This study evaluated hepatocyte-targeted silencing of *Tmprss6* using a GalNAc-conjugated siRNA (SLN124, 3 mg/kg monthly subcutaneous) versus oral deferiprone (1.25 mg/mL) in the NUP98-HOXD13 (NHD13) mouse model of MDS, focusing on iron overload, inflammasome activation, disease progression, and survival.
SLN124 produced the most pronounced reduction in tissue iron deposition and ASC-speck (inflammasome) abundance. Long-term SLN124 treatment significantly prolonged survival: 30% of treated mice survived beyond 450 days, versus complete mortality by Day 420 in both controls and deferiprone-treated mice.
Results are from a single preclinical mouse model (NHD13); translation to human MDS is unconfirmed. No human or clinical trial data are presented. Deferiprone dose/route may not reflect optimal human-equivalent chelation therapy.
TMPRSS6 silencing via SLN124 is not yet in clinical use, but these preclinical data suggest it may offer disease-modifying benefit beyond conventional iron chelation in MDS. Clinicians managing iron overload in MDS should watch for clinical trials of SLN124 or similar hepcidin-upregulating agents.
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