TY - CHAP M1 - Book, Section TI - Gene Therapy for Sickle Cell Disease A1 - Townes, Tim M. A1 - Cavazzana, Marina A2 - Gladwin, Mark T. A2 - Kato, Gregory J. A2 - Novelli, Enrico M. Y1 - 2021 N1 - T2 - Sickle Cell Disease AB - 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.1Figure 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. SN - PB - McGraw-Hill Education CY - New York, NY Y2 - 2024/03/29 UR - hemonc.mhmedical.com/content.aspx?aid=1179345611 ER -