Summary of progress
Our CIRM-funded effort aims to develop a treatment for beta-thalassemia. Beta-thalassemia is an inherited genetic disorder that is caused by mutations (changes in the DNA) in a gene called beta-globin. This gene produces a protein that forms hemoglobin in red blood cells that carry oxygen to through the body. In an individual with beta-thalassemia, beta-globin is not produced (or is made in dramatically reduced quantities), and so the person does not make enough healthy red blood cells. The treatment, which is essential for life in these patients, is repeated blood transfusions (typically once a month or more frequently). The transfusion of blood this frequently results in a dangerous condition called “iron overload,” which must be treated with costly drugs. In general, the quality of life of many people with beta-thalassemia is poor.
At present, there is only one cure, and that is to carry out a bone marrow transplant. This involves taking special cells from a healthy person called “hematopoietic stem cells” that give rise to blood cells for the whole of a person’s life, and giving them to the patient so that they that they are now able to make healthy red blood cells for their lifetime. However, the cell donor must be an immunologic match to the patient and for many people with beta-thalassemia, such donors are not available.
Our approach to treating beta-thalassemia aims to genetically engineer a person’s hematopoietic stem cells (change the DNA inside the cell) to allow them to make healthy red blood cells using a technology that we have developed called “zinc finger nucleases,” or ZFNs. We plan to obtain stem cells from a beta-thalassemia patient, genetically engineer them by transiently exposing them to ZFNs, and then transplant them back into the same individual, making the patient their own donor. The genetic engineering is designed to replicate a situation observed in certain people with beta-thalassemia who have milder symptoms than others. Such patients have a much higher than average level of a “backup” form of beta-globin, called fetal globin, in their blood.
All people make fetal globin while in utero and after birth, but in infancy the levels of fetal globin decrease and the child begins to make adult beta-globin. It is at this stage that the symptoms of beta-thalassemia become evident. However, if person with beta-thalassemia has high level of fetal globin, they will be spared the severe effects of the disease.
We know that certain individuals who have an elevated level of fetal globin do so because they have a less active form of a gene called BCL11A that normally shuts down the production of fetal globin during infancy. Making use of this observation, our approach is to knock out BCL11A in a patient’s own stem cells, transplant them back into the patient to allow the production of fetal hemoglobin and, as a consequence, increase production of healthy red blood cells.
In order to test drugs in humans investigators must consult with the US Federal Drug Administration (FDA) and ultimately submit data about the investigational drug to various regulatory bodies including the FDA as part of Investigational New Drug (IND) application. This past year, we held a meeting with the Center for Biologics Evaluation and Research of the FDA known as a “pre-IND” and received useful guidance on issues that we should address in preparing the IND filing. We also presented our program to the Recombinant DNA Advisory Committee of the NIH (RAC); our proposed preclinical safety assessment program and plan for the phase I clinical trial received unanimous approval from the RAC.
Our work this year focused on two major deliverables that are necessary to achieve the goal of beginning a clinical trial of our approach. The first one relates to our ability to purify and efficiently genetically engineer a sufficient quantity of stem cells from a patient with beta-thalassemia. Working with healthy volunteers, and in a setting that is identical to the one we plan to use during our clinical trial, we have been able to consistently obtain sufficient quantities of hematopoietic stem cells to treat an individual with beta-thalassemia, and attain high levels of targeted genetic engineering in those cells.
As part of a preclinical safety assessment program, we have initiated and completed a series of studies to determine whether the genetic engineering we perform has any unforeseen untoward consequences in the cell. When we have completed this effort, we aim to file the IND application with the FDA before the end of the year and, pending FDA acceptance, initiate the phase 1 clinical trial in 2015.