Current and novel therapies for the prevention of vaso-occlusive crisis in sickle cell disease

Abstract

Individuals with sickle cell disease (SCD) are living further into adulthood in high-resource countries. However, despite increased quantity of life, recurrent, acute painful episodes cause significant morbidity for affected individuals. These SCD-related painful episodes, also referred to as vaso-occlusive crises (VOCs), have multifactorial causes, and they often occur as a result of multicellular aggregation and vascular adherence of red blood cells, neutrophils, and platelets, leading to recurrent and unpredictable occlusion of the microcirculation. In addition to severe pain, long-term complications of vaso-occlusion may include damage to muscle and/or bone, in addition to vital organs such as the liver, spleen, kidneys, and brain. Severe pain associated with VOCs also has a substantial detrimental impact on quality of life for individuals with SCD, and is associated with increased health care utilization, financial hardship, and impairments in education and vocation attainment. Previous treatments have targeted primarily SCD symptom management, or were broad nontargeted therapies, and include oral or parenteral hydration, analgesics (including opioids), nonsteroidal anti-inflammatory agents, and various other types of nonpharmacologic pain management strategies to treat the pain associated with VOC. With increased understanding of the pathophysiology of VOCs, there are several new potential therapies that specifically target the pathologic process of vaso-occlusion. These new therapies may reduce cell adhesion and inflammation, leading to decreased incidence of VOCs and prevention of end-organ damage. In this review, we consider the benefits and limitations of current treatments to reduce the occurrence of VOCs in individuals with SCD and the potential impact of emerging treatments on future disease management.

Cell and Gene Therapy for Anemia: Hematopoietic Stem Cells and Gene Editing

“…Beneficial effects include the induction of fetal hemoglobin (HbF) for inhibiting erythrocyte adhesion, conceivably ensuring nitric oxide donor bioavailability; myelosuppression (resulting in the reduced availability of leukocytes, reticulocytes, and platelets) and reduced frequency of acute pain; and alleviation of acute chest syndrome, reduced hospital admissions, and reduced blood transfusions. It may also protect against progressive organ damage, including nephropathy [47,53]. Moreover, clinical trials in infants and toddlers have shown very promising results [12].…”

“…Gene-modified HSPC graft repopulates the hematopoietic stem compartment, producing genetically corrected RBC progeny. Sickle HSPCs can be genetically modified through zinc finger nucleosomes (ZFNs), transcription activator-like effector nucleases (TALENs), or clustered regularly interspaced short palindromic repeats/CRISPR-associated nuclease 9 (CRISPR/Cas9) techniques (NCT03745287) [47][48][49][50].…”

Multi‐organ dysfunction secondary to abrupt discontinuation of voxelotor in a patient with severe sickle cell disease

“…Three new drugs have been approved in the recent years: L-glutamine, voxelotor, and crizanlizumab. 2 Importantly, <200 individuals were treated with each medication at the approved dose prior to approval. Further, these clinical trials restricted the inclusion of people with SCD who had significant cardio renal disease.…”

“Into the Lion’s Den”: COVID-19 Experiences of Black Adults with Sickle Cell Disease

“…In addition to pain management and routine acquisition of prescription medications, such as Hydroxyurea (SCD-modifying agent) and opioid analgesics, individuals with SCD may need transfusion therapy (Telen et al, 2019). They also experience complications that include acute chest syndrome, infections, stroke, and chronic organ impairment (Abboud, 2020; Osunkwo et al, 2020). Consequently, individuals with SCD require thorough assessments and frequent monitoring.…”