Neurological Efficacy and Safety of RNA Therapeutics in Hereditary Transthyretin Amyloidosis (hATTR): A Systematic Review and Meta-analysis
Maha Sajjad1, Huzaifa Nawaz2, Sajjad Ul Hasan3, Rabia Ashraf4, Riya Bhagwan5, Hassan Ijaz1, Ayesha Ejaz1, Hifza Qadeer ud din6, Amna Hussain7, Aizaz Ali8, Hafiz Sohail Ashraf9
1King Edward Medical University, 2Services Institute of Medical Sciences (SIMS), Ghaus-ul-Azam Jail Road, Lahore, Pakistan 54000, 3Amna Inayat Medical College, Sheikhupura, Pakistan, 4Karachi Medical and Dental College, Karachi, Pakistan, 5Dow University of Health Sciences, 6Jinnah Sindh Medical University, Karachi, Pakistan, 7Liaquat University of Medical and Health Sciences, Jamshoro, Pakistan, 8Khyber Medical College, Peshawar, Pakistan, 9Carle foundation Hospital Urbana Illinois
Objective:
To evaluate the neurological efficacy and safety of RNA therapeutics in hATTR patients.
Background:
Hereditary transthyretin amyloidosis (hATTR) is a progressive disease caused by mutations in the transthyretin (TTR) gene. These mutations result in misfolded TTR proteins that deposit as amyloid in peripheral nerves, heart, and gastrointestinal tract. Recently, RNA-based therapies like small interfering RNAs (siRNAs) and antisense oligonucleotides (ASOs) have been approved for treating hATTR.
Design/Methods:
A comprehensive search on Medline, Cochrane Library, and ClinicalTrials.gov was conducted from inception to August 14, 2024. Primary outcomes included changes in Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QoL-DN) score, modified Neuropathy Impairment Score+7 (mNIS+7), and modified body mass index (mBMI). Safety endpoints encompassed adverse events, serious adverse events, and all-cause mortality. Continuous and dichotomous outcomes were analyzed using mean differences (MD) and risk ratios (RR), respectively, with 95% confidence intervals (CI), under a random-effects model.
Results:
Four randomized controlled trials involving 842 participants (568 receiving RNA therapeutics; 274 receiving a placebo) were included. Compared to placebo, RNA therapeutics demonstrated significant improvements in Norfolk QoL-DN (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%). RNA therapeutics also exhibited better preservation of mBMI (MD: 114.98; 95% CI: 90.64–139.32; p<0.00001; I²=59%). No significant differences were observed in the risk of adverse events (RR: 0.89; 95% CI: 0.69–1.15; p=0.36; I²=34%), serious adverse events (RR: 0.70; 95% CI: 0.31–1.58; p=0.39; I²=20%), and all-cause mortality (RR: 0.70; 95% CI: 0.31–1.58; p=0.39; I²=20%).
Conclusions:
RNA therapeutics effectively slow neurological progression and improve quality of life in hATTR patients, with a favorable safety profile comparable to placebo. Subgroup analyses indicated superior efficacy of siRNAs over ASOs. These findings support the use of RNA therapeutics as an effective and well-tolerated treatment option for hATTR.
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