About 100 years ago, a curious blood disease was discovered that was characterized by the presence of peculiarly-shaped red blood cells, which had a crescent, or “sickle” shape, instead of the normal disc-shaped cells. This disease was coined sickle cell disease, or SCD. As the disease progresses, SCD patients experience increasingly debilitating pain crises, and damage to the brain, liver, heart, lung, and other organs. Today, SCD affects 100,000 people in the US alone.
About 40 years ago, it was discovered that SCD was an inherited disease, passed on from parent to child if both parents carried a copy of the “sickling” gene, a mutated version of the beta-globin gene.
Beta-globin is one of the four core units of hemoglobin, which is essential to carry oxygen to tissues throughout the body. Normal disc-shaped red blood cells are flexible and can easily move through large and small blood vessels to deliver oxygen to tissues.
In sickle cell disease, mutations in beta-globin turn hemoglobin into stiff rods, changing the normal disc-shaped red blood cells into a sickle form. These inflexible, sickle-shaped red blood cells can stick to vessel walls, causing a blockage that slows or stops blood flow, preventing oxygen from reaching all tissues and causing pain and organ damage.
In 1973, the life expectancy for sickle cell disease was 14 years. Since then, much progress has been made and now, SCD patients in the US can expect to live 40-60 years, although with recurring chronic pain.
Sickle cell disease can be cured by blood stem cell transplantation: where a patient’s diseased bone marrow (where red blood cells are produced) is eliminated and blood-forming cells including stem cells from the bone marrow of a healthy donor are introduced. Over time, they will produce healthy disc-shaped red blood cells to replace the sickle ones, curing SCD.
However, access to bone marrow from someone who is a perfect immune system match is extremely rare. Only 10-15% of sickle cell patients find that perfect bone marrow to cure their disease but for the 85-90% of those who don’t, stem cell therapies offer the best, immediate hope.
Research funded by California’s stem cell agency, the California Institute for Regenerative Medicine (CIRM) is focusing on the development of safer, more effective stem cell therapies to treat of sickle cell disease patients. One CIRM Disease Team, led by Dr. Donald Kohn at UCLA, has developed a procedure by which they may be able to permanently cure the disease with significantly less toxicity than a bone marrow transplant. The procedure involves a harvesting SCD patients’ stem cells and genetically correcting them to prevent sickling. The hope is that this procedure will not only provide an improvement to the current standard of care, but to a permanent cure for this debilitating disease.
Dr. Kohn and his team are using a combination of stem cell research and gene therapy to make patients their own red blood cell donors, using the patients’ own stem cells. With funding from California’s Proposition 71, the UCLA team is enriching blood stem cells from the bone marrow of SCD patients and introducing a modified version of the beta-globin gene. The engineered stem cells make red blood cells with the modified beta-globin, which blocks sickling of red blood cells. In the laboratory petri dish, the presence of the modified beta-globin gene makes the red blood cells disc-shaped. The engineered stem cells are then returned to the patient, where they should start producing new, disc-shaped red blood cells containing the modified beta-globin gene, eventually replacing all of the sickled red blood cells.
The scientists have tested this technique in a mouse model of sickle cell, where the modified stem cells created disc-shaped red blood cells and cured SCD. A human clinical trial is currently underway at UCLA to test this approach in SCD patients.
Sickle Cell Disease is not the first disease in which Dr. Kohn has made significant strides in gene therapy to cure blood disorders. Just last year, Dr. Kohn’s and his team developed a cure for Severe Combined Immunodeficiency Syndrome, also known as SCID or “Bubble Baby Disease,” by correcting the genetic mutation that causes it. 
Kohn, speaking to the critical importance of continuing to explore all promising treatment options for this devastating condition, offered the following insight:
“Finding varied ways to conduct stem cell gene therapies is important because not every treatment will work for every patient. Both methods could end up being viable approaches to providing one-time, lasting treatments for sickle cell disease and could also be applied to the treatment of a large number of other genetic diseases.” 
The implications of this work are significant. With an efficient way to engineer stem cells, we can replace abnormal cells in many diseases, including immune deficiencies, neurodegenerative, metabolic, or autoimmune diseases. Only with continued support for biomedical research can we make this possible.
As scientists and patient advocates build on the progress that Proposition 71 funding has enabled, we must keep the momentum going, understanding that there is still much work to be done. We must remember that human trials will celebrate successes; but, barriers will surface, along with complications and challenges, so patience and understanding of the scientific discovery process are essential.
Selected disease and research progress information provided by the California’s stem cell research funding agency, the California Institute for Regenerative Medicine (CIRM). Visit www.cirm.ca.gov for more updates.
1. Holden, Anne. “One-Time, Lasting Treatment for Sickle Cell Disease May be on Horizon, According to New CIRM-Funded Study.” 4 March 2015. California Institute for Regenerative Medicine. http://blog.cirm.ca.gov/2015/03/04/one-time-lasting-treatment-for-sickle-cell-disease-may-be-on-horizon-according-to-new-cirm-funded-study/
2. Kohn, Donald et al. “Correction of the sickle-cell disease mutation in human hematopoietic stem/progenitor cells.” 7 February 2015. American Society of Hematology. http://www.bloodjournal.org/content/early/2015/03/02/blood-2014-12-615948?sso-checked=true
3. “Sickle Cell Disease Fact Sheet.” Updated April 2015. California Institute for Regenerative Medicine. Web. https://www.cirm.ca.gov/our-progress/disease-information/sickle-cell-disease-fact-sheet
4. UCLA Press Release: SCID. “Stem Cell Breakthrough: UCLA Researcher Pioneers Gene Therapy Cure for Children with ‘Bubble Baby’ Disease.” UCLA. https://www.stemcell.ucla.edu/news/stem-cell-breakthrough-ucla-researcher-pioneers-gene-therapy-cure-children-%E2%80%9Cbubble-baby%E2%80%9D-diseas
5. CIRM Spotlight on Disease: Sickle Cell Disease. Seminar: Nancy Rene. “ Spotlight on Stem Cell Gene Therapy for Sickle Cell Anemia- A Patient’s Perspective.” California Institute for Regenerative Medicine. https://www.cirm.ca.gov/our-progress/video/spotlight-stem-cell-gene-therapy-sickle-cell-anemia-patients-perspective
6. “Stem Cell Gene Therapy for Sickle Cell Disease.” CIRM Disease Team Grant Summary. California Institute for Regenerative Medicine. https://www.cirm.ca.gov/our-progress/awards/stem-cell-gene-therapy-sickle-cell-disease
 “Stem Cell Breakthrough: UCLA Researcher Pioneers Gene Therapy Cure for Children with ‘Bubble Baby’ Disease.” 20 November 2014. UCLA Eli & Edythe Broad Center of Regenerative Medicine and Stem Cell Research. https://www.stemcell.ucla.edu/news/stem-cell-breakthrough-ucla-researcher-pioneers-gene-therapy-cure-children-%E2%80%9Cbubble-baby%E2%80%9D-diseas