Sickle cell disease (SCD) is a genetic blood disease that affects ~100,000 Americans, and millions more worldwide. It is caused by a single nucleotide mutation in the adult beta-globin gene. Beta-globin protein is a building block of hemoglobin, which carries the iron and oxygen that give red blood cells their color. Beta-globin with the sickle cell disease mutation has a tragic flaw: it causes hemoglobin to clump up within the red blood cells. These clumps distort and weaken the cell, which adopts an elongated “sickle” shape that has a hard time fitting through our smallest blood vessels. This progressively wreaks havoc on the body. Episodic severe pain is an early symptom. Organs become progressively and irreversibly damaged. Ultimately, life-threatening symptoms appear: stroke, pulmonary hypertension, and acute chest syndrome. Even in developed health systems such as that of the United States, the life expectancy of individuals with sickle cell disease is only 45 years. As guest blogger Shakir Cannon poignantly illustrates in his post “Prioritizing Sickle Cell Patients: A Chance to Mend Broken Ties,” quality of life with sickle cell disease is dramatically affected as well.
Sickle cell disease has no universally applicable cure. The standard of care for individuals with more advanced disease is chronic blood transfusions coupled with chelation therapy, which has severe side effects. For some patients, a bone marrow transplant (BMT) is an option that can cure sickle cell disease (the stem cells in our bone marrow produce our blood cells), but this is a risky and intensive procedure that is limited by availability of a bone marrow donor. That’s the bad news. The good news is that new technologies may dramatically improve the outlook for individuals affected by SCD in the coming years.
Some improvements in SCD treatment will be through improved clinical practice, particularly for BMT, but the brightest future lies in so-called “autologous” procedures. These are procedures that genetically correct a patient’s own (hence the “auto,” or “self”) bone marrow cells in a lab. The corrected cells can be injected back into the patient, where they engraft and produce healthy red cells, thus curing the disease. The autologous procedure that is most developed is viral gene therapy. In this procedure, a virus is used to introduce a healthy beta-globin gene into the genome. If enough cells get this new gene, they will express enough healthy beta-globin to fend off sickling. This approach is already in clinical trials run by several academic and private sector organizations.
The latest road to a curative therapy for sickle cell disease is something readers of this blog have already heard of: genome editing. Managing sickle cell disease is a complex challenge for doctors and patients, but the genetic cause is very simple: one single mutation in one gene. Genome editing enables us to fix that mutation. This is done by cutting the DNA at the site of the mutation using CRISPR-Cas9, and then “pasting” in a healthy sequence. Genome editing can be used in other innovative ways as well, without the need for any “pasting.”
Here at the IGI, I manage a multi-disciplinary team that is harnessing our skills at CRISPR-Cas9 gene editing to develop a gene correction protocol with the real possibility of curing the disease. Things are going well, but we still have a long way to go. Things that work perfectly in the laboratory often fail in the clinic. In addition to our team, there are several other academic teams pushing towards curing sickle cell disease with gene editing at top institutions such as Harvard, Stanford, UCLA, and the NIH. For too long, the biomedical research community neglected sickle cell disease. Thanks to the advocacy of doctors and patients like Shakir, I am happy to say it is finally getting the attention it deserves. A cure for sickle cell disease is finally in sight.