New Therapeutic Frontiers in Sickle Cell Disease

A panoply of potential new therapies for sickle cell disease (SCD) has emerged in just the past five years. Pharmaceutical companies are now actually interested in SCD. Many sickle cell centers now run more than one clinical trial at the same time, and even decline participation in others because of limited resources and competing enrollment. While this may be unsurprising to many readers of The Hematologist, especially those who treat patients with hematologic malignancies, this is a strange, new world for the sickle cell community. This column highlights three publications from 2015 that reported new therapeutic frontiers in different stages of development: gene therapy, antiadhesive therapy, and modulation of coagulation.

Gene therapy for SCD has always been "just around the corner." Now it is actually here for humans, albeit in an extremely limited and experimental basis. Five individuals with SCD have undergone some form of gene transfer therapy to date, but the durability of clinical benefit of the current generation of gene therapy methods remains to be demonstrated. Even so, next-generation gene therapy techniques are already being studied in preclinical models. An ideal gene therapy for SCD would avoid the problems of insertional mutagenesis and difficulty achieving proper spatiotemporal expression of a transgene by permanently correcting the sickle mutation in situ. In an effort to achieve this goal, Dr. Megan Hoban and colleagues used specifically engineered zinc-finger nucleases and a donor nucleotide template to effect cleavage of the β-globin locus and homology-directed repair of the sickle mutation in hematopoietic stem and progenitor cells (HSPCs).¹  These modified HSPCs could engraft in immunodeficient mice and produce cells from multiple lineages. Moreover, gene-corrected CD34+ cells from the bone marrow of individuals with SCD could produce wild-type hemoglobin tetramers. Clearly, more work needs to be done until this gene correction technique is ready for studies in humans, including elimination of off-target cleavage and nonhomologous end joining. Different gene editing techniques (e.g., TALEN- and CRISPR-based systems) are also being actively studied. So, while gene therapy for SCD is “already here,” even better gene therapy is just around the corner.

Until gene therapy delivers a universal cure, the painful vaso-occlusive episode (VOE) will remain a vexing therapeutic challenge. A number of studies have demonstrated a key role for intercellular adhesive interactions in the pathophysiology of vaso-occlusion, and several antiadhesive therapies are being tested for VOE. Among these is the pan-selectin inhibitor, GMI-1070, now known as rivipansel. Dr. Marilyn Telen and colleagues reported the results of a prospective, multicenter, randomized, placebo-controlled, double-blind, phase II study of 76 patients with VOE.²  Although the time to resolution of VOE was not statistically different between the groups, the medication appeared to be safe, and a secondary analysis showed a significant reduction in opioid usage in the GMI-1070 group. These results provided support for a phase III study of GMI-1070 that is currently recruiting (NCT02187003). GMI-1070 exemplifies the renewed optimism that exists for alternative therapeutic options beyond hydration, analgesics, and supportive care for VOE and related complications of SCD.

SCD is characterized by activation of the coagulation system and chronic inflammation. This knowledge has prompted a handful of trials of anticoagulant and anti-inflammatory therapies. None had resounding success, perhaps because these agents (e.g., heparins, corticosteroids) have targets that are too broad. As a specific therapeutic target for SCD, thrombin is attractive because it is both a central effector and regulator of coagulation and a key modifier of inflammation. Dr. Paritha Arumugam and colleagues demonstrated that targeted reduction of prothrombin levels, using both antisense oligonucleotides and genetic diminution techniques, significantly ameliorated vaso-occlusion, vasculopathy, and inflammation in sickle cell mice.³  Importantly, these benefits were achieved with only a modest increase in the prothrombin time and without hemorrhagic complications. These findings indicate that prothrombin is a modifier of end-organ damage in SCD in mice and support the study of dabigitran and other direct thrombin inhibitors for the treatment of SCD.

While promising new therapies and cures for SCD such as these are hotly pursued and eagerly anticipated, we must not forget what we can do for our patients now: Prescribe hydroxyurea.⁴  Hydroxyurea decreases SCD-related morbidity and mortality and improves quality of life. It is effective and has very few serious side effects. Sadly, it is still not prescribed as broadly as it should be. Looking forward to 2016, we will certainly see expanded indications for hydroxyurea.

In particular, the results of the TWiTCH Trial were presented at the Plenary Scientific Session of the 2015 ASH Annual Meeting but not published in time for this Year’s Best in Hematology.^5,6  The TWiTCH trial demonstrated that hydroxyurea was not inferior to chronic transfusions for primary stroke prevention in select children with SCD. I predict that these practice-changing findings will top next year’s list.