databases were searched through August 2025 for randomized controlled trials evaluating RNAi therapies or transthyretin stabilizers versus placebo in ATTR-PN patients. Primary outcomes included neuropathy impairment (mNIS+7) and quality of life (Norfolk QOL-DN). Secondary outcomes were modified BMI, disability (R-ODS), gait speed (10-MWT), and treatment discontinuation due to adverse events. Study quality was assessed using Cochrane RoB 2.0. Random-effects models pooled mean differences for continuous outcomes and risk ratios for dichotomous outcomes with 95% confidence intervals.
Results:
Four RCTs involving 716 patients (499 intervention, 217 placebo) were included. Interventions significantly improved neuropathy impairment (mNIS+7: MD −26.93, 95% CI −32.77 – −21.09, P<0.0001). Quality of life improved substantially (Norfolk QOL-DN: MD −18.47, 95% CI −22.78 – −14.16, P<0.0001). Gait speed increased (MD 0.28 m/s, 95% CI 0.20–0.36, P<0.0001), modified BMI improved (MD 112.60, 95% CI 79.02–146.18, P<0.0001), and disability scores decreased (R-ODS: MD 8.63, 95% CI 7.19–10.07, P<0.0001). Treatment discontinuations were reduced 63% versus placebo (RR 0.37, 95% CI 0.14–0.97, P=0.04).
Conclusions:
Transthyretin-targeting therapies improve neuropathy, quality of life, and functional outcomes, with RNAi showing greater efficacy. Head-to-head trials are needed to better define comparative risk-benefit profiles.
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