Presentation is loading. Please wait.

Presentation is loading. Please wait.

Erythropoietin-stimulating agents resistance and new anemia therapies

Similar presentations


Presentation on theme: "Erythropoietin-stimulating agents resistance and new anemia therapies"— Presentation transcript:

1 Erythropoietin-stimulating agents resistance and new anemia therapies
Narrative Review Erythropoietin-stimulating agents resistance and new anemia therapies Fellow 潘恆之 /VS 鄭昌錡

2 ESA resistance and new anemia therapy
Fellow 潘恆之/ Dr.鄭昌錡

3 Outline Introduction EPO resistance New anemia therapies

4 Hemotologic Aspects of Kidney Disease
Introduction Brenner & Rector’s The Kidney 9th Edition Chapter 56 Hemotologic Aspects of Kidney Disease

5 Introduction Definition of anemia in CKD:
Hgb <13.5 g/dl for male; Hgb <12.0 g/dl for female Erythropoietin-stimulating agents: Recombinant human erythropoietin was introduced as a treatment for the anemia associated with chronic kidney disease (CKD) since 1989. Erythropoietin therapy rendered many patients free of blood transfusions with dramatic benefits on quality of life (particularly physical capacity) and other physiologic effects of increasing hemoglobin levels from ~6 g/dL up to approximately g/dL.

6 Introduction Limitations of EPO:inconveniences of the need for regular administration 3 times a week and the need to inject this protein parenterally. => Longer acting erythropoietin analogue, darbepoetin alfa (2001) and pegylated epoetin beta (2007)

7 Introduction Several studies showed that partial correction of anemia (to hemoglobin levels in the range of g/dL) was a safer strategy, reducing the risk of increased arterial and venous thromboembolism and other possible harmful effects in CKD patients. Rajiv Agarwal, Clin J Am Soc Nephrol , 2010 (5): 1340–1346

8 Large Randomized Controlled trials
Trial to Reduce Cardiovascular Events with Aranesp Therapy (TREAT) -- the first large trial to compare ESA therapy with placebo in patients with CKD not on dialysis CREATE trial

9 TREAT Objectives to determine whether treating the anemia associated with CKD with DPO to a target Hgb of 13g/DL would reduce the occurrence of primary composite endpoints – 1. CV primary end point:All- cause death, MI, stroke, CHF requiring medical attention or hospitalization for MI 2. Renal primary end point:All-cause death or progression to ESRD

10 (“rescue” darb if Hgb < 9)
TREAT: Study design Darbepoetin alfa To target Hgb 13 N=2026 4038 subjects with CKD (eGFR ≥ 20 and ≤ 60 ml/min/1.73 m2 Type 2 DM Anemia Hgb ≤ 11 g/dL Iron Replete transferrin sat ≥ 15% Randomize 1:1 Control (“rescue” darb if Hgb < 9) N=2012 Randomized, controled, double blind, international trial Stratified by baseline proteinuria and cardiovascular disease Control subjects received darbepoetin if Hgb dropped below 9 g/dL All subjects could receive RBC transfusion if needed Event driven – to conclude when 1203 subjects experienced a primary event

11 Normal Hct Caridac Trial (NHCT)

12 Cardiovascular risk Reduction by Early Anemia Treatment with Epoetin Beta (CREAT) trial

13 CHOIR study

14 Vascular access thrombosis
Hb EPO dose erythropoiesis Hb > 13 g/dL A recent meta-analysis of studies evaluating higher Hb target with the use of ESA in chronic kidney disease (CKD) suggests there is a greater risk for stroke, cardiovascular events, and mortality rate. However, it is not clear whether the adverse outcomes are related to EPO dosing, higher Hb mass, or some (hidden) variables. CV risk Mortality Stroke Vascular access thrombosis

15 Naturally Occurring Higher Hemoglobin Concentration Does Not Increase Mortality among Hemodialysis Patients Goodkin D A et al. JASN 2011;22: Among 29,796 HD patients in 12 nations 545 Endogenous EPO patients were included in each model. Adjusted risk of mortality does not differ significantly for Endogenous compared with Other patients( RR, 0.81; 95% CI, 0.66 to 0.98 RR, 0.98; 95% CI, 0.80 to 1.19 Adjusted risk of mortality does not differ significantly for Endogenous EPO patients compared with Other patients. 545 Endogenous EPO patients were included in each model. The models were stratified by region and study phase, accounted for facility clustering effects, and adjusted for age, sex, black versus other race, vintage, smoking, cause of ESRD, catheter hemoaccess, serum PTH and albumin concentrations, Kt/V, and 14 summary comorbid conditions. RR 0.94 (95% CI, 0.72 to 1.22

16 Effect of erythropoietin levels on mortality in old age: the Leiden 85-plus study
den Elzen W P et al. CMAJ 2010;182: Cumulative all- cause mortality among 428 CKD 1~2 patient aged 86 at baseline, by tertile of erythropoietin level at baseline (lowest = 3.4– 8.6 IU/L, middle = 8.7–12.3 IU/L, highest = 12.4– 103.0 IU/L). Cumulative all-cause mortality among 428 participants aged 86 at baseline, by tertile of erythropoietin level at baseline (lowest = 3.4–8.6 IU/L, middle = 8.7–12.3 IU/L, highest = 12.4–103.0 IU/L). Higher concentration of endogenous EPO => fatal outcome ↑ Excessive EPO synthesis => off-target biological consequences ↑ ?? Limitations: undiagnosed hypoxemia? Impaired bone marrow response? EPO resistance?

17 Association of Mean Weekly Epoetin Alfa Dose with Mortality Risk in a Retrospective Cohort Study of Medicare Hemodialysis Patients Am J Nephrol 2011;34:298–308 The cohort included 137,918 HD patients. Mean age was 63.2 years Relative hazards of death over mean EPO dose per week during 3-month exposure period, in patient- months with mean hemoglobin The distribution of mean EPO dose per week is displayed in the shaded area, and the referent dose is shown by the solid vertical line.

18 Oluwatoyin F. Bamgbola, Kidney international (2011) 80, 464-474
Review Pattern of resistance to erythropoietin-stimulating agents in chronic kidney disease Oluwatoyin F. Bamgbola, Kidney international (2011) 80, Uremic toxins/Oxidative stress/ Inflammation Nutrition deficiency Heavy metal Hematologic disorders Angiotensin-modulating agents EPO inhibitors

19 Erythropoietin-stimulating agents (ESA) resistance:
Hb < 11g/dL over 3 month despite of EPO dose > 400 IU/kg/wk or IU/wk (≥1.0μg/ kg for darbepoietin) 1. Age and gender: Greater need of EPO in adult females due to androgenic stimulation of erythropoiesis in males and blood loss from menstrual cycles in females.

20 The risk factors, pathogeneses, and therapeutic modulation of erythropoietin resistance in chronic kidney disease

21 Uremic toxins/Oxidative stress/Inflammation

22 Uremic toxins The mechanism is uncertain
There is fair correlation of urea nitrogen clearance with improved cytokine profiles (IL-6, CRP) and lower requirement for ESA. Uremia may be related to: Poor bone marrow response to ESA Accelerated turn over rate of RBC from altering erythrocyte morphology by inducing outward expression of the phosphatidyl-serine content of its inner membrane Uremia alters erythrocyte morphology by inducing outward expression of the phosphatidyl-serine content of its inner membrane, which is removed by circulating macrophages.19,20 In addi- tion, there is impaired cellular generation of ATP by uremic inhibition of pentose phosphate shunt and tricarboxylic acid cycle.21,22 These cells, which are depleted of ATP, manifest poor capacity for cytosolic calcium efflux and thereby inhibit mitochondrial oxidative phosphorylation, thus, setting up a vicious cycle.23,24 and progressive depletion of adenosine triphosphate (ATP) Uremic toxins -- EPO synthesis / erythroid response -- Longer effective dialysis

23 Oxidative stress Depletes the capacity of ATP generation
Downregulates the generation of hypoxic-inducible factor (HIF) protein, thereby reducing EPO synthesis. 1. Depletes the capacity of ATP generation

24 ✗ Oxidative stress *Oxidative stress downregulates the generation
of hypoxic inducible factor (HIF) protein. Haase V H Am J Physiol Renal Physiol 2010;299:F1-F13

25 Inflammation CKD pro-inflammatory cytokines: IL-6 * Pro-inflammatory cytokines such as IL-1, IL-6, INF-γ, TNF could disrupt iron recycling and absorption Oluwatoyin F. Bamgbola, Kidney international (2011) 80, DMT 1, divalent methyl transporter-1 Process of physiological iron recycling involving macrophages and enterocytes

26 Inflammation * Pro-inflammatory cytokines promote EPO resistence by activation of suppressor of cytokine signaling and inhibition of nuclear factor κB 4.5% USA dialysis patient had at least one failed allograft. Transplant rejection, persistent elevation of inflammatory indices and intractable anemia despite of large doses of ESA => nephrectomy is a reasonable arrpoach. *Failed allograft – nephrectomy is a reasonable approach for transplant rejection with persistent elevation of inflammatory indices and intractable anemia. * Dialysis catheters Pro-inflammatory cytokines (+) SOCS, suppressor of cytokine signaling; STAT-5 signal transducer and activator of transcription-5 Oluwatoyin F. Bamgbola, Kidney international (2011) 80, Erythropoietin receptor activation and intracellular signal transduction

27 Inflammation Failed allograft – nephrectomy is a reasonable approach for transplant rejection with persistent elevation of inflammatory indices and intractable anemia. Dialysis catheters – additional sources of oxidative inflammation are the use of per-cath and synthetic grafts as vascular access in HD subjects.

28 Nutrition deficiency 1. Iron 2. Folate 3. Vitamin C

29 Nutrients deficiency Iron
Principally due to poor diet, frequent blood sampling and high frequency of infection Annual loss of 2g of elemental Fe among HD patient Diagnosis: serum iron < 100 mg/dl, TSAT <20%, and serum Ferritin < 100mg/dl ~ at least 2 indices Treatment: 1. Iron therapy 2. Vit-C – mobilize iron from RES (hold if serum ferritin > mg/dl) Vit-C – mobilize iron from RES

30 Nutrients deficiency Folate
Principally due to poor gastrointestinal absorption, poor diet, water-soluble nutrient loss, and high catabolic status An essential ingredient for nucleotide synthesis, DNA repair, and re-methylation of homocysteine Folic acid deficiency produces oxidative vascular injury by potentiating uremic inhibition of homocysteine catabolism 血管壁中的上皮細胞(Epithelial cells)具有毒性,而且能夠促進凝血及膠原蛋白(Collagen)的製造,並減少一氧化氮的利用率,而導致動脈硬化的形成。改變了血液的凝結機制,增加血管的斑痕與傷害。

31 Nutrients deficiency Vitamin C
A cofactor for several enzymatic metabolism Promotes GI absorption of iron and enhances its mobilization from RES. Increases Hb synthesis by facilitating incorporation of Fe into protoporphyrin An anti-oxidative free oxygen scavenger, downregulates hepatic synthesis of cytokines Greater loss of Vit-C in HD compared with PD its deficiency must be considered in the event of persistent anemia that failed to respond to EPO and Fe supplements

32 Heavy metal 1. Aluminum 2. Cadmium 3. Lead 4. Mercury

33 Heavy metal Bone marrow function is often impaired in individuals with heavy metal poisoning Aluminum toxicity – P-binder, dialysate, poor control of pharmaceutical standards Cadmium, lead, mercury – industrial pollution, some folk remedies of Indian and Middle Eastern origins Increases gastrointestinal absorption of heavy metals

34 Heavy metal Lead toxicity is more likely to occur in patient with CKD due to: Iron and calcium deficiencies => GI absorption  Uremia may increase mobilization of lead from bone tissue stores Lead toxicity causes anemia by precluding incorporation of iron into a protoporphyrin ring for heme synthesis Lead 95% bone, hair

35 Hematologic disorders

36 Hematological disorders
The mechanism of EPO resistance includes bone marrow infarction, hemolysis, hypersplenism, and ineffective erythropoiesis. Common chronic hemolytic conditions are auto-immune diseases, sickle cell disease, thalassemia, hereditary spherocytosis, glucose 6-phosphate dehydrogenase deficiency. *comorbid hemato- logical disorders (B-thal, HbS, HbA2, HbH), is frequently associated with elevated endogenous EPO 。 The most common hemoglobinopathy is sickle cell disease. *Hemolytic diseases are more susceptible to the morbid impact of oxidative stress, nutrient deficiency, and dialysis blood loss.

37 Hematological disorders
Autoimmune hemolytic anemia occurs in 5-10% of patient with SLE. It is frequently associated with renal or neurological involvement. As reticulocytosis is common in patients on ESA therapy, early diagnosis of hemolytic events may be missed. It should be suspected when there is a progressive increase in EPO requirement while there is rapidly decreasing Hb concentration with megakaryocytic cell line and serum titer of anti-DS DNA.

38 Angiotensin-modulating agents

39 Angiotensin-modulating agents
The influlence is controversial. A prototype study showed there is a higher EPO requirement in dialysis hypertensive patients who were treated with ACEI/ARB compared with CCB. ACEI suppresses the enzymatic degradation of N-acetyl-seryl-aspartyl- lysyl-proline (AcSDKP), a naturally occurring inhibitor of erythropoiesis. Stimulation of erythroid cellular proliferation by angiotensin binding of its type II surface receptor is inhibited by ARB => therapeutic use of ARB in post-transplant erythrocytosis.

40 Circulating EPO inhibitors

41 Circulating EPO inhibitors
Circulating EPO inhibitors may result in pure red cell aplasia. Pure red cell aplasia should be suspected: 1. Received ESA therapy for 44 weeks 2. Rapid decrease in Hb mass (> 0.5 g/dl per week), 3. Reduction in absolute reticulocyte count <10, 000/ ml and/or 1U of RBC transffusion per week 4. Leucocytes and platelets are normal. 5. The more common causes of EPO-resistant anemia should be excluded. Routine blood transfusion should be avoided except for life-threatening anemia.

42 Circulating EPO inhibitors
Diagnosis: 1. Absence of erythroid precursors on bone marrow sample and low EPO content of the serum. 2. The serum sample inhibits growth of erythroid colonies in a bone marrow culture. 3. Radioimmunoassay identifies circulating neutralizing anti-EPO IgG in serum Treatment: 1. Discontinuation of rhEPO 2. Steroid and/or calcineurin inhibitor 3. Plasma exchange and/or allograft transplantation will result in rapid fall of the neutralizing antibody.

43 Secondary hyperparathyroidism and 1,25-vitamin D deficiency

44 Secondary hyperparathyroidism
There is a higher prevalence of anemia and greater EPO requirement HD subjects who are in the upper 50th percentile of intact parathyroid hormone. As a proof of causal relationship, surgical parathyroidectomy led to an improved control of anemia and a lower need for ESA Nevertheless, there is no evidence for a direct inhibition of erythropoiesis by excessive PTH.

45 1,25-vitamin D deficiency Vit-D may have synergistic effect on ESA control of anemia Calcitriol treatment in subjects with uremic bone disease increases the proliferation of erythroid precursors. Lower EPO requirement among subjects with BB gene of vitamin D receptor genotype compared with those with the Bb/bb gene.

46 Etiology of ESA resistance
Risk factor Mechanism of ESA resistance Therapeutic intervention Uremic toxins EPO synthesis / erythroid response Longer effective dialysis Oxidative stress Downregulation of HIF Vit E and Vit C Inflammation Cytokines: IL-1, IL-6, TNF-α Avoid sepsis and malnutrition Iron deficiency Hemoglobin synthesis Replenish iron/ blood loss Hyperparathyroidism/ Vit D deficiency Vitamin D synergism (erythropoiesis) Low P diet/ 1,25 (OH)2 vit D Aluminum toxicity Aluminum bone disease Avoid aluminum intake Hemolysis HbSS/G6PDD/AIHA Treat underlying diesease Drug: angiotensin-modulating agents Erythroid ANG II receptors/  endogenous EPO inhibitor, AcSDKP Dose of ACEI/ARB

47 Potential Pharmacological intervention in EPO resistance
Anti-inflammatory agents Nutritional supplements EPO-mimetic peptide Endogenous induction of EPO

48 Iain C. Macdougall, Am J Kidney Dis. 2012;59(3):444-451
Narrative Review New anemia therapies: Translating Novel Strategies From Bench to Bedside Iain C. Macdougall, Am J Kidney Dis. 2012;59(3): EPO-mimetic peptide HIF Stabilization Hepcidin Modulation GATA-2 Inhibitors EPO gene therapy

49 EPO-mimetic peptide

50 EPO-mimetic peptide The concept that a peptide could activate the erythropoietin receptor and stimulate erythropoiesis was described first by Wrighton et al in 1996 in Science. EMP-1 (erythropoietin-mimetic peptide 1) was able to stimulate cellular proliferation of erythroid cells in a dose-dependent manner and also increase reticulocyte counts in animal models. However, EMP-1 had low affinity for the erythropoietin receptor and low biological activity.

51 Iain C. Macdougall, Am J Kidney Dis. 2012;59(3):444-451
EPO-mimetic peptide Peginesatide is a dimeric peptide joined with a spacer linker to a pegylation chain to enhance its metabolic stability in vivo. No structural homology between peginesatide and erythropoietin. Antibodies against erythropoietin do not cross-react with peginesatide, and vice versa. => potential therapeutic use for pure red cell aplasia Iain C. Macdougall, Am J Kidney Dis. 2012;59(3): => pure red cell aplasia

52 Peginesatide Phase 3 Clinical Trials Overview
Iain C. Macdougall, Am J Kidney Dis. 2012;59(3):

53 HIF Stabilization

54 HIF Stabilization It is now clear that the anemia associated with CKD is not due simply to deficient erythropoietin production, but rather to defective EPO gene regulation. Prolyl hydroxylase inhibitors results stabilization of HIF and consequently transcription of the EPO gene. (eg, the erythropoietin receptor, transferrin, transferrin receptor, ferroportin, and divalent metal transporter 1 )

55 Regulation of hypoxia inducible factor (HIF) activity
HIF stabilization It is now clear that the anemia associated with CKD is not due simply to deficient erythropoietin production, but rather to defective EPO gene regulation. Prolyl hydroxylase inhibitors results stabilization of HIF and consequently transcription of the EPO gene. (eg, the erythropoietin receptor, transferrin, transferrin receptor, ferroportin, and divalent metal transporter 1 ) Iain C. Macdougall, Am J Kidney Dis. 2012;59(3):

56 HIF Stabilization Prolyl hydroxylase inhibitors Advantages –
1. Orally active 2. Modulate other genes involved in erythropoiesis in addition to the EPO gene. Disadvantages – 1. Upregulate several hundred other hypoxia-sensitive genes, including those involved in glucose regulation, angiogenesis, such as VEGF (vascular endothelial growth factor) => enhance tumor growth or proliferative diabetic retinopathy ?? 1. In phase 2 clinical trial

57 HIF Stabilization The first-generation HIF stabilizer molecule (prolyl hydroxylase inhibitors) -- FG 2216 => Patients developed abnormal liver enzyme test results, and one developed fatal hepatic necrosis in phase 2 clinical trial The second-generation HIF stabilizer molecule – FG 4592 => Significantly increase Hct and decrease serum Hepcidin levels => This is now in phase 2 clinical trial. In addition to Fibrogen, several other companies are developing HIF stabilizers.

58 Hypoxia coordinates EPO synthesis with iron metabolism
Hypoxia coordinates EPO synthesis with iron metabolism. Shown is a simplified overview of hypoxic and HIF-mediated effects on iron metabolism. HIF-2 induces renal and hepatic EPO synthesis in response to hypoxia, which results in increased serum EPO levels (circle), stimulating erythropoiesis. Renal and liver EPO responses are modulated by dermal HIF-1 (see the text). Also, included in this schematic is the recently described contribution of glial cell-derived EPO to the serum EPO pool. An adjustment of iron metabolism is needed to satisfy increased iron demand in the bone marrow. In the duodenum, duodenal cytochrome b (DcytB) reduces ferric iron (Fe3+) to its ferrous form (Fe2+), which is then transported into the cytosol of enterocytes (square) by divalent metal transporter-1 (DMT1). DcytB and DMT1 are both hypoxia inducible and HIF-2 regulated. Absorbed iron is released into the circulation by ferroportin (FPN) and is then transported in complex with transferrin to liver, reticuloendothelial cells, bone marrow, and other organs. Transferrin (Tf) is HIF regulated, and hypoxia increases its serum levels. Hypoxia, low serum iron levels, and increased “erythropoietic drive” inhibit hepcidin synthesis in the liver, resulting in diminished FPN cell surface expression in different tissues. As a result, more iron is released from enterocytes, hepatocytes, and reticuloendothelial cells (RES). When intracellular iron levels are low, iron regulatory protein (IRP) inhibits HIF-2α translation and diminishes hypoxia-induced erythropoiesis. Haase V H Am J Physiol Renal Physiol 2010;299:F1-F13 ©2010 by American Physiological Society

59 Hepcidin Modulation

60 Hepcidin Modulation Hepcidin is a small defensin-like peptide produced largely by the liver, macrophage and adipocyte. Hepcidin has antimicrobial properties and it is the master regulator of iron metabolism. , controlling the amount of dietary iron absorbed from the duodenum and also the release of iron from cells in the reticuloendothelial system (Kupffer cells, splenic macrophages)

61 Hepcidin Modulation Hepcidin is a small defensin-like peptide produced largely by the liver, macrophage and adipocyte. Hepcidin has antimicrobial properties and it is the master regulator of iron metabolism. , controlling the amount of dietary iron absorbed from the duodenum and also the release of iron from cells in the reticuloendothelial system (Kupffer cells, splenic macrophages)

62 Hepcidin Modulation * Hepcidin inhibits ferroportin, which controls
iron efflux from duodenal enterocytes, hepatocytes, and macrophages * Uremia is a chronic inflammatory state. Dialysis patients have much higher serum hepcidin levels. The regulation of hepci- din is complex, but one of the major stimuli to its production is interleukin 6 (IL-6), produced as part of the inflammatory response. Other molecules, such as hemojuvelin and BMP-6 (bone morphogenetic protein 6), also have a role.39 Babitt JL, Molecular mechansms of hepcidin regulation: implications for the anemia of CKD. Am J Kidney Dis (55):

63 Hepcidin Modulation It currently is believed that this has a part in the pathogenesis of anemia in CKD by limiting iron availability to the bone marrow. At a molecular level, hepcidin binds to the main iron exporter protein ferroportin, which controls iron efflux from duodenal enterocytes, hepatocytes, and macrophages. It currently is believed that this has a part in the pathogenesis of anemia in CKD by limiting iron availability to the bone marrow.

64 Hepcidin Modulation Strategies:
Monoclonal antibody against hepcidin (NOX-H94) has been shown the effect on inhibition of IL-6 induced anemia in mouse models. Inhibition of the hepcidin production by using antisense oligonucleotides or sliencing messenger RNA transcribed from the hepcidin gene(HAMP) None of the strategies have been subjected to clinical trials. => Hepcidin has antimicrobial properties. Inhibition of hepcidin might exacerbate the risk of infection ? => Is there a “safe” levels not to suppress hepcidin activity completely?

65 GATA-2 inhibitors

66 Iain C. Macdougall, Am J Kidney Dis. 2012;59(3):444-451
GATA-2 Inhibitors GATA-2 inhibitors: K-7174 and K GATA-2 inhibitor Iain C. Macdougall, Am J Kidney Dis. 2012;59(3): Series of experiments studied the effects of K-7174 in both a human hepatoma cell line and an animal model of anemia and showed that this GATA-specific inhibitor potentiate erythropoietin protein production and EPO promoter activity that previously had been suppressed with IL-1β, TNF-α, or NG-monomethyl L-arginine (L-NMMA). Imagawa S. Negative regulation of the erythropoietin gene expression by the GATA transcription factors. Blood. 1997(89):

67 GATA-2 Inhibitors K was found to evoke greater hypoxic induction compared with K-7174, possibly through stimulation of HIF-1 binding activity in addition to GATA inhibition. Potential role for an orally administered GATA inhibitor in the treatment of anemia. the HIF stabilizers, there is concern that GATA inhibition will promote activation of other genes in addition to erythropoietin. Imagawa S. Negative regulation of the erythropoietin gene expression by the GATA transcription factors. Blood. 1997(89):

68 Erythropoietin gene therapy

69 Erythropoietin Gene Therapy
In 2005, a group of Israeli scientists developed a functional delivery system for the EPO gene using skin cells on SCID mice (using adenovirus vector). The mice responded by producing increased levels of erythropoietin, and this was associ- ated with an increase in hematocrit. No such effect was seen with the vector alone. * using an adenovirus vector in which the cytomegalovirus immediate early promoter drives EPO * One patient maintained hemoglobin levels in the normal range for more than 18 months without erythropoietin injections. Further evaluation of this novel therapeutic strategy is ongoing.

70 Erythropoietin Gene Therapy

71 Erythropietin Gene Therapy
In 2010, a small group of patients with CKD in Israel have taken part in a proof-of-concept phase 1-2 clinical trial of this delivery system for the EPO gene. All patients showed increased erythropoietin production, with most showing sustained eleva- tion of hemoglobin levels (the primary end point) in the target range of g/dL for 6-12 months without receiving additional erythropoietin injections.

72 Conclusion

73 Conclusion It took us nearly 20 years to realize the limitations of ESAs and the potential for harm if used too aggressively. This review summarizes our current knowledge about a variety of new strategies for stimulating erythropoiesis. They will need to be subjected to the same degree of scientific investigation as the existing ESAs, and it may be many years before the true efficacy-safety balance of these novel scientific strategies is realized. None of the newer agents has outcomes data showing superiority to existing ESAs, and none has been tested in sufficient numbers of hyporesponsive patients to know whether the outcomes in these patients are different from those with conventional ESAs

74 Currently Available Erythropoiesis-Stimulating Agents

75 Future Erythropoiesis-Stimulating Agents

76 Oluwatoyin F. Bamgbola, Kidney international (2011) 80, 464-474
Clinical evaluation of resistance to erythropoietin stimulating agent in chronic kidney disease Al toxicity Pb toxicity Cu deficiency Hypothyroidism Oluwatoyin F. Bamgbola, Kidney international (2011) 80,

77 Proposed role of the bone morphogenetic protein(BMP) signaling pathway, HJV, HFE, and TFR 2 in iron sensing and hepcidin regulation in the liver

78 Hypoxia-inducible factor (HIF)-2 regulates erythropoietin (EPO)
Hypoxia-inducible factor (HIF)-2 regulates erythropoietin (EPO). Shown is an overview of EPO gene regulation by the von Hippel-Lindau (VHL)/HIF/prolyl-4-hydroxylase domain (PHD) oxygen-sensing pathway. Proteasomal degradation of HIF-2α by the VHL tumor suppressor (pVHL)-E3-ubiquitin ligase complex (shown are key components of this complex) requires hydroxylation by oxygen- and iron-dependent PHDs. Binding to hydroxylated HIF-α occurs at the β-domain of pVHL, which spans amino acid residues 64–154. The C-terminal α-domain links the substrate recognition component pVHL to the E3 ubiquitin ligase via elongin C. In the absence of molecular oxygen, HIF-2α is not degraded and translocates to the nucleus where it forms a heterodimer with HIF-β, also known as the aryl hydrocarbon receptor nuclear translocator (ARNT). HIF-2α/β heterodimers bind to the HIF consensus binding site 5′-RCGTG-3′ and increase EPO transcription in the presence of transcriptional coactivators, such as CREB-binding protein (CBP) and p300. Hypoxic induction of EPO in the liver is mediated by the liver-inducibility element located in the 3′-end of the EPO gene and in renal interstitial fibroblast-like cells by the 5′-kidney-inducibility element, which is located 6–14 kb upstream of its transcription start site. Nitric oxide, reactive oxygen species, Krebs cycle metabolites succinate and fumarate, cobalt chloride (CoCl2), and iron chelators such as desferrioxamine inhibit HIF PHDs in the presence of oxygen, resulting in increased EPO transcription. EPO mRNA is encoded by 5 exons depicted by boxes. Coding sequences are shown in red. Nontranslated regions are shown in blue, and numbers indicate distance from the transcription start site in kb (not drawn to scale). Also shown are binding sites for hepatocyte nuclear factor (HNF)-4 in the 3′-liver-inducibility region. Fe2+, ferrous iron; NO, nitric oxide; ROS, reactive oxygen species; ub, ubiquitin. Haase V H Am J Physiol Renal Physiol 2010;299:F1-F13 ©2010 by American Physiological Society

79 Thanks For You Attention !!


Download ppt "Erythropoietin-stimulating agents resistance and new anemia therapies"

Similar presentations


Ads by Google