The sickle mutation is a transversion from A to T in the sixth codon of the β-globin gene. The sixth codon is normally GAG, which encodes glutamic acid, but the transversion results in GTG, which encodes valine. Valine forms a hydrophobic projection on the surface of the hemoglobin tetramer (α2βS2; HbS), and when HbS releases oxygen, the valine fits into a natural hydrophobic pocket on a second tetramer in a nucleation event that stimulates the polymerization of thousands of HbS tetramers. The elongated polymers interact with each other to form a 14-stranded polymer, which is one of the most interesting and destructive polymers in nature. The HbS polymers convert normally pliable red blood cells (RBCs) into fragile, rigid rods and sickle-shaped structures that occlude small vessels and that lyse and release a host of products causing extensive tissue and organ damage.1 Figure 29-1 is a magnetic resonance angiography of the brain of a young sickle cell patient who has suffered a massive stroke. Her left internal carotid artery is completely occluded and, therefore, invisible in the image. She has permanent right hemiplegia. Occlusions of smaller vessels in the brain in 53% of sickle patients result in “silent infarcts,” which is a misnomer because they result in cognitive impairment.2 Pathology caused by occlusions and by extensive oxidative stress in many other tissues and organs result in a severe disease that affects 100,000 patients in the United States and millions worldwide.
Magnetic resonance angiography of the brain of a young sickle patient who suffered a massive stoke. Her left internal carotid artery is completely occluded and, therefore, invisible in the image. She is permanently paralyzed on her right side. Occlusions of smaller vessels in the brain in 53% of sickle patients result in “silent infarcts,” which are not at all “silent” because they result in cognitive impairment.
At present, the only curative approach for sickle cell disease (SCD) is allogeneic hematopoietic stem cell transplant (HSCT) with a full conditioning regimen and immunosuppression. The choice donor is represented by a human leukocyte antigen (HLA) genoidentical sibling even if some trials with matched unrelated donors or mismatched family donors are ongoing with significantly less satisfying results. The overall probability of survival for patients with SCD transplanted with an HLA-identical sibling graft ranges from 91% to 100%, with an event-free survival of 73% to 100%, and results are significantly better when the patients are transplanted early in life.3
Gene Therapy by Gene Addition and Gene Editing
Modern molecular biology provides tools that can be used to develop an autologous, curative treatment for most if not all patients with SCD, and many dedicated scientists and clinicians are working diligently to bring a safe, efficacious, and cost-effective solution to individuals suffering from this debilitating ...