Sickle cell anemia genetics

The landscape of sickle cell disease (SCD) treatment continues to evolve rapidly, with new disease-modifying therapies in development and potentially curative options on the horizon. Until recently, allogeneic stem cell transplant has been the only proven cure for SCD. Gene therapy is rising to the forefront of the discussion as a potentially curative or highly disease- modifying option for abating the complications of the disease. Understanding the different types of gene therapy in use, the differences in their end points, and their potential risks and benefits will be key to optimizing the long-term use of this therapy. A 22-year-old woman with sickle cell anemia (HbSS disease) presents to you, a sickle cell specialist (as a referral from her community hematologist-oncologist), to discuss the possibilities of curative treatment. She has a history of frequent vaso-occlusive (VOC) crises and goes to the emergency department about 5 times per year, where she is admitted most of those times. She has never had a stroke (that she is aware of). She has been on hydroxyurea (HU), 1000 mg per day, since she was 9, pretty reliably. She takes 30 mg of morphine sulfate extended release tablets (MS Contin, Purdue) taken by mouth twice a day, 10 mg of oxycodone every 4 hours as needed, and folic acid (in addition to HU). She is on no other medications. She has no full siblings and does not know her father. She lives with her mother and 2 half siblings approximately 2 hours from your c...

Sickle cell patients such as Cassandra Trimnell and Evie James Junior and UCSF physician Mark Walters talk about the severe pain experienced by those with the disease and the potential benefits of a CRISPR cure. (Video by UC Berkeley Public Affairs; video of Evie Junior by Colin Weatherby, courtesy UCLA’s Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research) In 2014, two years after her Nobel Prize-winning invention of CRISPR-Cas9 genome editing, Jennifer Doudna thought the technology was mature enough to tackle a cure for a devastating hereditary disorder, sickle cell disease, that afflicts millions of people around the world, most of them of African descent. Some 100,000 Black people in the U.S. are afflicted with the disease. Mobilizing colleagues in the then-new Innovative Genome Institute (IGI) — a joint research collaboration between the University of California, Berkeley, and UC San Francisco — they sought to repair the single mutation that makes red blood cells warp and clog arteries, causing excruciating pain and often death. Available treatments today typically involve regular transfusions, though bone marrow transplants can cure those who can find a matched donor. After six years of work, that experimental treatment has now been approved for clinical trials by the U.S. Food and Drug Administration, enabling the first tests in humans of a CRISPR-based therapy to directly correct the mutation in the beta-globin gene responsible for sickle ce...

Gene therapy as a potential cure for sickle cell disease (SCD) has long been pursued, given that this hemoglobin (Hb) disorder results from a single point mutation. Advances in genomic sequencing have increased the understanding of Hb regulation, and discoveries of molecular tools for genome modification of hematopoietic stem cells have made gene therapy for SCD possible. Gene-addition strategies using gene transfer vectors have been optimized over the past few decades to increase expression of normal or antisickling globins as strategies to ameliorate SCD. Many hurdles had to be addressed before clinical translation, including collecting sufficient stem cells for gene modification, increasing expression of transferred genes to a therapeutic level, and conditioning patients in a safe manner that enabled adequate engraftment of gene-modified cells. The discovery of genome editors that make precise modifications has further advanced the safety and efficacy of gene therapy, and a rapid movement to clinical trial has undoubtedly been supported by lessons learned from optimizing gene-addition strategies. Current gene therapies being tested in clinical trial require significant infrastructure and expertise, given that cells must be harvested from and chemotherapy administered to patients who often have significant organ dysfunction and that gene-modification takes place ex vivo in specialized facilities. For these therapies to realize their full potential, they would have to be ...