Fetal hemoglobin levels in sickle cell disease and normal individuals are partially controlled by an X-linked gene located at Xp22.2

Dover, GJ; Smith, KD; Chang, YC; Purvis, Shirley H.; Mays, A; Meyers, DA; Sheils, Catherine A.; Serjeant, G. R.

doi:10.1182/blood.v80.3.816.816

Cited by 154 publications

(57 citation statements)

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“…In this study, three months of sildenafil with HU therapy slightly increased relative %HbF in SCD patients; f‐cells also trended higher in these patients, most of whom were female. X‐linked polymorphisms have been associated with higher basal HbF levels in SCD (21), but gender differences have not predicted response to pharmacologic augmentation of HbF (22). Single‐nucleotide polymorphisms in the PDE7B gene have been associated both with high basal levels of HbF and with increased HbF responsiveness to HU in SCD (23, 24), and both cAMP and cGMP have been implicated in the pharmacologic up‐regulation of HbF.…”

Section: Discussionmentioning

confidence: 99%

Hematologic, biochemical, and cardiopulmonary effects of l‐arginine supplementation or phosphodiesterase 5 inhibition in patients with sickle cell disease who are on hydroxyurea therapy

Little

Hauser

Martyr

et al. 2009

European J of Haematology

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Objectives-Fetal hemoglobin (HbF) induction involves NO-cGMP signaling pathways. Larginine, an NO precursor, and the phosphodiesterase (PDE) 5 inhibitor sildenafil, which potentiates cGMP, were studied in adults with sickle cell disease (SCD) who were stably on HU.Methods-24 courses of L-arginine (0.1-0.2 g/Kg divided TID) or sildenafil (25-100 mg TID), assigned based on gender due to concerns about sildenafil-related priapism, were successfully completed. Biochemical assays, pulmonary pressures, and cardiopulmonary exercise capacity are reported from patients in whom serial values are available. Hematologic responses are reported in 14 subjects with HbSS who had stable baseline HbF levels.Results and Conclusions-L-arginine increased plasma arginine and ornithine, but not citrulline, suggesting diversion by plasma arginase from NO, and citrulline, generation. Glutathione (GSH) increased only in patients on L-arginine. Sildenafil increased plasma cGMP and citrulline, but not other amino acids. Pulmonary pressures and 6-minute walk distances improved only in patients on sildenafil.In subjects with stable baseline HbF levels, HbF levels changed little from a normalized baseline on L-arginine, decreasing by 2.9±16.1%, n=6; p=n.s., but increased on sildenafil, by 7.5±11.7%, n=8, p<.05. Absolute reticulocyte counts initially decreased in patients on sildenafil.L-arginine, at doses that increase plasma arginine levels, altered redox potential in red cells. The lack of clinically detectable efficacy of L-arginine may be due to increased arginine metabolism in SCD patients.In vivo augmentation of the cyclic nucleotide pathway by PDE inhibition may induce HbF slightly, but strikingly improves hemodynamic and functional status in SCD †

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Section: Discussionmentioning

confidence: 99%

Hematologic, biochemical, and cardiopulmonary effects of l‐arginine supplementation or phosphodiesterase 5 inhibition in patients with sickle cell disease who are on hydroxyurea therapy

Little

Hauser

Martyr

et al. 2009

European J of Haematology

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“…These early clinical findings now with sodium 2,2 dimethylbutyrate, in combination with prior studies in molecular, cellular, and nonhuman primate models, strongly suggest that HQK‐1001 offers potential for increasing HbF in sickle cell disease without cytotoxicity, and its PK profile is feasible for long‐term administration. Basal HbF levels vary widely in association with diverse genetic modifier profiles, which are likely to influence responses to HbF‐inducing therapeutics [39–47, 48]. It is therefore encouraging that five of seven subjects who received the highest dose level had a detectable rise in HbF above baseline in the presence of quite different basal HbF levels in this brief time‐frame.…”

Section: Discussionmentioning

confidence: 99%

A phase 1/2 trial of HQK‐1001, an oral fetal globin inducer, in sickle cell disease

et al. 2012

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Therapeutics which reduce the pathology in sickle cell syndromes are needed, particularly noncytotoxic therapeutics. Fetal hemoglobin (HbF, α2γ2) is established as a major regulator of disease severity; increased HbF levels correlate with milder clinical courses and improved survival. Accordingly, sodium dimethylbutyrate (HQK‐1001), an orally‐bioavailable, promoter‐targeted fetal globin gene‐inducing agent, was evaluated in a randomized, blinded, dose‐ranging Phase I/II trial in 24 adult patients with HbSS or S/β thalassemia, to determine safety and tolerability of three escalating dose levels. The study therapeutic was administered once daily for two 6‐week cycles, with a two‐week interim dose holiday. Twenty‐one patients completed the study. Five patients received study drug at 10 or 20 mg/kg doses, seven patients received study drug at 30 mg/kg/dose, and 4 patients received placebo. HQK‐1001 was well‐tolerated with no unexpected drug‐related adverse events; a dose‐limiting toxicity was not identified. Plasma drug levels were sustained above targeted levels for 24 hr. Increases in HbF above baseline were observed particularly with 30 mg/kg/day doses; in five of seven treated patients, a mean absolute increase in HbF of 0.2 g/dl and a mean increase in total hemoglobin (Hgb) of 0.83 g/dl above baseline were observed, whereas no increases occurred in placebo‐treated controls. These findings of favorable PK profiles, tolerability, early rises in HbF, and total Hgb indicate that trials of longer duration appear warranted to more definitively evaluate the therapeutic potential of HQK‐1001 in sickle cell disease. Am. J. Hematol., 2012. © 2012 Wiley Periodicals, Inc.

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“…Another possible cause is translation regulation by an X‐linked miRNA, which would allow a very rapid response to changes in α‐globin levels. Sex has also been reported to influence HbF levels through action of a gene at Xp22.2p 13 …”

Section: Discussionmentioning

confidence: 99%

α‐Hemoglobin stabilizing protein is not a suitable marker for a screening test for variant Creutzfeldt‐Jakob disease

et al. 2008

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Fetal hemoglobin levels in sickle cell disease and normal individuals are partially controlled by an X-linked gene located at Xp22.2

Cited by 154 publications

References 0 publications

Hematologic, biochemical, and cardiopulmonary effects of l‐arginine supplementation or phosphodiesterase 5 inhibition in patients with sickle cell disease who are on hydroxyurea therapy

Hematologic, biochemical, and cardiopulmonary effects of l‐arginine supplementation or phosphodiesterase 5 inhibition in patients with sickle cell disease who are on hydroxyurea therapy

A phase 1/2 trial of HQK‐1001, an oral fetal globin inducer, in sickle cell disease

α‐Hemoglobin stabilizing protein is not a suitable marker for a screening test for variant Creutzfeldt‐Jakob disease

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