The LSD1 inhibitor RN-1 recapitulates the fetal pattern of hemoglobin synthesis in baboons (P. anubis)

Rivers, Angela; Vaitkus, Kestis; Ibanez, Vinzon; Ruiz, Maria Armila; Jagadeeswaran, Ramasamy; Saunthararajah, Yogen; Cui, Shuaiying; Engel, James Douglas; DeSimone, Joseph; Lavelle, Donald

doi:10.3324/haematol.2015.140749

Cited by 49 publications

(55 citation statements)

References 45 publications

(47 reference statements)

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“…In baboons ( P. anubis ), ChIP analysis showed that RN-1 increased the levels of activating chromatin marks (H3K4Me2, H3K4Me3 and H3K9ac) associated with the γ-globin, but not the ε-globin which suggests a specific effect of the drug on γ-globin expression. (30) In our experiments, RN-1 induction of ATG7 and other key mitophagy genes indicates that RN-1 might induce mitochondrial clearance in SCD via epigenetic up-regulation of pro-mitophagy genes. Previous mouse models with specific deletions in mitophagy genes showed a reduced survival of RBC due to mitochondria retention in RBCs.…”

Section: Discussionmentioning

confidence: 54%

Pharmacological inhibition of LSD1 and mTOR reduces mitochondrial retention and associated ROS levels in the red blood cells of sickle cell disease

Jagadeeswaran

Vazquez

Thiruppathi

et al. 2017

Experimental Hematology

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Sickle cell disease (SCD), an inherited blood disorder caused by a point mutation that renders hemoglobin susceptible to polymerization when deoxygenated, affects millions of people worldwide. Manifestations of SCD include chronic hemolytic anemia, inflammation, painful vaso-occlusive crises, multisystem organ damage, and reduced life expectancy. Part of SCD pathophysiology is the excessive formation of intracellular reactive oxygen species (ROS) in SCD red blood cells (RBCs) which accelerates their hemolysis. Normal RBC precursors eliminate their mitochondria during the terminal differentiation process. Strikingly, we observed an increased percentage of RBCs which retain mitochondria in SCD patients’ blood samples compared to healthy individuals In addition, we demonstrate that excessive levels of ROS in SCD are associated with this abnormal mitochondrial retention by an experimental SCD mouse model. Interestingly, LSD1 inhibitor RN-1 and mitophagy inducing agent mTOR inhibitor, Sirolimus, increased red blood cell lifespan and reduced ROS accumulation in parallel with reduction of mitochondria retaining RBCs in the SCD mouse model. Furthermore, gene expression analysis of SCD mice treated with RN-1 showed increased expression of mitophagy genes. Our findings suggest that reduction of mitochondria retaining RBCs may provide a new therapeutic approach to prevent excessive ROS in SCD.

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Section: Discussionmentioning

confidence: 54%

Pharmacological inhibition of LSD1 and mTOR reduces mitochondrial retention and associated ROS levels in the red blood cells of sickle cell disease

Jagadeeswaran

Vazquez

Thiruppathi

et al. 2017

Experimental Hematology

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“…LSD1 demethylates lysine 4 and lysine 9 in histone H3K4 and H3K9 respectively, during hematopoietic differentiation and was found to demethylate the HBG 5′ promotor region . RN‐1 induced HbF production in both murine and primate models but was accompanied by dose‐dependent neutropenia . Compared with hydroxyurea, RN‐1 was associated with a significant increase in F‐cells in mice, an effect similar to that seen with decitabine …”

Section: Introductionmentioning

confidence: 82%

“…RN‐1, a tranylcypromine monoamine oxidase inhibitor analog, irreversibly and selectively inhibits lysine‐specific demethylase1 (LSD1) . LSD1 demethylates lysine 4 and lysine 9 in histone H3K4 and H3K9 respectively, during hematopoietic differentiation and was found to demethylate the HBG 5′ promotor region . RN‐1 induced HbF production in both murine and primate models but was accompanied by dose‐dependent neutropenia .…”

Section: Introductionmentioning

confidence: 99%

Fetal hemoglobin in sickle cell anemia: The Arab‐Indian haplotype and new therapeutic agents

2017

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Fetal hemoglobin (HbF) has well-known tempering effects on the symptoms of sickle cell disease and its levels vary among patients with different haplotypes of the sickle hemoglobin gene. Compared with sickle cell anemia haplotypes found in patients of African descent, HbF levels in Saudi and Indian patients with the Arab-Indian (AI) haplotype exceed that in any other haplotype by nearly two-fold. Genetic association studies have identified some loci associated with high HbF in the AI haplotype but these observations require functional confirmation. Saudi patients with the Benin haplotype have HbF levels almost twice as high as African patients with this haplotype but this difference is unexplained. Hydroxyurea is still the only FDA approved drug for HbF induction in sickle cell disease. While most patients treated with hydroxyurea have an increase in HbF and some clinical improvement, 10 to 20% of adults show little response to this agent. We review the genetic basis of HbF regulation focusing on sickle cell anemia in Saudi Arabia and discuss new drugs that can induce increased levels of HbF.

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“…Other approaches are being explored, including use of lysine specific demethylase-1 inhibition, which appears effective in anima models. 10 …”

Section: Modulating Haemoglobin F and S Expressionmentioning

confidence: 99%

Developing new pharmacotherapeutic approaches to treating sickle‐cell disease

Telen

2016

ISBT Science Series

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Survival for patients with SCD has been prolonged by improvements in supportive care, including vaccinations, antibiotic prophylaxis, and overall medical management, including tra nsfusion. However, there remains only one approved, partially effective drug for sickle cell disease—hydroxyurea (hydroxycarbamide). The world desperately needs better ways of both treating and preventing the recurrent painful vaso-occlusive episodes pathognomonic of sickle cell disease as well as the end-organ damage that still leads inexorably to severely shortened life expectancies throughout the world. Based on accumulating knowledge about how the abnormal red blood cells of sickle cell disease cause the double scourge of acute painful episodes and progressive end-organ damage, both pharmaceutical enterprises and individual investigators are now pursuing multiple new avenues for treating sickle cell disease. As a result, many compounds are in active development, both in preclinical models as well as in phase I, II, and III clinical trials. These agents target many pathophysiologic processes thought to be critical in sickle cell disease, including the chemical and physical behavior of haemoglobin S, cell adhesion, coagulation pathways, platelet activation, inflammatory pathways, and upregulation of haemoglobin F expression. In addition, recent explorations of the genetic variations that predispose to certain types of sickle cell disease-related tissue injury, such as stroke or nephropathy, are expected to lead to identification of drugs targeting the pathways uncovered by such work. Thus, the next five to ten years holds a promise of new treatments for sickle cell disease.

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The LSD1 inhibitor RN-1 recapitulates the fetal pattern of hemoglobin synthesis in baboons (P. anubis)

Cited by 49 publications

References 45 publications

Pharmacological inhibition of LSD1 and mTOR reduces mitochondrial retention and associated ROS levels in the red blood cells of sickle cell disease

Pharmacological inhibition of LSD1 and mTOR reduces mitochondrial retention and associated ROS levels in the red blood cells of sickle cell disease

Fetal hemoglobin in sickle cell anemia: The Arab‐Indian haplotype and new therapeutic agents

Developing new pharmacotherapeutic approaches to treating sickle‐cell disease

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