Page 11 - 2020_07-Haematologica-web

Editorials
mone through exogenous preparations. Unfortunately, replacing hepcidin is not as easy as in the case, for exam- ple, of levothyroxine in hypothyroidism, or different insulin preparations in type 1 diabetes mellitus. Hepcidin is a small peptide mainly produced by the liver, consisting of only 25 amino acids including eight cysteines which form four disulfide bonds determining a highly folded structure.12 Attempts to synthesize a sufficient amount of the hormone in its natural conformation have proven exceedingly difficult.13 Moreover, the natural hormone has a short plasma half-life, being rapidly eliminated by proteolysis and renal clearance.14
An alternative approach is represented by the produc- tion of long-acting molecules, collectively called “mini- hepcidins”.15 Minihepcidins are synthetic peptides con- taining the minimal N-terminal sequence (7 to 9 amino acids) of hepcidin still able to bind ferroportin and induce its degradation, further engineered to be resistant to pro- teolysis. Minihepcidins have been used previously in mouse models of severe hemochromatosis (with knock- out of hepcidin anti-microbial peptide; HAMP-/-),16 and NTDT β-thalassemia.17 In the latter model, minihepcidins proved useful in reducing iron overload and splenomegaly, but also improved anemia by either decreasing ineffective erythropoiesis or increasing red blood cell lifespan through reduced formation of hemichromes and reactive oxygen species17 (Figure 1).
In this issue of Haematologica,18 Casu and colleagues present the first mouse model of TDT β-thalassemia available so far. Previous attempts to model this disease were hampered by the early death of the animals. To resolve this problem, using an elegant approach the authors intercrossed two previous NTDT strains (Hbbth1/th1 and Hbbth2/+) and then transplanted Hbbth1/th2 fetal liver cells into irradiated recipients to obtain Hbbth1/th2 bone marrow chimera (BMC). These mice showed a severe phenotype resembling β-thalassemia major, requiring red blood cell transfusions for survival. As in the previous NTDT mod- els, the administration of minihepcidins not only reduced splenomegaly and iron overload (especially in the heart, where it is particularly deadly), but also improved ery- thropoiesis and anemia (Figure 1). The latter effect is like- ly related to the apparent paradoxical benefit of iron restriction on thalassemic erythropoiesis, through a reduction in the synthesis of heme, which in turn decreases the production of α-globin chains and toxic hemichromes in a coordinated manner.19
The study by Casu and colleagues does, however, have several limitations. For example, minihepcidin treatment was started simultaneously with the first transfusion, i.e. before the massive iron accumulation that usually occurs in chronically transfused β-thalassemic patients. Thus, it remains to be demonstrated whether or not minihep- cidins could also be beneficial in a setting more closely resembling clinical practice, in which typical TDT patients are kept on balance within acceptable iron over- load by using iron chelators, which in turn are far from being optimal and easy to use.20 Another limitation is that the Hbbth1/th2 mice were treated with red blood cell transfu- sions only for a short period (6 weeks). Finally, these mice appear to maintain a particularly high level of iron absorption, which may not mirror what happens in
chronically transfused β-thalassemic patients.
Anyway, the question is: are we ready for hepcidin replacement therapy in the clinic? Despite the promising results of Casu and colleagues, it is still too early to say. No human study on minihepcidins is currently underway. It is unknown whether technical or economic issues will hamper the translation of minihepcidins into the clinic. While, in principle, minihepcidins could be bioavailable after oral administration,14 studies in animals used intraperitoneal or subcutaneous administration, which is not as convenient as the oral route. Interestingly, one study with a hepcidin analogue, LJPC-401, is ongoing in adult patients with genetic hemochromatosis (https://clin- icaltrials.gov/ct2/show/NCT03395704), but results are not yet available. Despite extraordinary advances toward a definitive cure for β-thalassemia, by either allogeneic hematopoietic cell transplantation21 or gene therapy,22 much of the disease’s burden occurs in low-income pop- ulations with limited access to such sophisticated resources, in which red blood cell transfusions and iron chelation remain the mainstay of therapy.23 The research by Casu and colleagues provides a proof of concept that hepcidin replacement therapy or hepcidin agonists repre- sent a fascinating and pathophysiologically sound approach24 for treating iron overload in a variety of condi- tions, including iron-loading anemias.25 In the near future, we will understand the place of such drugs in the rapidly evolving and exciting scenario of novel anti-anemic drugs, including activin type II receptor agonists26 and
others.27
References
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2. Pietrangelo A. Hemochromatosis: an endocrine liver disease. Hepatology. 2007;46(4):1291-1301.
3. Ganz T. Systemic iron homeostasis. Physiol Rev. 2013;93(4):1721- 1741.
4. Gulec S, Anderson GJ, Collins JF. Mechanistic and regulatory aspects of intestinal iron absorption. Am J Physiol Gastrointest Liver Physiol. 2014;307(4):G397-409.
5. Girelli D, Nemeth E, Swinkels DW. Hepcidin in the diagnosis of iron disorders. Blood. 2016;127(23):2809-2813.
6. Camaschella C, Nai A, Silvestri L. Iron metabolism and iron disor- ders revisited in the hepcidin era. Haematologica. 2020;105(2):260- 272.
7. Sleiman J, Tarhini A, Bou-Fakhredin R, Saliba AN, Cappellini MD, Taher AT. Non-transfusion-dependent thalassemia: an update on complications and management. Int J Mol Sci. 2018;19(1).
8. Ganz T. Erythropoietic regulators of iron metabolism. Free Radic Biol Med. 2019;133:69-74.
9. Coffey R, Ganz T. Erythroferrone: an erythroid regulator of hepcidin and iron metabolism. Hemasphere. 2018;2(2):e35.
10. Angelucci E, Barosi G, Camaschella C, et al. Italian Society of Hematology practice guidelines for the management of iron over- load in thalassemia major and related disorders. Haematologica. 2008;93(5):741-752.
11. PasrichaSR,FrazerDM,BowdenDK,AndersonGJ.Transfusionsup- presses erythropoiesis and increases hepcidin in adult patients with beta-thalassemia major: a longitudinal study. Blood. 2013;122(1): 124-133.
12. Clark RJ, Tan CC, Preza GC, Nemeth E, Ganz T, Craik DJ. Understanding the structure/activity relationships of the iron regula- tory peptide hepcidin. Chem Biol. 2011;18(3):336-343.
13. Jordan JB, Poppe L, Haniu M, Arvedson T, Syed R, Li V, et al. Hepcidin revisited, disulfide connectivity, dynamics, and structure. J Biol Chem. 2009;284(36):24155-24167.
14. SchmidtPJ,FlemingMD.Modulationofhepcidinastherapyforpri-
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