Sickle cell disease is a blood disorder that currently affects approximately 100,000 Americans. It occurs when an individual inherits genes that make an abnormal form of the oxygen-carrying protein hemoglobin. Red blood cells filled with this abnormal hemoglobin interfere with normal blood flow by becoming rigid and sickle-shaped as they release oxygen into tissues all over the body. These misshapen red blood cells may block small blood vessels and produce painful tissue damage or even cause bleeding in or about vital structures, such as the brain.
This disease is caused by a variation in the genetic code that dictates the chemical structure of the oxygen-carrying protein, hemoglobin. We all carry two genes responsible for the manufacture of the hemoglobin typically occurring in children and adults. Individuals with African ancestry are at highest risk for sickle cell disease, with about 1 in 13 African-Americans carrying one copy of the gene for the atypical hemoglobin. To acquire sickle cell disease, an individual must inherit copies of this atypical hemoglobin gene from both of his or her parents. If the fetus gets a normal hemoglobin [so-called hemoglobin A] gene from one parent and a sickle hemoglobin [so-called hemoglobin S] gene from the other parent, he or she will not develop sickle cell disease. Only those fetuses that get the hemoglobin S gene from both parents are at risk for the disease and a lifetime of pain and disability.
Because there are millions of Americans with one copy of the hemoglobin S gene who are at risk of having a child with another American with one copy of the hemoglobin S gene, the disease continues to be a major public health problem. Ideally, physicians would ‘fix’ the faulty gene in people carrying it or alternatively activate a gene or genes that would compensate for the presence of the sickle cell hemoglobin. The latter option appears to be in hand.
More than a decade ago, researchers discovered a phenomenon, which they called CRISPR cas9, which allowed for the targeting and alteration of the chemicals that constitute genes. Using this to cut out a piece of a gene controlling the production of a type of hemoglobin formed by fetuses [so-called hemoglobin F], investigators were able to restart the production of a type of hemoglobin, hemoglobin F, that the body customarily stops making at or shortly after birth. Red blood cells with hemoglobin F do not become sickle-shaped or obstruct blood flow when they release oxygen into tissues. Replacing blood-manufacturing cells that made red blood cells packed with hemoglobin S with cells that made red blood cells packed with hemoglobin F was a straight-forward, but technically complex, way of curing sickle cell disease. Early results with this gene tinkering seem to have been successful.
Before the celebration gets too raucous, we must watch for longterm consequences of this assault on Mother Nature. The human body stops making hemoglobin F early in life, and we can propose several logical reasons for our genes having an off switch to halt the manufacture of this type of hemoglobin, but there may be a reason for this switch from hemoglobin F to hemoglobin A [or hemoglobin S in people who develop sickle cell disease] of which we are unaware.. We believe that switching from the manufacture of hemoglobin F to the manufacture of hemoglobin A in people without sickle cell disease is just the body’s way of adjusting for getting oxygen from the lungs rather than the placenta. We assume that the persistence of any fetal hemoglobin F is inconsequential. If our hypotheses are correct, there will be no negative effects of this resurrection of hemoglobin F to block the ravages of hemoglobin S. If we are wrong, we should soon find out.
An additional problem with this genetic treatment is that the cells in the bone marrow that manufacture hemoglobin S must be destroyed and replaced with cells producing hemoglobin F. The measures needed to accomplish this replacement are potentially lethal. Radiation, isolation, and a protracted hospitalization are currently needed to achieve this essential transformation.
Rarely discussed but often insurmountable is the cost of this treatment. It is available under the brand name Casgevy for just over $2,000,000 per patient. The Food and Drug Administration [FDA] has tentatively approved this material for use in the treatment of sickle cell disease, but no insurance program has agreed to cover the cost of this treatment, and none is likely to agree to pay the retail price for the foreseeable future.
Despite the cost and uncertainty of long-term benefit, this gene therapy is a major treatment advance. Having established the feasibility of altering at least some elements of our genetic make-up, physicians can attack the thousands of genetic diseases that cause misery for millions of people. Obviously, there are dangers associated with any tool that can alter the basic chemistry of people, as is the case for CRISPR cas9, but the suffering this approach can relieve makes its further development worth the risks.
Dr. Lechtenberg is an Easton resident who graduated from Tufts University and Tufts Medical School in Massachusetts and subsequently trained at The Mount Sinai Hospital and Columbia-Presbyterian Medical Center in Manhattan. He worked as a neurologist at several New York Hospitals, including Kings County and The Long Island College Hospital, while maintaining a private practice, teaching at SUNY Downstate Medical School, and publishing 15 books on a variety of medical topics. He worked in drug development in the U.S., as well as in England, Germany, and France.
