by Sophia Renauld
figures by Salvador Balkus

Our understanding of the genetic material, or DNA, that makes up organisms has exploded over the last several decades. We have discovered that DNA is made up of multiple genes, and that different genes have different functions. We have also found that there is inherent variability in genes, meaning that the DNA of one organism is not identical to the DNA of another. Scientists have used this new understanding to develop tools to edit DNA, creating technology that has largely been restricted to scientific studies. Recently, however, a genetic editing technique has shown success in treating the genetic disorder sickle cell disease in humans, fundamentally changing the lives of patients with the disease. In December 2023, the FDA approved two different gene-editing therapy treatments for sickle cell disease. This approval represents a massive technological advance in our ability to alter the genetic material of humans to treat debilitating diseases.

Sickle Cell Disease: An overview

Sickle cell disease affects around 100,000 people in the United States, predominantly Black patients. This disease is a genetic blood disorder that affects the patient’s red blood cells (RBCs). RBCs need a protein called hemoglobin to carry oxygen from the lungs to the rest of the body. In patients with sickle cell disease, the gene that makes hemoglobin is mutated, decreasing the ability of hemoglobin to carry oxygen. Instead, the proteins stick together and form long chains within RBCs, causing the cells to turn from a normal doughnut shape into the characteristic “sickle cell” shape (Figure 1).

The diseased cells cause multiple problems in the body. For example, sickle cells can block blood vessels, which means that organs such as the liver, kidney, spleen, and brain do not receive the oxygen they need. This causes transient organ damage called ischemia, which can become permanent if oxygen flow is not restored. Ischemia then triggers an immune response. This cascade of symptoms is called a vaso-occlusive crisis. Patients also experience symptoms such as dizziness, swollen fingers or toes (dactylitis), yellowing of the skin or eyes (jaundice), and periodic episodes of extreme pain, known as pain crises (Figure 1). Sickle cell disease can also cause acute chest syndrome, a combination of fever and pulmonary symptoms that can be fatal. 

Patients with sickle cell disease are usually diagnosed at birth and spend much of their lives in the hospital from disease-related complications. Historically, this disease was lethal in childhood, but medical advancements have made it possible for patients to live to be middle aged. The only curative treatment is a transplant of healthy blood stem cells, which requires finding a genetically matched donor, and can have serious side effects like graft rejection, graft versus host disease, and infections. Graft rejection and graft versus host disease happen because the patient’s immune system launches an attack on the donated material, recognizing it as foreign and rejecting it.

How to Fix Hemoglobin

Today, there are two new therapies to improve the lives of patients with sickle cell disease. Both work by compensating for the lack of functional hemoglobin due to the mutated hemoglobin gene, but use two different strategies. One strategy is to correct the genetic mutation by supplying the correct DNA for producing hemoglobin. This can be done by introducing an unmutated copy of the hemoglobin gene into the DNA of the patient. The other strategy is to shift from relying on adult hemoglobin to a different form of hemoglobin, fetal hemoglobin, which is encoded by a different, unmutated piece of DNA. Fetal hemoglobin is only expressed early in life, allowing fetuses to share blood with their mother. To get oxygen, fetal hemoglobin must remove oxygen from maternal hemoglobin. Therefore, fetal hemoglobin has an even higher affinity for oxygen than the adult form. Normally, fetal hemoglobin stops being produced soon after birth, but scientists have figured out how to turn fetal hemoglobin production back on. Both strategies have been shown to treat the symptoms associated with sickle cell disease and restore the oxygen-carrying capacity of blood.

Gene Editing

Both of these approaches, inserting a functional copy of the hemoglobin DNA or turning on the production of fetal hemoglobin, are achieved through editing the genes of blood stem cells. Blood stem cells are immature cells in the blood and the bone marrow that grow into different types of blood cells. These therapies take blood stem cells from patients with sickle cell disease, edit them, and then infuse the edited cells back into the patient (Figure 2). The edited blood stem cells are then able to produce cells with normal functioning hemoglobin, treating the sickle cell symptoms. Unlike blood stem cell transplants, this treatment does not require a genetically matched donor as patients act as their own donors. This means, unlike with traditional blood stem cell transplants, it is unlikely the donated material will trigger an immune response, since the material is from the patient themselves.

One way to edit genes is by adding DNA sequences. The drug Lyfgenia uses a viral vector to add additional copies of the un-mutated, functional hemoglobin gene to the patient’s blood stem cells. Viral vectors are a way to deliver genetic material inside cells, made by replacing the disease-causing genetic material within viruses with the DNA used to treat a disease. The vector used in Lyfgenia delivers and incorporates unmutated hemoglobin DNA into the DNA of blood stem cells, which will be used to make normal hemoglobin protein (Figure 3). This method of delivering DNA to cells through viral vectors has shown promise in treating other diseases, such as severe combined immunodeficiency (SCID), muscular dystrophy, and hemophilia, but has only recently been approved to treat sickle cell disease.

The other method, Casgevy, utilizes CRISPR-Cas9 gene editing to increase the production of fetal hemoglobin and is the first approved treatment of its kind. CRISPR-Cas9, sometimes called “molecular scissors”, is a way to cut and paste DNA at specific sites. To increase fetal hemoglobin production, this therapy disrupts the activity of another gene, BCL11A, which usually switches off fetal hemoglobin production. Casgevy causes a double-stranded DNA break in BCL11A, markedly decreasing the production of the BCL11A protein. Disrupting BCL11A production increases fetal hemoglobin production, compensating for the non-functional hemoglobin in sickle cell disease (Figure 3). 

The FDA approval of these therapies represents a massive step forward in allowing genetic editing in humans. Casgevy is the first therapy using the CRISPR-Cas9 method to be approved, paving the way for potential future CRISPR-Cas9 gene editing therapies to treat genetic diseases.

What This Means for Patients

These two therapies have been approved for patients over the age of 12 with severe sickle cell disease, and are in clinical trials for children 2-12 years old. Gene therapies for sickle cell have shown incredible effects in preventing vaso-occlusive crises in patients and improving quality of life. While effective, some side effects have been noted, including fevers, mouth sores, and low levels of platelets and white blood cells.

It is important to note, though, that these treatments are incredibly expensive. Casgevy is priced at $2.2 million and Lyfgenia at $3.1 million per treatment, comparable to the cost of gene therapies for other diseases. Even with insurance, this cost could pose a significant barrier for patients. Since around 70% of people with sickle cell disease are on Medicaid, there are numerous concerns with the financial feasibility of these treatments. The development of the two therapies required decades of careful scientific research and promising clinical trials. Yet, ensuring this treatment will make it into the blood cells of patients with sickle cell disease requires action at the health policy level.

Although questions remain about the cost and delivery of these new sickle cell disease gene therapies, their approval is truly a scientific milestone. Not only will these therapies help thousands of individuals with sickle cell disease, but they also show that our ability to alter human DNA has tremendous therapeutic potential. The successes of these therapies inspire hope for additional gene therapy treatments for other genetic diseases.

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Sophia Renauld is a student in the Harvard-MIT MD-PhD Program and is currently a first year PhD Candidate in the Neuroscience Program at Harvard University. You can find her on twitter @Sophia_Renauld.

Salvador Balkus is a PhD student in Biostatistics at the Harvard T.H. Chan School of Public Health.

Cover image by motionstock from pixabay.

For more information:

• Read here for more information on how CRISPR-Cas9 works.
• For more information on viral vectors in the treatment of genetic diseases, read here.
• To learn more about the published clinical trial results, read here for Casgevy, and here for Lyfgenia.
• If you have sickle cell disease, talk to your provider about whether Casgevy or Lyfgenia may be an option for you. For more information on Casgevy, read here for information from the manufacturer (Vertex Pharmaceuticals). For more information on Lyfgenia, read here for information from the manufacturer (Bluebird Bio).