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Advances in gene therapies and drug development have led to a resurgence in research for more effective sickle cell anemia treatments. This article discusses stem cell transplant options and avenues of drug development.

Sickle cell anemia (SCA) results from a point mutation in the gene for the beta globin chain of hemglobin. After delivering oxygen, the mutated hemoglobin polymerizes into a long fiber, distorting the cell into a sickle shape and blocking circulation.
Currently, SCA treatment is largely based on supportive care; however, recent drug developments, the use of curative stem cell transplantation, and promising gene therapies have sparked new interest in SCA research.

Treatment Options

The goal of sickle cell anemia treatment is to minimize painful occurrences, alleviate symptoms, and avoid any painful consequences that may result from the disease.

Stem cell transplant: A stem cell transplant involving complete bone marrow replacement has shown a 95% cure rate, mostly in children. An approach adapted for adults that requires only 20% bone marrow replacement has yielded a 90% rate of disease reversion. A compatible sibling donor, who does not have sickle cell anemia can be used. However, only 10% of patients in the U.S. have that option. Research into ways to use half-matched family donors is ongoing and shows promise.

Methods for autologous transplantation of the patientโ€™s bone marrow, genetically modified, are being investigated. Development of a modified HIV1 gene transfer system has allowed integration of a therapeutic beta globin gene into stem cell DNA. Zynteglo is an autologous genetically modified stem cell transplantation therapy that was recently approved by the European Commission for use in adolescents with transfusion-dependent ฮฒ-thalassemia.
Safety concerns related to genetic manipulation include vector-based insertional mutagenesis, editing of off-target genes, and inherent risks involved with high-dose chemotherapy required in autologous bone marrow transplantation.
Drugs under development for SCD: These include anti-adhesion agents, sickling inhibitors, and anti-inflammatory agents. Voxelotor, an anti-sicking drug, received FDA approval in 2019. However, delaying polymerization of hemoglobin is more important, therapeutically, than developing a drug that fully prevents sickling. Four different strategies are being explored for the former. These include: increasing cell volume to decrease intracellular hemoglobin concentration, decreasing fiber stability, shifting allosteric equilibrium away from the polymerizing conformation, and binding an intermolecular contact site within the fiber.

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Reference

Okpala, I., & Tawil, A. (2002). Management of pain in sickle-cell disease. Journal of the Royal Society of Medicine, 95(9), 456-458. https://doi.org/10.1126/science.aba3827