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Targeting sickle cell root-cause pathophysiology
to be considered with small molecules aiming to chemical- ly modify HbS, and with small molecules aiming to sub- stitute HbS with HbF.
Ultimately, the risk/benefit calculus for any therapeutic approach requires careful clinical trial determination.
Combinatorial approaches
In oncology, combinations of drugs are almost manda- tory, because the target cell population is evolving, and will select to evade the effects of drugs. Although target cells in SCD are not evolving, other biological realities compel consideration of combination therapies. One real- ity is that most SCD patients will already have tissue/organ damage that can undermine the potential benefits of novel small molecule therapeutics. For exam- ple, diminished bone marrow reserve from vaso-occlusive damage and/or replication-mediated exhaustion, which decreases compensatory reticulocytosis, and which con- tributes to early death,2,15,31,33,37,38,40 could limit the scope of potential benefit that can be produced by HbF inducers or HbS modifiers. Another biological reality, but potentially positive, is demonstrated by the approval by the FDA of the amino acid glutamine as a treatment to reduce the fre- quency of vaso-occlusive crises in SCD patients.129 Natural substances, which in most humans can be assumed to be satisfactorily maintained by a normal diet, might actually be important pharmaceuticals for SCD patients. By way of bringing such negative and potentially positive biologi- cal realities together, it is noteworthy that the natural sub- stance nicotinamide (vitamin B3) markedly expands hematopoietic stem cells in vitro at concentrations that can be readily and safely produced in vivo with oral supple- mentation.130-132 Moreover, nicotinamide is a direct precur- sor for the vital energy currency nicotinamide adenine dinucleotide (NAD) which is depleted in SCD RBC, increasing their susceptibility to oxidative damage. In fact, replenishing NAD is one of the rationales for glutamine administration to SCD patients.129 In short, in considering combination therapy, there could be important, highly feasible, but unexplored opportunities around relatively non-toxic natural substances (glutamine, nicotinamide, vitamin D, etc.). Other under-evaluated natural molecules include the kidney hormone erythropoietin, since declin- ing kidney erythropoietin production also contributes to declining compensatory reticulocytosis.2
Combining small molecules to inhibit more than one co-repressing enzyme in the BCL11A hub, each used at
doses low enough to avoid side-effects from off-target actions, and with non-overlapping side-effects from on- target actions, might produce greater HbF induction than achieved with a single target. Such molecules should have non-cytotoxic mechanisms of action, to avoid potential injury to needed bone marrow capacity. Unfortunately, there are few non-cytotoxic small molecule drugs target- ing rational epigenetic targets, and even fewer for which optimal single molecule application has been character- ized (Table 1). That is, more non-cytotoxic epigenetic drugs, and more information on their profiles of side- effects from on-target and off-target actions, are needed to guide any consideration of combination therapy.
What about combining HbF inducers with HbS modi- fiers? This has in effect been evaluated in the clinical trials of GBT440, since this drug was added to stable doses of hydroxyurea in >60% of clinical trial participants. Hemoglobin increases of >1 g/dL occurred in ~40% of patients taking GBT440 1500 mg alone versus ~55% of patients taking GBT440 1500 mg + hydroxyurea in the phase III trial, but whether vaso-occlusive crisis frequency and other adverse events varied between these two groups was not described.124 The efficacy calculus and hope is that increases in oxygen delivery from better RBC deformability and higher total hemoglobin will exceed decreases in oxygen delivery caused by greater blood vis- cosity and chemical modification of HbS.
Conclusions
Clinical proof-of-principle that substantial total hemo- globin increases can be produced by non-cytotoxic inhibi- tion of specific epigenetic enzymes, to shift RBC precursor hemoglobin manufacturing from HbS to HbF, and by chemical modification of hemoglobin to promote the high oxygen affinity ‘R’ quarternary structure of the hemoglo- bin molecule, has already been generated in SCD patients. Clinical evaluation to determine the long-term safety, the impact on symptoms and multi-organ pathophysiology, and the durability of any benefits, is ongoing. There is hope that one or more of the small molecules being eval- uated will pass rigorous scrutiny and culminate in practi- cal, accessible, cost-effective, safe and potent disease- modifying therapy for SCD patients worldwide.
Funding source: National Heart, Lung and Blood Institute UO1 HL117658.
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