A TMPRSS6-inhibiting mAb improves disease in a β-thalassemia mouse model and reduces iron in healthy humans

β-Thalassemia is a genetic disorder arising from mutations in the β-globin gene, leading to ineffective erythropoiesis and iron overload. Ineffective erythropoiesis, a hallmark of β-thalassemia, is an important driver of iron overload, which contributes to liver fibrosis, diabetes, and cardiac disease. Iron homeostasis is regulated by the hormone hepcidin; BMP6/hemojuvelin-mediated (BMP6/HJV-mediated) signaling induces hepatic hepcidin expression via SMAD1/5, with transmembrane serine protease 6 (TMPRSS6) being a negative regulator of HJV. Individuals with loss-of-function mutations in the TMPRSS6 gene show increased circulating hepcidin and iron-refractory iron-deficiency anemia, suggesting that blocking TMPRSS6 may be a viable strategy to elevate hepcidin levels in β-thalassemia. We generated a human mAb (REGN7999) that inhibits TMPRSS6. In an Hbbth3/+ mouse model of β-thalassemia, REGN7999 treatment led to significant reductions in liver iron, reduced ineffective erythropoiesis, and showed improvements in RBC health, running distance during forced exercise, and bone density. In a phase I, doubleblind, randomized, placebo-controlled study in healthy human volunteers (NCT05481333), REGN7999 increased serum hepcidin and reduced serum iron with an acceptable tolerability profile. Our results suggest that, by both reducing iron and improving RBC function, inhibition of TMPRSS6 by REGN7999 may offer a therapy for iron overload and impaired erythropoiesis in β-thalassemia.

Authors

Institutions

Publication Details

Journal
JCI Insight
Published
2025-06-22
DOI
https://doi.org/10.1172/jci.insight.191813
Citations
2
Primary Topic
Hemoglobinopathies and Related Disorders
Type
article
Field-Weighted Citation Impact
3.25

Funders

Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
OCT
article

A TMPRSS6-inhibiting mAb improves disease in a β-thalassemia mouse model and reduces iron in healthy humans

Matthew C. Franklin, Aris N. Economides, Heinrich E. Lob, Yonaton Ray et al.
2 citations
JCI Insight
Hemoglobinopathies and Related Disorders
3.25
article

A TMPRSS6-inhibiting mAb improves disease in a β-thalassemia mouse model and reduces iron in healthy humans

Matthew C. Franklin, Aris N. Economides, Heinrich E. Lob, Yonaton Ray, John J. Flanagan, William C. Olson, Olivier Harari, Kusha Mohammadi, Harvey F. Chin, Lorah Perlee, Sylvie Rottey, Marc W. Retter, Beth Crowell, Leah Kravets, Hazem E. Hassan, Lorna A. Farrelly, Elif Kabuloglu Karayusuf, Griet Van Lancker, Jee Hae Kim, Vincent Idone, Leigh Spencer Noakes, Nikhil Singh, Kalyan C. Nannuru, Kei Saotome, Hyon J. Kim, Emily Labriola–Tompkins, Michael E. Burczynski, Nanditha Das, Marilena Preda, Sarah Hatsell, Andrew Murphy, L. R. Ivanova
article en
2 citations

Abstract

β-Thalassemia is a genetic disorder arising from mutations in the β-globin gene, leading to ineffective erythropoiesis and iron overload. Ineffective erythropoiesis, a hallmark of β-thalassemia, is an important driver of iron overload, which contributes to liver fibrosis, diabetes, and cardiac disease. Iron homeostasis is regulated by the hormone hepcidin; BMP6/hemojuvelin-mediated (BMP6/HJV-mediated) signaling induces hepatic hepcidin expression via SMAD1/5, with transmembrane serine protease 6 (TMPRSS6) being a negative regulator of HJV. Individuals with loss-of-function mutations in the TMPRSS6 gene show increased circulating hepcidin and iron-refractory iron-deficiency anemia, suggesting that blocking TMPRSS6 may be a viable strategy to elevate hepcidin levels in β-thalassemia. We generated a human mAb (REGN7999) that inhibits TMPRSS6. In an Hbbth3/+ mouse model of β-thalassemia, REGN7999 treatment led to significant reductions in liver iron, reduced ineffective erythropoiesis, and showed improvements in RBC health, running distance during forced exercise, and bone density. In a phase I, doubleblind, randomized, placebo-controlled study in healthy human volunteers (NCT05481333), REGN7999 increased serum hepcidin and reduced serum iron with an acceptable tolerability profile. Our results suggest that, by both reducing iron and improving RBC function, inhibition of TMPRSS6 by REGN7999 may offer a therapy for iron overload and impaired erythropoiesis in β-thalassemia.

JCI InsightVol. 10(12)
Regeneron (United States) (US), Ghent University Hospital (BE)
Pfizer, AstraZeneca, Regeneron Pharmaceuticals, Astellas Pharma, Ipsen
Zero hunger
Openalex Percentile: Top 8%
Hemoglobinopathies and Related Disorders
3.25
DOIOpen Access PDFOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.