Genetic diseases such as Sickle Cell Anemia and others have posed a serious and seemingly intractable problem for the science of medicine since any cure would require the repair of the damaged gene(s) involved. However a number of significant technological breakthroughs in recent years have begun to change that bleak impasse. In 2003, the complete mapping of the human genome was accomplished. This technology and the information provided with its use have led to discoveries that have pinpointed the genetic origin of many diseases and continues to do so. In 2012 a new tool was fashioned – the genomic editor referred to as CRISPR. This remarkable tool can precisely edit particular sequences within the introns of targeted genes. The designers of this capability, Jennifer Doudna and Emmanuelle Charpentier were awarded the Nobel Prize in Chemistry in 2020. These two advances are changing the prospects for the treatment of genetic diseases. CRISPR and an additional methodology (described below) have demonstrated great promise.
It has recently been reported in the prestigious scientific journal Science that, “Two strategies for directly fixing malfunctioning blood cells have dramatically improved the health of a handful of people with these genetic diseases. One relies on CRISPR, marking the first inherited disease clearly helped by the powerful tool created just 8 years ago. And both treatments are among a wave of genetic strategies poised to expand who can get durable relief from the blood disorders. The only current cure, a bone marrow transplant, is risky, and matched donors are often scarce.”
The two genetic diseases referred to are so-called, “blood disorders.” One is Sickle Cell Anemia, and the other is Beta Thalassemia. Sickle Cell Anemia is a disease in which the red blood cells are mishappen and their ability to carry oxygen to the tissues is seriously compromised. The origin of this disease is genetic -the alteration of both alleles that carry the blueprint for hemoglobin protein, the protein responsible for binding oxygen. This disease particularly impacts the African-American population. In Beta Thalassemia, the patient makes little or no functional hemoglobin. The result, for the patient, is a dangerous and debilitating anemia since the body’s tissue cannot receive enough oxygen to effectively function.
The treatment devised that has been applied to both Sickle Cell Anemia and Beta Thalassemia involve modifying the genes that carry the information for the structure of hemoglobin in the following way. The stem cells responsible for producing red blood cells resident in the bone marrow are harvested from the patient, and the BCL11A gene responsible for shutting off the fetal form of hemoglobin is disabled thereby allowing it to be produced. The research tool utilized for this kind of genetic modification is CRISPR. The patient then receives chemotherapy to destroy any resident diseased cells and the modified stem cells are then reintroduced into the patient. If successful, the patient will then produce red blood cells with the completely functional fetal hemoglobin.
In addition, Dr. David Williams from Boston Children’s Hospital has achieved the same result using a novel technique - a specially genetically engineered virus is utilized to introduce a fragment of DNA encoded RNA into the harvested stem cells that effectively silences the BCL11A gene (referred to earlier).
It has been reported that, “Patients treated in both trials have begun to make sufficiently high levels of fetal hemoglobin and no longer have sickle cell crises or, except in one case, a need for transfusions.” The Boston team described a particular case in of a teenager, “who can now swim without pain, and a young man who once needed transfusions but has gone without them for nearly 2.5 years.”
These are, indeed, exciting developments, but represent only the beginnings of what could be an amazing era in the approach to many other diseases of this kind.