December 2023 saw FDA approval of two novel treatments for Sickle Cell Disease. Taking a gene therapy approach to the disease, researchers hope that this new technology heralds a revolution in how doctors treat this chronic inherited condition.
Misshapen Cells
In sickle cell disease, defective haemoglobin impairs the function of red blood cells by making them sticky and abnormally shaped. Scientists have designed the new treatments, Casgevy and Lyfgenia, to replace the faulty gene that causes red blood cells to take on their ‘sickle’ like shape.
Sickle cell disease is a genetic condition. The patient inherits a faulty version of the adult haemoglobin gene from their parents. The sickled cells can clog up blood vessels and impair oxygen delivery to tissues. This leads to vaso-occlusive events, and it can cause strokes in sickle cell patients. The body also breaks the faulty red blood cells down faster, which can result in anaemia. When congested blood vessels stop blood flowing to organs, it can trigger bouts of extreme pain often called ‘sickle cell crises’.
New Technology
Casgevy, made by Vertex Pharmaceuticals, is based on a gene-editing technology called CRISPR/Cas 9. With this technology, the patients’ cells can be reprogrammed to produce normal haemoglobin by editing specific genetic information to compensate for the coding errors.
Lyfgenia, made by Bluebird Bio takes a slightly different approach, using a gene delivery tool to insert a new gene into cells to produce standard haemoglobin.
Limited Solutions for a Wide Spread Condition
In 2021, over half a million babies were born with sickle cell disease with more than three quarters being in Sub-Saharan Africa. Globally, almost eight million individuals are living with sickle cell disease, according to a study published in The Lancet haematology. The CDC states that, sickle cell affects 100,000 people in the United States with more than 90% of them being non-Hispanic Black or African American.
Until now, there have been limited options for treating sickle cell disease. Doctors work with patients to manage their condition by addressing symptoms. For example, giving painkillers for pain, and blood transfusions for anaemia. These approaches, however, provide only temporary relief without addressing the root cause of the illness.
Here Comes the Science Part
In some cases, bone marrow transplants have successfully resolved the disorder. This involves replacing the red blood cell factories stored inside a sickle cell patient’s bones with correctly functioning blood stem cells from another person. Unfortunately stem cell transplants are hard on both the donor and the recipient, and often lead to complications. These troubles have been exacerbated by the difficulty patients experience in finding matching donors.
Gene therapy avoids the complications inherent to transplanting stem cells from another person. Instead of hoping that a patient’s immune system will not attack the new blood stem cells, making use of a patient’s own stem cells ensures that the new cells are a perfect match. Harvesting a patient’s own stem cells, adding new genetic code for the haemoglobin gene in the lab, then grafting them back in, greatly lowers the chances of graft rejection.
The Results are In
Clinical trials for the two treatments have yielded encouraging results.
In the case of Casgevy, 44 patients were treated and 31 of them were followed for up to two years. Among the 31, 29 did not have the painful crises associated with sickle cell for at least 12 consecutive months. None of the patients experienced graft rejection or graft failure during the subsequent 24-month follow-up. The side effects associated with Casgevy were minor, including mouth sores, abdominal pain, muscle pain, nausea, low platelets and white cells. However, no major concerns were reported.
In the follow-up study for Lyfgenia, 28 of the 32 patients did not experience painful crises for a period of 6 to 18 months after treatment. The common side effects reported were mouth sores, low levels of platelets, white cells and red blood cells. However, two of the subjects developed acute myeloid leukaemia, which is a type of blood cancer, and the manufacturers have issued a warning regarding this.
Molecular Scissors and Gene Replacement
Casgevy and Lyfgenia work in different ways to restore normally functioning haemoglobin.
Cut
Casgevy employs CRISPR/Cas 9 gene editing tools. With this technology, scientists can make direct alterations to the genetic material contained in the blood stem cells using molecular scissors to cut out specific sections of DNA. This allows scientists to switch genes on and off or to rewrite portions of the code.
The strategy taken with Casgevy is to reactivate a healthy but silenced haemoglobin gene. People with sickle cell disease produce a defective type of haemoglobin called haemoglobin S. Normal adult haemoglobin is called haemoglobin A.
When we are in our mother’s wombs, we produce fetal haemoglobin or haemoglobin F. However, during our early lives, we gradually replace production of fetal haemoglobin with haemoglobin A.
Casgevy alters the genetic makeup of individuals so that they start producing fetal haemoglobin again. Casgevy targets and deletes the gene that keeps the Haemoglobin F gene silent. When this gene is switched off, the cells start producing Haemoglobin F again. Circulating haemoglobin F can compensate for the faulty haemoglobin S, so the cells will be less likely bend into their sticky, troublesome sickle shape.
Paste
Lyfgenia works by using a virus to paste a gene into the stem cell’s DNA. The virus literally grafts a copy of the new gene into the chromosome. This gene directs the production of a potent form of haemoglobin A which is very effective in transporting oxygen to tissues. As with Casgevy, the aim is to out compete the faulty haemoglobin S.
Stem Cells are Go
The process of treatment with both options requires close monitoring. Initially, doctors assess the patient to determine whether they are suitable for the therapy. They undergo a series of blood transfusions to reduce the number of circulating sickle cells.
Next, the patient’s blood-producing cells are harvested and modified using the respective therapies. Later, doctors infuse modified blood-producing cells back into the patient and they then start producing the functional haemoglobin. Before infusion of the modified stem cells, the patient undergoes chemotherapy to reduce the defective blood-producing cells in the bone marrow.
The patients are then monitored to ensure the transplanted stem cells take hold and start producing healthy red blood cells.
Looking to the Future
Gene-based treatments for sickle cell shine a ray of hope to the patients, initial reports have had great results. These therapies present an opportunity for people to get treatment for a genetic condition and they have set a foundation for experts to use these principles to come up with treatments for other genetic disorders. Although the gene editing therapies are currently costly, those in need of the treatments can only hope that the authorities will come to their rescue by negotiating subsidies and insurance payment models that will make the treatment accessible.
References
GBD 2021 Sickle Cell Disease Collaborators. Global, regional, and national prevalence and mortality burden of sickle cell disease, 2000–2021: a systematic analysis from the Global Burden of Disease Study 2021 [published correction appears in Lancet Haematol. 2023 Aug;10(8):e574]. Lancet Haematol. 2023;10(8):e585-e599. doi:10.1016/S2352-3026(23)00118-7
- ‘Data and Statistics on Sickle Cell Disease.’ Centers for Disease Control and Prevention, Centers for Disease Control and Prevention, 15 May 2024, www.cdc.gov/sickle-cell/data/?CDC_AAref_Val=https%3A%2F%2Fwww.cdc.gov%2Fncbddd%2Fsicklecell%2Fdata.html.
- ‘FDA Approves First Gene Therapies to Treat Patients with Sickle Cell Disease.’ U.S. Food and Drug Administration, FDA, 8 Dec. 2023, www.fda.gov/news-events/press-announcements/fda-approves-first-gene-therapies-treat-patients-sickle-cell-disease.
