By Allen Taylor | 25 December 2019
Many diseases, including very serious ones, are caused or made more likely by mutations in a person’s DNA. For most of such diseases, multiple mutations must be present for the corresponding disease to manifest. However, there are serious diseases that are due to a mutation in a single gene. These diseases are the low hanging fruit of stem cell therapy. In such cases, the correction of a single mutation could prevent a life of suffering and early death. The first two pieces of low hanging fruit have just been harvested.
Stem cell therapy can be applied to diseases of the blood. Mutations in a person’s DNA cause defective blood cells to be manufactured in the bone marrow rather than healthy ones. The low hanging fruit for this intervention are beta-thalassemia and sickle cell disease. Throughout the world, three hundred thousand babies are born every year with the mutation that virtually guarantees that they will contract sickle cell disease before they celebrate their four-month birthday. A different mutation to the same gene (beta-globulin gene) will give sixty-thousand babies beta-thalassemia by that same milestone. Both diseases distort the shape of red blood cells, impairing their ability to carry oxygen throughout the body, and causing pain as they block circulation.
Hemoglobin is the molecule in a red blood cell (erythrocyte) that carries oxygen to the tissues of the body. There are multiple known variants of the hemoglobin molecule. The most common in adults is hemoglobin A (HbA). The most common in embryos and fetuses is hemoglobin F (HbF). As a fetus matures in the womb, the level of HbF declines, along with a corresponding rise of HbA. At birth, the concentration of both is about equal and by age three months, there is little HbF left.
Beta-thalassemia and sickle cell disease tend to become symptomatic at about three months, due to the mutant version of HbA. The embryo, fetus, and newborn are protected from this by HbF, which is not susceptible to the mutation.
As a fetus moves toward term, tremendous changes occur. Many “switches” are thrown that turn some things on and other things off. One of those switches turns off the production of HbF and another turns on the production of HbA. If the switch that turns off HbF could be reversed, the production of HbF into adulthood would eliminate or at least greatly reduce the impact of these diseases. This solution would apply to both beta-thalassemia and sickle cell disease because both conditions are rescued by the presence of an ample supply of HbF.
To address this problem, two companies, CRISPR Therapeutics and Vertex Pharmaceuticals have joined forces to create a therapy that is designed to restart the production of HbF in diseased individuals. They are using the CRISPR/Cas9 technology to create a gene edited therapy name CTX001.
In the CTX001 therapy, blood is drawn from a patient and then CRISPR/Cas-9 technology is used to edit the hematopoietic stem cells into CTX001 stem cells. These modified cells are then infused back into the patient. Once within the patient’s circulation, the stem cells naturally migrate to the bone marrow where they begin to produce new blood cells and immune system cells, in a process called engraftment.
A pilot Phase I/II trial of CTX001 is now being conducted in one beta-thalassemia patient and one sickle cell disease patient, and initial results are in. The transfusion-dependent beta thalassemia patient achieved neutrophil engraftment 33 days after CTX001 infusion and platelet engraftment 37 days after. At nine months, the patient was transfusion independent, and 99.8 percent of erythrocytes were HbF cells. The patient experienced two serious adverse events, but both were resolved and were determined not to be related to CTX001.
The sickle cell disease patient achieved neutrophil and platelet engraftment 30 days after CTX001 infusion. At four months after infusion, 94.7% of erythrocytes were expressing fetal hemoglobin. Prior to infusion, the patient was experiencing seven vaso-occlusive crises (VOCs) per year. At four months, the patient was free of VOCs. As was the case with the beta-thalassemia patient, the sickle cell patient experienced serious adverse events, three in number. However, they were all resolved, and considered not to be related to CTX001.
Subjects are currently being recruited for a larger trial. On the horizon is the applicability of the technology to Duchenne muscular dystrophy and myotonic dystrophy type 1. If all goes well with the ongoing program, health and extended life could come to hundreds of thousands of people who have had very little hope up to now.
Reprinted with permission from the author.
Allen G. Taylor, a 30-year veteran of the computer industry, is an internationally best-selling author, educator, consultant, and speaker on technology and society. He is the author of 43 books, including SQL For Dummies, Seventh Edition, Crystal Reports 2008 For Dummies, SQL All-in-One Desk Reference For Dummies, and Database Development For Dummies.
— Allen G. Taylor (@SQLwriter) November 14, 2010
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