The first drug for sickle cell disease with the help of CRISPR gene-editing technology was approved by the Food and Drug Administration on December 8th. This innovative sickle cell disease treatment offers a potential solution to individuals who are born with the chronic and life-limiting blood disorder. Researchers Jennifer Doudna and Emmanuelle Charpentier first reported the novel method of editing genes known as CRISPR in a scientific publication just eleven years ago. Both of them won the 2020 Nobel Prize in Chemistry for their groundbreaking discovery, which has the potential to revolutionize the treatment of hereditary diseases.
The FDA approved the first treatment using this technology in the nation on December 8. That’s exceptionally quick in the field of medicine. Berkeley Doudna, professor of chemistry and molecular and cell biology at the University of California, says, “It’s remarkable.” “It’s amazing to observe how quickly—and, to be honest, how safely and successfully—this therapy is being implemented in humans.”
Vertex Pharmaceuticals and CRISPR Therapeutics produce the novel medicine Casgevy. The technology that can effectively and accurately repair DNA mutations has advanced scientifically with its approval, opening the door to an exciting new age of genetic therapies for inherited medical conditions. Therefore, Beta thalassemia and sickle cell disease patients can now receive the CRISPR medicine exa-cel (brand name: Casgevy), developed by Vertex Pharmaceuticals and CRISPR Therapeutics (co-founded by Charpentier), with approval from the FDA in the UK.
A Brief about Sickle Cell Disease
A genetic condition known as sickle cell disease alters the structure of red blood cells responsible for carrying oxygen throughout the body. Individuals suffering from these medical conditions are born with blood cells that are modified genetically. When hemoglobin-coding genes are mutated, blood cells with sickle cell disease adopt a sickle shape instead of a spherical one. This clogs small blood vessels and increases the possibility of stroke and possibly deadly pain episodes. Although bone marrow transplants can also be used for swapping sickled cells with healthy cells, most patients are not eligible for this treatment because it works best when both the recipient and donor are perfectly matched.
Since sickle cell is inherited, patients with the condition have an even lower probability of getting a healthy sibling donor. Although related donors make the most suitable matches, there is a chance of just 25% that a sibling with the condition would be compatible with the patient. Although they are possible through databases, transplants from non-related donors have substantially lower efficacy. However, this method is tedious, cannot be administered in younger individuals, and has meagre success rates.
CRISPR Gene-Editing Technology
CRISPR technology can boost the number of healthy blood cells in both patient groups. By March 2024, the FDA will call on whether to treat beta-thalassemia after approving exa-cel for sickle cell disease. The agency recently approved lovo-cel, a more conventional gene therapy for the condition, from Bluebird Bio (brand name: Lyfgenia). This means that sickle cell sufferers now have two potent new methods for dealing with the terrible and crippling attacks that are the disease’s signs and symptoms.
How do Lovo-cel and Exa-cel Function?
Since CRISPR relies on altering mutated genes in a single treatment that may result in an effective remedy, it is an excellent therapeutic for various medical conditions. Blood stem cells are derived from a patient’s bone marrow, from which the body produces all blood and immune-related cells. The cells are then extracted from the blood and cultured in a solution with higher oxygen-carrying capacity than adult hemoglobin but often departs after delivery.
- After learning that approximately 10% of individuals naturally continue to produce fetal hemoglobin throughout their later years and stay healthy, researchers searched for ways to boost the level of fetal hemoglobin. Those with sickle cell disease also appeared to have fewer variants among them.
- According to their analysis, boosting the blood’s fetal hemoglobin levels might significantly lower the possibility that sickled cells will bind together and block tiny capillaries by giving healthy blood cells an advantage over sickled ones.
- Exa-cel targets the gene that turns off fetal hemoglobin with the help of CRISPR technology to achieve this. It’s like erasing the stop sign and letting the vehicle propel forward for fetal hemoglobin. This is how Sharl Azar, medical director of Massachusetts General Hospital’s comprehensive sickle cell disease treatment department, explains things.
Using a modified virus incapable of causing disease, Lovo-cel introduces a new hemoglobin gene that resembles the standard form and has an anti-sickling function specified. Hemoglobin from lovo-cel “cuts down the chain, so they cease to produce the long rods anymore,” according to Rich Colvin, chief medical officer at Bluebird. Sickled cells typically form long, stiff chains that may block vessels and cause discomfort. Patients have less painful blockages because they possess healthier, unsickled blood cells.
The Success of Gene Editing in Sickle Cell Patients Presents Concerns and Hope
Gene editing is being researched as a potential treatment for several diseases, from prevalent conditions like cancer, heart disease, diabetes, AIDS, and Alzheimer’s to uncommon genetic disorders like muscular dystrophy. This is because gene editing makes it easier for scientists to modify the fundamental building blocks of life.
- A genetic disorder that results in an abnormal form of hemoglobin, a protein that red blood cells need for carrying oxygen throughout the body, is the underlying cause of sickle cell disease. Consequently, sickle cell patients’ red blood cells develop into abnormal sickle-shaped cells that become blocked in blood vessels. This shortens the lives of patients by damaging vital organs and causing terrible, unexpected pain attacks.
- About 100,000 people in the United States and millions worldwide are affected by sickle cell disease, which is disproportionately common in persons of African, Middle Eastern, and Indian origin. Sickle cell disease is among the most prevalent inherited infections despite being uncommon.
- While some individuals can recover from bone marrow transplants, most cannot find a suitable donor. The severe type of the disease will initially be treated with CRISPR therapy in about 20,000 patients in the United States.
The FDA’s Verdict
The FDA considered research involving 31 sickle cell disease patients who had recurring blood vessel clogging before deciding to approve exa-cel. Twenty-nine did not experience any such threats for an entire year following their exa-cel treatment. Experts anticipate that these initial findings lead to prolonged, maybe lifetime, independence from hospitalizations and painful episodes, even though it’s unclear how long the consequences will last.
- The agency reviewed a study of 32 patients using lovo-cel; 28 did not have an attack during the two-year trial period.
- The agency took potential adverse effects into account as well. When it comes to CRISPR, off-target editing—a technique where the CRISPR modifies genes that are incorrectly edited or that could cause cells to begin proliferating uncontrollably into tumors—is the most harmful.
- Patients undergoing the therapy so far have not reported these or any other significant side effects. The exact position of the healthy hemoglobin gene insertion in lovo-cel is a considerable problem.
- Still, according to Colvin, a research analyst, research till now indicates that the gene can be introduced up to three times in a single cell without being likely to cause abnormal cell division.
However, Dr. Markus Mapara, clinical director of the adult bone marrow transplant and cell therapy program at NewYork, who has directed multiple gene therapy trials and advised CRISPR Therapeutics, says that “only time will reveal whether we caused more damage than good by carrying out these genetic modifications.”
A Challenging Journey but a One-Time Therapy
Even though both therapies can potentially change lives, therapy is demanding and takes several months. These treatments include an invasive bone marrow transplant as well as testing and treatments lasting almost a year. Head of the pediatric stem-cell transplant program at NewYork-Presbyterian/Columbia, Dr. Monica Bhatia, further states, “It’s not for the faint of heart.” People must have experienced numerous instances of blockages from sickle cell disease to be capable of receiving either therapy. They must also be more than 12 years old.
- First, sickled cells are exchanged with healthy ones through multiple exchange blood transfusions. Before therapy, the three- to four-month-long outpatient process temporarily minimizes inflammation and lowers the chance of blocks and strokes.
- When sickle cell counts are sufficiently low, patients are admitted to the hospital so medical professionals can extract enough stem cells from their bone marrow for CRISPR editing or remodeling to produce healthy hemoglobin. Then, they reintroduce the cells back into the patients.
- This may require multiple extraction rounds because sickle cell patients’ bone marrow isn’t as strong as that of healthy individuals, and some patients may not be able to generate enough cells to be eligible for treatment, according to a research expert, Mapara.
- When enough stem cells are recovered, the doctors send them to the labs of Vertex and Bluebird, where researchers undertake gene therapy or CRISPR editing, which generally takes eight to twelve weeks, to get the cells to begin regenerating normal hemoglobin.
- When the CRISPR or gene therapy cells become available, patients undergo rigorous chemotherapy to eliminate preexisting bone marrow to provide space for the newly modified cells. These cells will then seed a population of healthy defense and blood cells. Even more demanding and more dangerous than the exa-cel or lovo-cel itself, this chemotherapy is probably the most challenging aspect of the entire process. It may hurt as well.
- Patients eventually receive an injection of CRISPR or gene therapy cells three to four days post-chemotherapy. After that, they spend a further four to six weeks in the hospital as medical professionals check for infections and gauge how rapidly healthy blood cells grow again.
Most sickle cell doctors think the majority of patients would benefit from both treatments in the coming years. The long-term organ dysfunction that sickle cell disease leaves behind could be avoided for patients if a medicine is developed that could effectively cure the condition. According to Mapara, the sooner individuals receive treatment, the more likely they will continue to lead pretty healthy lives with functional organs.
According to him, “once tissue is dead, it’s not recoverable,” so sickle cell attacks can harm, for instance, bones. He is happy that the treatment is now authorized for use in patients 12 years of age and above, allowing even younger people to benefit from the chance to treat their condition before it causes severe organ damage.