Table 1.

Gene-silencing and gene-editing therapies for ATTR-amyloidosis

Medication	Patisiran	Revusiran	Vutrisiran	Inotersen	Eplontersen	NTLA-2001
Mechanism of action	siRNA	siRNA	siRNA	ASO	ASO	CRISPR-Cas9
Dosage	80-min intravenous infusion based on body weight every 3 weeks: < 100 kg = 0.3 mg/kg; > 100 kg = 30 mg	500 mg subcutaneous injection daily for 5 days, then weekly for 18 months	25 mg subcutaneous injection every 3 months	284 mg subcutaneous injection once weekly	45 mg subcutaneous injection monthly	0.1 mg/kg or 0.3 mg/kg single intravenous infusion
Stage of approval	FDA approved for ATTRv-PN	Drug development discontinued	FDA approved for ATTRv-PN	FDA approved for ATTRv-PN	Ongoing evaluation	Ongoing evaluation
Neurological trial outcomes	APPOLO: ↓ mNIS+7 ↓ Norfolk QOL-DN ↓ COMPASS-31 ↑ Gait speed [23, 33]	NA (trial terminated early) [39]	HELLIOS-A: ↓ mNIS+7 ↓ Norfolk QOL-DN [41]	NEURO-TTR: ↓ mNIS+7 ↓ Norfolk QOL-DN ↑ QOL [24]	NA (NEURO-TTRansform ongoing) [61]	NA (awaiting trials)
Cardiology trial outcomes	APOLLO cardiac subgroup: ↓ NT-proBNP ↑ Gait speed ↓ LV wall thickness ↑ LVEDV [34] APOLLO-B: ↑6MWT [37]	NA (trial terminated early) [39]	NA (HELLIOS-B trial ongoing) [43]	NA (phase II trial ongoing) [55]	NA (CARDIO-TTRansform ongoing) [63]	NA (awaiting trials)
Potential adverse effects	Infusion related reactions Vitamin A deficiency Peripheral oedema	Increased mortality when compared to placebo	Infusion related reactions Vitamin A deficiency Nasopharyngitis Headache Urinary tract infections Dyslipidaemia	Thrombocytopenia Glomerulonephritis Infusion related reactions Vitamin A deficiency	Headache Vitamin A deficiency	Headache Vitamin A deficiency

ASO antisense oligonucleotide, ATTR transthyretin amyloidosis, CRISPR Clustered Regularly Interspaced Short Palindromic Repeats, FDA Food and Drugs Administration, ATTRv-PN variant ATTR polyneuropathy, LV left ventricular, LVEDV left ventricular end diastolic volume, mNIS+7 Modified Neuropathy Impairment Score +7, NT-proBNP N-terminal pro B-type natriuretic peptide, QOL-DN Quality of Life Questionnaire-Diabetic Neuropathy, siRNA small interfering RNA