Red blood cells as therapeutic target to treat sickle cell disease

Sickle cell disease (SCD) is the most common inherited diathesis affecting mostly underserved populations globally. SCD is characterized by chronic pain and fatigue, severe acute painful crises requiring hospitalization and opioids, strokes, multi-organ damage, and a shortened lifespan. Symptoms may appear shortly after birth, and, in less developed countries, most children with SCD die before attaining age five. Hematopoietic stem cell transplant and gene therapy offers a curative therapeutic appraoch, but due to many challenges are limited in their availability and effectiveness for majority of persons with SCD. Hydroxyurea, the most widely used intervention for SCD management, has improved the survival in the Western world and more recently, Voxelotor, L-glutamine, and Crizanlizumab have been approved by the FDA for use in SCD. The recent FDA approval emphasizes the need to revisit the advances in understanding the core pathophysiology of SCD to accelerate novel evidence-based strategies to treat SCD. The biomechanical breakdown of erythrocytes is the core pathophysiology of SCD, associated with intrinsic factors, including the composition of hemoglobin, membrane integrity, cellular volume, hydration, and oxidative stress. This review focuses on advances in emerging non-genetic interventions directed towards the therapeutic targets intrinsic to sickle red blood cells (RBCs), which can prevent impaired rheology of RBCs to impede disease progression and reduce the sequelae of comorbidities including pain, vasculopathy and organ damage. Additionally, given the intricate pathophysiology of the disease, it is unlikely that single pharmacotherapeutic intervention will comprehensively ameliorate the multifaceted complications associated with SCD.