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M.C. Carden and J. Little et al.
Red blood cell intrinsic targets
The emerging disease-modifying approaches to SCD that target intrinsic characteristics of RBC are outlined in Online Supplementary Table S1 and discussed below.
Targeting HbS polymerization through the induction of HbF
Several recently developed agents aim to reduce deoxy- HbS polymerization, the root cause of SCD pathology, through delayed deoxygenation of HbS, reduced intracel- lular HbS concentration (via cellular hydration), or induc- tion of the anti-sickling HbF.29 Hydroxyurea, a ribonu- cleotide reductase inhibitor with HbF-inducing properties, is the paradigmatic HbF-inducing agent and was the first drug approved by the FDA for the treatment of adults and children with SCD. Hydroxyurea induces HbF and increases RBC volume, thereby reducing the likelihood of HbS polymerization. Hydroxyurea also decreases neu- trophil and platelet counts and increases plasma nitric oxide levels, and is overall associated with decreased mor- bidity and improved mortality.30,31 The 2014 NHLBI guide- lines state that hydroxyurea therapy should be initiated in adults with severe SCD, especially when quality of life is affected, and offered as a prophylactic treatment in young children with sickle cell anemia.20 Novel studies assessing the benefits of hydroxyurea are evaluating individualized pharmacokinetic-based dosing strategies (NCT03789591), the safety and feasibility of adding hydroxyurea to simple transfusions for stroke prevention (NCT03644953), and using patient navigators to reduce barriers to availability and non-adherence (NCT02197845).
However, some patients with SCD may not respond adequately to hydroxyurea or refuse treatment because of unwanted side-effects. As such, other agents that modify γ-globin gene silencing and induce HbF are being repur- posed or newly investigated. Many drugs being, or previ- ously, investigated work through novel epigenetic mecha-
nisms within erythroid progenitors in the bone marrow. Decitabine with (NCT01685515) or without (NCT01375608) tetrahydrouridine (a cytidine deaminase inhibitor that prevents rapid deactivation of decitabine, thereby allowing the use of an oral formulation of this lat- ter) is a chemotherapy used to treat myelodysplastic syn- drome and acute myeloid leukemia. Decitabine and its historic antecedent 5-azacytidine inhibit DNA methyl- transferase-1 (DNMT1), thereby reducing overall DNA methylation.32 Perturbed DNA methylation, in animal models and humans, appears to be the major mechanism for derepressed γ-globin expression arising from this class of agents.33 A phase I, first in-human trial of decitabine/tetrahydrouridine found this drug combination to be safe (without cytotoxicity or genotoxicity), well-tol- erated, and effective, increasing HbF levels to 4-9%, while doubling F-cell populations.34 Unlike 5-azacytidine, decitabine does not affect RNA metabolism and is likely to have an improved safety profile, although the impact of its irreversible incorporation into DNA has not been fully elucidated and long-term follow-up in large populations is not yet available.
Dimethyl butyrate (HQK-1001), an orally bioavailable short-chain fatty acid derivative and inhibitor of histone deacetylases, was active in animal models. However, a phase II double-blind placebo-controlled study (NCT01601340) was terminated early as the drug was associated with an insignificant rise in HbF and more pain episodes when compared to placebo.35 Other histone deacetylase inhibitors that work in part by reversing γ-glo- bin silencing and show promise in phase I trials in SCD include the multiple myeloma drugs panobinostat (NCT01245179) and pomalidomide (NCT01522547).36-38 Again, long-term risk-benefit analyses are not yet avail- able.
Lysine-specific demethylase-1 (LSD1) is another enzyme and epigenetic target that modifies histones through demethylation in the process of γ-globin gene
Figure 2. Red cell extrinsic targets. The figures shows the therapeutic targets and pathways extrinsic to the red blood cell (RBC), which are most likely to be useful for managing sickle cell disease, palliating symptoms, and improving organ function. NO: nitric oxide. [RBC image: https://steemit.com/stemng/@gbindinazeez/sick- le-cell-anaemia-an-endemic-disease-20181122t215228805z-post]
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haematologica | 2019; 104(9)