SLN124, a GalNac‐siRNA targeting transmembrane serine protease 6, in combination with deferiprone therapy reduces ineffective erythropoiesis and hepatic iron‐overload in a mouse model of β‐thalassaemia

Vadolas, Jim; Ng, Garrett Z.; Kysenius, Kai; Crouch, Peter J.; Dames, Sibylle; Eisermann, Mona; Nualkaew, Tiwaporn; Vilcassim, Shahla; Schaeper, Ute; Grigoriadis, George

doi:10.1111/bjh.17428

Cited by 16 publications

(20 citation statements)

References 48 publications

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“…To the best of our knowledge, RPM loss was not extensively studied in a mouse model of thalassemia. However, interestingly, thalassemic mice display enhanced splenic Perls’-stained deposits that appear extracellular and are not amenable to iron chelation therapy (Sanyear et al, 2020; Vadolas et al, 2021), possibly resembling those identified by the present study.…”

Section: Discussionsupporting

confidence: 73%

Impaired iron recycling from erythrocytes is an early hallmark of aging

Mandal

Slusarczyk

Zurawska

et al. 2022

Preprint

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Aging affects iron homeostasis and erythropoiesis, as evidenced by tissue iron loading in rodents and common anemia in the elderly. Since red pulp macrophages (RPMs) continuously process iron, their cellular functions might be susceptible to age-dependent decline, affecting organismal iron metabolism and red blood cells (RBCs) parameters. However, little is known about the effects of aging on the functioning of RPMs. To study aging RPMs, we employed 10-11-months-old female mice that show serum iron deficiency and iron overload primarily in spleens compared to young controls. We observed that this is associated with iron loading, oxidative stress, diminished mitochondrial and lysosomal activities, and most relevantly, decreased erythrophagocytosis rate in RPMs. We uncovered that these impairments of RPMs lead to the retention of senescent RBCs in the spleen, their excessive local hemolysis, and the formation of iron- and heme-rich large extracellular protein aggregates, likely derived from damaged RBCs and RPMs. We further found that feeding mice an iron-reduced diet alleviates iron accumulation and reactive oxygen species build-up in RPMs, restores mitochondrial and lysosomal functions, and improves their ability to clear erythrocytes. Consequently, this diet improves splenic RBCs fitness, limits hemolysis and formation of iron-rich aggregates, normalizes splenic iron levels, and tends to increase serum iron availability in aging mice. Mechanistically, using readouts from aged RPMs and in vitro cultures of RPM-like cells, we show that diminished erythrophagocytic activity of RPMs can be attributed to a combination of increased iron levels, reduced expression of heme-catabolizing enzyme heme oxygenase 1 (HO-1), and endoplasmic reticulum stress. Taken together, we identified RPM dysfunction as an early hallmark of physiological aging and demonstrated that dietary iron reduction improves iron turnover efficacy.

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Section: Discussionsupporting

confidence: 73%

Impaired iron recycling from erythrocytes is an early hallmark of aging

Mandal

Slusarczyk

Zurawska

et al. 2022

Preprint

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“…Similar to patients with TDT, the impact of such therapies on iron overload prevention versus reduction, in the context of iron chelation therapy, will need to be carefully analyzed and interpreted as more trial data become available. At least data from animal models indicate that effects can be synergistic with the use of iron chelation therapy 107–110 …”

Section: Expert Commentarymentioning

confidence: 99%

“…At least data from animal models indicate that effects can be synergistic with the use of iron chelation therapy. [107][108][109][110] Lastly, all novel developments need to go in parallel with programs that ensure access to patients in resource-limited countries, since the majority of β-thalassemia patients live in such regions.…”

Section: Expert Commentarymentioning

confidence: 99%

2021 update on clinical trials in β‐thalassemia

Musallam¹,

Bou‐Fakhredin

Cappellini

et al. 2021

American J Hematol

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The treatment landscape for patients with β-thalassemia is witnessing a swift evolution, yet several unmet needs continue to persist. Patients with transfusiondependent β-thalassemia (TDT) primarily rely on regular transfusion and iron chelation therapy, which can be associated with considerable treatment burden and cost.Patients with non-transfusion-dependent β-thalassemia (NTDT) are also at risk of significant morbidity due to the underlying anemia and iron overload, but treatment options in this patient subgroup are limited. In this review, we provide updates on clinical trials of novel therapies targeting the underlying pathology in β-thalassemia, including the α/non-α-globin chain imbalance, ineffective erythropoiesis, and iron dysregulation. | INTRODUCTIONThe β-thalassemias are a group of inherited disorders of hemoglobin (Hb) synthesis characterized by chronic anemia of varying severity.The degree of anemia relies on several genetic and environmental factors and determines the need for regular transfusion therapy. It is now common practice to classify patients as having transfusion-The TDT patients (β-thalassemia major and severe forms of HbE/β-thalassemia) are those who commonly present in early childhood with severe anemia and require lifelong transfusion therapy for survival. 1 Although the introduction of transfusions improved survival in TDT patients, it did not come without its own side-effect, systemic iron overload leading to end-organ damage and increased mortality from cardiac or hepatic disease. [2][3][4] Advances in iron chelation therapy and the introduction of MRI techniques to detect organ-specific iron overload have led to improved management and patient outcomes. 5,6 Still, TDT comes with considerable burden to the patient, clinician, and overall healthcare system owing to persistent morbidity and high healthcare utilization, poor access to optimal care and high treatment cost especially in resource-limited countries, and several unmet needs in terms of efficacy, safety and adherence to conventional therapies. 7 Allogeneic hematopoietic stem-cell transplantation (HSCT) has been used successfully for the past few decades to offer curative therapy for patients with TDT, but is only available to a minority of patients with compatible donors. 1 Patients with NTDT (β-thalassemia intermedia and mildmoderate forms of HbE/β-thalassemia) usually present later in childhood or even in adolescence with mild-moderate anemia that does not require immediate placement on a regular transfusion program. 1,8 Progress made over the past few decades has indicated that the diagnosis of NTDT carries greater morbidity than previously recognized.Ineffective erythropoiesis and anemia have been linked to an array of morbidities stemming from chronic hypoxia and an established hypercoagulable state. 1 Patients with Hb levels < 10 g/dl are at an increased risk of morbidity development, and variations of 1 g/dl can change a patient's morbidity risk. 9,10 There are currently no approved agents for the management of anem...

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“…The inhibition of hepcidin mediated by Erfe allows iron absorption and recirculation, increasing its availability for physiological and pathological processes [29,32]. Besides, and independently of Erfe, hepcidin is regulated by matriptase-2, a transmembrane serine protease encoded by the gene TMPRSS6, whose inactivation by deletion or silencing improves IE in a mouse model of thalassaemia [33][34][35]. (2) A significant contribution to the total amount of circulating iron is due to haemolysis.…”

Section: Iron Metabolism Dysregulationmentioning

confidence: 99%

“…Parallelly, SLN124 was developed based on a similar approach. After showing promising results in the preclinical phase [35], it has recently entered a first-in-human phase 1 trial on patients affected by NTDT (NCT04176653).…”

Section: Inhibitors Of Tmprss6mentioning

confidence: 99%

Ineffective Erythropoiesis in β-Thalassaemia: Key Steps and Therapeutic Options by Drugs

Longo

Piolatto

Ferrero

et al. 2021

IJMS

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β-thalassaemia is a rare genetic condition caused by mutations in the β-globin gene that result in severe iron-loading anaemia, maintained by a detrimental state of ineffective erythropoiesis (IE). The role of multiple mechanisms involved in the pathophysiology of the disease has been recently unravelled. The unbalanced production of α-globin is a major source of oxidative stress and membrane damage in red blood cells (RBC). In addition, IE is tightly linked to iron metabolism dysregulation, and the relevance of new players of this pathway, i.e., hepcidin, erythroferrone, matriptase-2, among others, has emerged. Advances have been made in understanding the balance between proliferation and maturation of erythroid precursors and the role of specific factors in this process, such as members of the TGF-β superfamily, and their downstream effectors, or the transcription factor GATA1. The increasing understanding of IE allowed for the development of a broad set of potential therapeutic options beyond the current standard of care. Many candidates of disease-modifying drugs are currently under clinical investigation, targeting the regulation of iron metabolism, the production of foetal haemoglobin, the maturation process, or the energetic balance and membrane stability of RBC. Overall, they provide tools and evidence for multiple and synergistic approaches that are effectively moving clinical research in β-thalassaemia from bench to bedside.

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SLN124, a GalNac‐siRNA targeting transmembrane serine protease 6, in combination with deferiprone therapy reduces ineffective erythropoiesis and hepatic iron‐overload in a mouse model of β‐thalassaemia

Cited by 16 publications

References 48 publications

Impaired iron recycling from erythrocytes is an early hallmark of aging

Impaired iron recycling from erythrocytes is an early hallmark of aging

2021 update on clinical trials in β‐thalassemia

Ineffective Erythropoiesis in β-Thalassaemia: Key Steps and Therapeutic Options by Drugs

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