Emerging Therapies Targeting the Pathophysiology of Sickle Cell Disease

Preface Emerging Therapy in Hemoglobinopathies: Lessons from the Past and Optimism for the Future

Elliott P. Vichinsky, MD Editor

Hemoglobinopathies are a worldwide public health problem. Millions of people are affected, with over 400,000 annual births of new cases. Major, recent advances in understanding the complex pathophysiology of hemoglobinopathies have led to the development of several promising therapeutic options. This issue reviews these bench-to-bedside discoveries.1 The investigation of these disorders has always provided a unique window to understand basic biology and disease pathophysiology. Yet these molecular and biologic discoveries have had limited clinical impact on the hemoglobinopathy population. Supportive care, transfusion therapy, and hydroxyurea remain the only available therapies for most patients, and these options have not changed in decades. As a clinician and investigator, I am optimistic that the accomplishments described within this issue will result in decreased morbidity and improved quality of life for the patient population. However, it is important to view these discoveries in a historical context to understand the scientific chain of events that led us to these advances and the disappointment of earlier, promising therapeutic discoveries that did not achieve efficacy for the medical and patient community. Historically, clinical symptoms of hemoglobinopathies appear to be mentioned in Hippocratic writings and have long been observed in African tribal histories. Centuries ago, the diseases were given onomatopoeic names that indicate severe pain and suffering.2 The African medical literature of the 1870s referred to a disease called “ogbanjes” (“children who come and go”) because of the high infant mortality rate with this

Hematol Oncol Clin N Am 28 (2014) xiii–xviii http://dx.doi.org/10.1016/j.hoc.2014.01.001 hemonc.theclinics.com 0889-8588/14/$ – see front matter Ó 2014 Elsevier Inc. All rights reserved.

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syndrome.3 In 1910, Drs Herrick and Irons described the sickle cell erythrocyte in the peripheral smear of Dr Noel, a dental student from Granada.4 This was rapidly followed by the work of Emmel and Hahn, who demonstrated that sickling was an oxygendependent phenomenon.5 In 1934, Drs Diggs and Ching concluded that the symptoms of sickle cell disease were caused by occlusion of the microvasculature.6 Sherman, in 1940, noted that polymerization was a key factor in the sickling process and secondary vascular obstruction.7 A decade later Singer and Singer observed this polymerization was inhibited in the presence of fetal hemoglobin.8 This was followed by Hofrichter and Eaton, who found that the delay time for the initiation of deoxyhemoglobin-S polymerization was dependent on hemoglobin S concentration and the transit time of red cells.9 Sickle cell was classified as the first molecular disease by Pauling and colleagues10 in 1949, who concluded from their electrophoretic studies that the basic pathology was due to a change in the amino acid structure of hemoglobin. Ingram then identified that sickle hemoglobin differed from normal hemoglobin by a single amino acid substitution of valine for glutamic acid, utilizing the newly developed fingerprinting technique to identify amino acid changes.11 In the early 1970s, recombinant DNA technology resulted in nucleic acid sequencing showing there was an A / T DNA change in the sickle hemoglobin DNA, which changes the glutamine codon to valine.12 In 1980, the understanding that sickle cell disease is a complex vasculopathy was initiated by the seminal work of Hebbel and colleagues,13 who wrote that sickled red cells abnormally adhere to endothelium and correlate with disease severity. These observations led to the central role of ischemia reperfusion injury and inflammation in sickle cell disease pathology. In 2002, Reiter and colleagues14 noted that nitric oxide depletion in sickle cell disease is induced by free hemoglobin and amplifies the vasculopathy. Critical advances in the pathophysiology of thalassemia and iron regulation were occurring concomitantly to discoveries in sickle cell disease. Weatherall and colleagues15 utilized quantitative methods of hemoglobin synthesis to determine that defective and imbalanced globin synthesis were an essential part of the pathophysiology in the thalassemia syndromes. Finch and Sturgeon,16 in studying iron and erythrokinetics in patients, demonstrated that marked ineffective erythropoiesis is a hallmark of thalassemia and is responsible for marrow expansion and increased iron absorption regardless of body iron stores. In 1978, Hershko and colleagues17 described the toxic non-transferrin-bound fraction of plasma iron, which leads to iron-induced free radical damage. In 2001, Park and colleagues18 discovered the peptide hepcidin, which drives the increased gastrointestinal iron absorption in thalassemia. In the last 50 years, several promising therapies have been proposed based on biologic discoveries. In the 1970s, anti-sickling agents designed to impair polymerization by altering hemoglobin ligands entered clinical trials. Urea, initially claimed to decrease sickling, was ineffective in clinical trials and may have increased morbidity.19 Cyanate, which appeared to increase oxygen affinity, resulted in severe neurologic toxicity.20 Many other anti-sickling agents designed to alter noncovalent and covalent ligands were clinically ineffective. These were followed by clinical trials with membrane-active drugs designed to increase cell hydration. Initial studies with the antidiuretic hormone DDAVP were encouraging, but were discontinued due to lack of efficacy and toxicity.21 Cetiedil induced significant improvement in red cell deformability and hydration by inhibiting the Gardos pathway. Initial clinical observations were positive, but definitive pharmaceutical trials were never undertaken.22 Several other membrane-active agents were initiated. A novel Gardos channel inhibitor, senicapoc,

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significantly increased hemoglobin levels and improved red cell deformability, but increased pain in phase III trials resulted in its abrupt abandonment.23 The results of these trials support the theory of different subphenotypes of sickle cell disease with the possibility of drug-induced phenotypic shifts.24 Agents that alter red cell rheology and vascular flow entered clinical studies in the early 1980s. Pluronic F-68 (poloxamer 188), a nonionic copolymer surfactant, showed promise in phase II trials for acute pain but was disappointing in phase III trials, with a benefit seen only in a subpopulation of children—again suggesting that drug response may be not be the same in all populations.25 The only successful FDA-approved pharmacologic approach to sickling has been in fetal hemoglobin induction. Following the seminal observations by DeSimone and colleagues26,27 that 5-azacytidine therapy increases hemoglobin F, multiple clinical trials were undertaken with different agents. 5-Azacytidine increased hemoglobin in both thalassemia and sickle cell patients. Its utilization was abandoned because of mutagenic and carcinogenic risks. Initially, it was thought to activate hemoglobin F synthesis by increased gamma gene expression by affecting methylation. However, several studies with multiple S-phase cytoxic drugs showed a similar hemoglobin F response. It was concluded that hemoglobin F was indirectly increased due to alteration of erythroid progenitor kinetics. Hydroxyurea, the least toxic, orally available agent underwent the most clinical studies, leading to its eventual FDA approval for use in adults with sickle cell disease.28 Exciting work with butyrate and other histone deacetylase inhibitors in the mid-1980s suggested they would be efficacious. However, clinical trials were less encouraging possibly due to drug metabolism and/or inhibition of erythropoiesis.29 Stimulation of fetal hemoglobin synthesis by erythropoietin has been demonstrated for decades, but the modest response and potential toxicity have prevented larger trials.30 The biologic advances in sickle cell disease and therapeutic options described in this issue grew out of the scientific foundation described above. The first two articles give an overview of the evolving understanding of the pathophysiology. Dr Kuypers discusses the red cell membrane changes—including increased phosphatidyl serine (PS) exposure—that result in the sickle cell initiating a red cell vasculopathy. He briefly discusses potential therapies to address membrane alterations such as D-annexin binding to PS surfaces. Dr Hebbel provides an insightful discussion of how ischemia reperfusion injury is most likely responsible for much of the clinical syndrome of sickle cell disease, and he reviews the therapeutic options for ischemic reperfusion injury. Therapeutic interventions can attack sickle cell pathology from the primary mutation to its downstream effects such as inflammation and thrombosis. Drs Chandrakasan and Malik discuss the advances in gene transfer vector technology and self-inactivating lentivirus that have resulted in the initial pilot success in thalassemia. They review recent discoveries that will improve clinical options, including gene editing technology, newer vectors, and induced pleuripotent stem cells. The re-emergence of research interest in the causal relationship between decreased oxygen affinity of hemoglobin S and increased polymerization has resulted in promising pilot clinical studies with hemoglobin modifiers that increase oxygen affinity. Dr Safo and Dr Kato review the pathophysiologic effects resulting from sickle red cells exposed to low oxygen affinity and relevant therapeutic approaches, including the investigations with the aldehyde Aes-1035-HMF. For several decades, increasing fetal hemoglobin has been a major focus in the treatment of hemoglobinopathies. Except for hydroxyurea, which received FDA approval 20 years ago, there remains no other commercially available hemoglobin

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F inducer. Drs Perrine, Pace, and Fowler review the history of hemoglobin F therapeutics and the recent advances in the understanding of fetal hemoglobin regulation. They discuss the new generation of noncytotoxic hemoglobin F inducers, including shortchain fatty acids, low-dose decitabine tetrahydrouridine, benserazide, as well as combinations with epigenetic modifiers and agents that increase translation. Dr Fibach and Dr Rachmilewitz review the effects of erythropoietin administration on hemoglobin F production as well as erythropoiesis, iron utilization, and oxidative stress. They discuss potential trials of erythropoietin alone or in combination with new emerging therapies. Sickle cell disease is now considered an acute and chronic inflammatory condition. Dr Hoppe summarizes the in vitro and in vivo studies indicating the importance of inflammation in the development of its vasculopathy. Her article provides an overview of the cellular mechanisms involved in the inflammatory response and therapeutic agents that target these pathways. Discussion of key pathways involving adenosine signaling, nitric oxide/arginine dysregulation, selectins, and coagulation is expanded in individual articles. Drs Field, Nathan, and Linden review the important beneficial and detrimental effects of adenosine signaling in SCD pathophysiology. They discuss the anti-inflammatory effect of adenosine resulting from decreased activation of invariant NKT cells mediated by the adenosine A2A receptor and the proinflammatory response to binding with the adenosine A2B receptor. The in vitro and clinical studies with adenosine therapeutics are reviewed, including A2AR agonist regadenoson, and A2BR antagonist pegylated -ADA. Dr Morris reviews the recent studies that demonstrate arginine metabolomics and the dysregulation of nitric oxide hemostasis that plays an important role in the pathophysiology of sickle cell disease. The clinical benefit of arginine supplementation alone or with hydroxyurea in the treatment of leg ulcers, pulmonary hypertension, priapism, and pain is discussed. Vaso-occlusion and impaired microvascular flow characterize the pathophysiology of sickle cell disease. The adhesive interactions involving erythrocytes, the endothelium, leukocytes, and platelets are central to this process. Selectins are adhesive receptors expressed on these cells that initiate the adhesive interactions. There are multiple species of selectins involved in this process. Drs Kultar and Embury discuss the key role of endothelial P-selectin-mediated cell adhesion as an initiator of abnormal blood flow in sickle cell disease. The authors reviewed the beneficial effects observed in pilot studies with P-selectin blocking agents, including pentosan polysulfate sodium. Dr Telen provides an informative review of the importance of E- and L-selectin in sickle cell disease pathology. GMI1070, a small carbohydrate molecule that binds to selectins—particularly E-selectin, is discussed in detail with highlights of the successful early trials. Dr Pakbaz and Dr Wun highlight the contribution of hemostatic abnormalities in the process of vaso-occlusion and impaired microvascular flow. They review the data showing increased risk of thromboembolic events, the potential role of platelet inhibitors, and anticoagulants. The issue concludes with recent advances in understanding pathways that modulate erythropoiesis and iron physiology. Drs Rivella and Breda discuss the important role that JAK2 activity has in stress erythropoiesis and the potential therapeutic benefits of JAK2 inhibitors. They discuss the effects of activin signaling in hematopoiesis and the therapeutic strategies targeting deregulation of activin signaling—including clinical studies with ACE/RAP-011 and ACE536. Drs Schmidt and Fleming review the advances in understanding the hepcidin-ferroportin iron regulatory axis. They discuss new approaches to treating iron overload diseases utilizing hepcidin mimetics or by altering endogenous heparin expression. They highlight lipid nanoparticle

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encapsulated siRNA and antisense oligonucleotide ASO-mediated inhibition of TMPRSS6, and mini-hepcidin therapy. In b-thalassemia intermedia, they discuss the murine model results with transferrin therapy and hepcidin up-regulation. Elliott P. Vichinsky, MD Children’s Hospital and Research Center Oakland 747 52nd Street Oakland, CA 94609, USA E-mail address: [email protected]

REFERENCES

1. Piel FB, Hay SI, Gupta S, et al. Global burden of sickle cell anaemia in children under five, 2010-2050: modeling based on demographics, excess mortality, and interventions. PLoS Med 2013;10(7):e1001484. 2. Konotey-Ahulu FID. Hereditary qualitative and quantitative erythrocyte defects in Ghana: an historical and geographical survey. Ghana Med J 1968;7:188–9. 3. Asakitikpi AE. Born to Die: The Ogbanje Phenomenon and its Implication on Childhood Mortality in Southern Nigeria. Anthropologist 2008;10(1):59–63. 4. Savitt TL, Goldberg MF. Herrick’s 1910 case report of sickle cell anemia. The rest of the story. JAMA 1989;261(2):266–71. 5. Emmel VE. A study of erythrocytes in a case of severe anemia with elongated and sickle-shaped red blood corpuscles. Arch Intern Med 1917;20:586–98. 6. Diggs LW, Ching RE. Pathology of sickle cell anemia. South Med J 1934;27: 839–45. 7. Sherman IJ. The sickling phenomenon, with special reference to the differentiation of sickle cell anemia from the sickle cell trait. Bull Johns Hopkins Hosp 1940;67:309–24. 8. Singer K, Singer L. The gelling phenomenon of sickle cell hemoglobin: its biological and diagnostic significance. Blood 1953;8:1008–23. 9. Hofrichter J, Ross PD, Eaton WA. Kinetics and mechanism of deoxyhemoglobin S gelation: a new approach to understanding sickle cell disease. Proc Natl Acad Sci USA 1974;71:4864–8. 10. Pauling L, Itano H, Singer SJ, et al. Sickle cell anemia: a molecular disease. Science 1949;14:279–84. 11. Ingram VM. A specific chemical difference between the globins of normal human and sickle-cell anemia haemoglobin. Nature 1956;178:792–4. 12. Marotta CA, Wilson JT, Forget BG, et al. Human b-globin messenger RNA III. Nucleotide sequences derived from complementary DNA. J Biol Chem 1977; 252:5040–51. 13. Hebbel RP, Boogaerts MA, Eaton JW, et al. Erythrocyte adherence to endothelium in sickle-cell anemia. A possible determinant of disease severity. N Engl J Med 1980;302(18):992–5. 14. Reiter CD, Wang X, Tanus-Santos JE, et al. Cell-free hemoglobin limits nitric oxide bioavailability in sickle-cell disease. Nat Med 2002;8(12):1383–9. 15. Weatherall DJ, Clegg JB, Naughton MA. Globin synthesis in thalassaemia: an in vitro study. Nature 1965;208(5015):1061–5. 16. Finch CA, Sturgeon P. Erythrokinetics in Cooley’s anemia. Blood 1957;12(1): 64–73.

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17. Hershko C, Graham G, Bates GW, et al. Non-specific serum iron in thalassaemia: an abnormal serum iron fraction of potential toxicity. Br J Haematol 1978;40(2): 255–63. 18. Park CH, Valore EV, Waring AJ, et al. Hepcidin, a urinary antimicrobial peptide synthesized in the liver. J Biol Chem 2001;276(11):7806–10. 19. Treatment of sickle cell crisis with urea in invert sugar. JAMA 1974;228(9):1125–8. 20. Langer EE, Stamatoyannopoulos G, Hlastala MP, et al. Extracorporeal treatment with cyanate in sickle cell disease: preliminary observations in four patients. J Lab Clin Med 1976;87(3):462–74. 21. Charache S, Moyer MA, Walker WG. Treatment of acute sickle cell crises with a vasopressin analogue. Am J Hematol 1983;15(4):315–9. 22. Benjamin LJ, Berkowitz LR, Orringer E, et al. A collaborative, double-blind randomized study of cetiedil citrate in sickle cell crisis. Blood 1986;67(5):1442–7. 23. Ataga KI, Reid M, Ballas SK, et al. ICAS-17043-10 Investigators. Improvements in haemolysis and indicators of erythrocyte survival do not correlate with acute vaso-occlusive crises in patients with sickle cell disease: a phase III randomized, placebo-controlled, double-blind study of the Gardos channel blocker senicapoc (ICA-17043). Br J Haematol 2011;153(1):92–104. 24. Castro OL, Gordeuk VR, Gladwin MT, et al. Senicapoc trial results support the existence of different sub-phenotypes of sickle cell disease with possible druginduced phenotypic shifts. Br J Haematol 2011;155(5):636–8. 25. Orringer EP, Casella JF, Ataga KI, et al. Purified poloxamer 188 for treatment of acute vaso-occlusive crisis of sickle cell disease: a randomized controlled trial. JAMA 2001;286(17):2099–106. 26. DeSimone J, Heller P, Hall L, et al. 5-Azacytidine stimulates fetal hemoglobin synthesis in anemic baboons. Proc Natl Acad Sci USA 1982;79(14):4428–31. 27. Ley TJ, DeSimone J, Noguchi CT, et al. 5-Azacytidine increases gamma-globin synthesis and reduces the proportion of dense cells in patients with sickle cell anemia. Blood 1983;62(2):370–80. 28. Charache S, Terrin ML, Moore RD, et al. Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia. Investigators of the Multicenter Study of Hydroxyurea in Sickle Cell Anemia. N Engl J Med 1995;332(20):1317–22. 29. Perrine SP, Ginder GD, Faller DV, et al. A short-term trial of butyrate to stimulate fetal-globin-gene expression in the beta-globin disorders. N Engl J Med 1993; 328(2):81–6. 30. Al-Khatti A, Veith RW, Papayannopoulou T, et al. Stimulation of fetal hemoglobin synthesis by erythropoietin in baboons. N Engl J Med 1987;317(7):415–20.

Emerging therapy in hemoglobinopathies: lessons from the past and optimism for the future.

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