Slicing and dicing DNA
By: Jeffrey Keefer, MD, PhD | December 07, 2015
The American Society of Hematology (ASH) is holding its 57th annual event in Orlando, Florida this week, where leaders in the field will discuss the incredible work being done in the area of malignant and non-malignant hematology. Many of the speakers will share ground-breaking results that could change the way people live with hemoglobinopathies (disorders of the hemoglobin molecule), like sickle cell disease (SCD) and beta thalassemia (B-Thal), which are among the most common genetic disorders in the world.
Currently there are no effective cures for SCD or B-Thal besides bone marrow transplant, which is a limited option due to the lack of fully matched donors; and carries with it dangerous complications, including graft versus host and graft rejection. This leaves most persons with SCD and B-Thal to live a life of treatment with blood transfusions, incompletely effective oral agents or even simply symptomatic therapy.
But that may soon change, thanks to significant advances in gene therapies that will be discussed at the event. This field of research has blossomed in recent years, both in the innovations being pursued, and in the fact that biopharmaceutical companies have gotten more involved in this work than they have been in the past. This confluence of trends makes the research being presented at this year’s event particularly exciting.
Genome therapies correct nature’s mistakes
Perhaps most exciting of all of the new therapeutic advances in beta hemoglobinopathies is gene therapy. Dr. John J. Strouse, a pediatric hematologist at Johns Hopkins University School of Medicine, is chairing a Scientific Session at ASH titled Genome Therapies for Hemoglobinopathies that explores methods to modify DNA and their clinical application to treat hemoglobinopathies. One of the speakers at this session, Dr. Philippe Leboulch, will discuss the introduction of genes into hematopoietic stem cells, using a lentiviral system, to compensate for defective genes — a process that is currently being tested in clinical trials. He will describe the preclinical development and clinical application of lentiviral vectors for SCD and B-Thal and will share some success stories from ongoing clinical trials.
The process involves harvesting stem cells from the patient, growing them in culture, then infecting the cells with the lentivirus carrying a gene that gets incorporated into the DNA of the stem cell, replacing a defective gene. The repaired stem cells are then reintroduced into the patient to populate the bone marrow after the patient receives conditioning chemotherapy to destroy remaining abnormal stem cells. The new stem cells produce repaired red blood cells which allow the patient to be free of their disease.
In two separate ongoing clinical trials, 13 B-Thal patients have undergone a version of this treatment to replace their defective beta globin gene with no toxicity events, and almost all are now either completely transfusion independent, or their reliance on transfusions has been dramatically reduced. One patient with SCD has been treated on this protocol and is also symptom-free (ASH abstracts 201 and 202 being presented in the oral abstract session 801, Gene Therapy and Transfer: Gene Therapy for Hemoglobinopathies and Inherited Bleeding Disorder).
Gene editing and the power of fetal hemoglobin
Also in the Genome Therapies for Hemoglobinopathies scientific session, Dr. Prashant Mali and Dr. Tim Townes will discuss an alternative to the lentiviral approach, called genome editing, and highlight its utility in treating hemoglobinopathies. This powerful new technology allows researchers to cut DNA at specified locations in the genome, using enzymes called nucleases, to correct defects in harvested stem cells before reintroducing them into patients. One example of this technology in preclinical development is the use of genome editing to remove an enhancer (a DNA segment that allows the gene to be expressed) from a gene in stem cells responsible for suppressing fetal hemoglobin production. The end result of this specific editing is that the red blood cells produced from the edited stem cells make very little of the fetal hemoglobin suppressor and, therefore, very high levels of fetal hemoglobin when transplanted into mice. High levels of fetal hemoglobin completely neutralize the toxicity caused by the abnormal hemoglobin made in SCD and effectively cures the disease. While this has not yet moved into human trials, these groups show that they can carry out this procedure efficiently and successfully enough to make this possible on a clinical basis (ASH abstracts 203 and 204).
These are just a few of the many exciting presentations that will be offered at ASH this year, underscoring why it is a truly exciting time for therapeutics in SCD and B-Thal, especially in the gene therapy arena. In a review article two years ago, Dr. Leboulch write that “the time is ripe for pharmaceutical companies to grab the baton and bring gene therapies to patients in need." From the looks of things at ASH that is certainly happening. These treatments are just a few steps away from becoming viable options, which could positively impact millions of SCD and B-THAL patients worldwide.