Introduction
After relentless efforts spanning over a period of nearly two decades, the first sickle-cell treatment, known as CRISPR (clustered regularly interspaced short palindromic repeats) therapy, has been finally developed. The treatment is expected to benefit thousands of patients suffering from this disease and lead a normal life. Regarded as an innovative and first-of-its-kind treatment, the therapy is referred to as Casgevy, and can be used for the treatment of two genetic blood disorders, namely, sickle-cell disease (SCD) and Thalassemia. The therapy includes gene-editing technology and has life-saving capabilities. It will soon be available to patients in the United Kingdom (UK), with the approval of the UK regulators.
On November 16, 2023, the UK’s Medicines and Healthcare products Regulatory Agency (MHRA) made one of its remarkable decisions and gave its first regulatory approval for Casgevy, also known as exagamglogene autotemcel or Exa-cel. The MHRA carried out a thorough examination of its quality, safety, and efficiency before giving its approval. This may serve as a catalyst for the emergence of a new age of gene therapy. The US Food and Drug Administration (FDA) has also declared the drug safe to use for clinical purposes.
MHRA acts as an executive agency of the Department of Health and Social Care in the UK. It is the authority responsible for standardising the medicines and medical instruments in the country. It ensures that they are effective, acceptable, and safe.
Sickle-Cell Disease
The sickle-cell disease is a lifelong genetic disorder that occurs due to the transformation in the genes and coding of haemoglobin. It is a medical emergency condition that causes the production of C-shaped red blood cells in the patient’s body instead of the usual round-shaped cells. These sickle-shaped blood cells get attached to each other and obstruct the blood vessels. This leads to anaemia in the patients. It might also put different organs of the body at great risk of failure along with causing spells of extreme pain, usually called ‘pain crises’.
Haemoglobin is a protein molecule found in the red blood cells, with the help of which they carry oxygen throughout the body. It is also used to make red blood cells.
Symptoms of SCD
Patients suffering from SCD often have to tolerate excruciating body pain that is often regulated by giving morphine. They need to be admitted to hospital to relieve their pain and prevent organ failure. Young SCD patients are more prone to stroke, severe infections, anaemia, and lethargy.
Why the SCD
SCD is a hereditary condition received from both the parents, who transfer a particular gene. It has been found that around 300 babies, born each year in the UK, have this disease. At present, around 15,000 people living in the UK are suffering from SCD. SCD is found to be predominant among people who belong to Africa or African-Caribbean region. It can be diagnosed with a simple blood test. However, it is very likely that a child may have the gene but not the disease.
It has been estimated that over 100,000 people in the United States are suffering from SCD. However, some populations have a greater number of SCD cases compared to others.
Function of Casgevy
Casgevy works on the basis of CRISPR, an innovative gene-editing technique, invented in 2012. In this technique, genes are pulled out from the DNA with the help of an enzyme, Cas9. Casgevy acts as molecular scissors that aim at DNA via an RNA molecule. It aims at BCL11A, a particular gene code that monitors the switching of haemoglobin from the fatal to the adult version once the baby has been born. However, the adult version of haemoglobin is found to be defective in the patients having SCD.
In 2020, the inventors of the CRISPR technology, Emmanuelle Charpentier and Jennifer Doudna, were conferred with the Nobel Prize in Chemistry.
Hence, Casgevy works at disabling BCL11A so that the fatal version of haemoglobin is continuously formed in the body, as the adult version malfunctions. For doing this, the doctors take out blood-making stem cells from the bone marrow of the patient and edit the BCL11A gene in the lab with the help of Casgevy. Then, they implant the modified cells containing the appropriate haemoglobin in the patient’s body. Prior to the implantation, busulfan, a chemotherapy drug is given to the patient so that the remaining unedited cells, if any, in their bone marrow can be removed. The patient’s body takes a long time to adjust to the edited cells. These cells start residing in the bone marrow and gradually make red blood cells using the reliable form of haemoglobin. The patient has to stay in hospital for a month or so for monitoring purposes.
Impact of Casgevy
It was observed that during a couple of late-stage clinical trials, Casgevy successfully fixed haemoglobin production and even reduced the symptoms in a large number of SCD patients. It was also noticed that when Casgevy was used for the treatment of SCD, no extreme pain crises occurred in twenty-eight out of twenty-nine patients for a year or so.
Although there were no safety concerns raised during these trials of Casgevy, only fever, tiredness, nausea, and other such temporary side effects were noticed. The therapy’s manufacturers, i.e., Vertex Pharmaceuticals and CRISPR Therapeutics, along with the regulatory bodies, the MHRA and the FDA, are continuing these trials in order to closely examine the effectiveness and long-term safety of Casgevy.
However, CRISPR therapies may have certain concerns, such as they may have off-target effects. This happens when the unintended parts of the genome are treated by Cas9, leading to unexpected side effects. Hence, it is critical to ensure that the therapy aims at only the mutated gene and not any other genes in the genome.
Regions that Approved Casgevy
So far, Casgevy has got the approval only in the UK. The MHRA has declared that it can be safely used for treating people who are 12 years old or above. As per Vertex, the Saudi Food and Drug Authority, the FDA and the European Union’s European Medicines Agency are still in the process of reviewing the treatment.
When Casgevy will Reach the Market
It is still uncertain when Casgevy will reach the market, but its cost will determine its scope. Gene therapies are highly expensive, and Casgevy will also follow suit. As a result, many people might not be able to use it. The authorities will have to work on making it accessible around the world.
According to Amanda Pritchard, the National Health Service (NHS) Chief Executive, “The moment that a new drug comes that is approved to be used, our job is to make sure that we can do a deal to ensure it is affordable and get it out as quickly as possible.” The charitable Sickle Cell Society asserted that the new treatment is a ‘ray of hope’ for all people suffering from the most common genetic blood condition in the world.
Conclusion
Though the genetic basis of SCD has been recognised since 1957, there have been very few treatment options. In recent years, the technology has advanced rapidly. Nevertheless, there has been no considerable improvement in the life expectancy of SCD patients. However, since the invention of CRISPR, the field of gene therapy has been revolutionised, as it has facilitated gene targeting. It is expected that the therapy will help SCD patients to manage their pain crises better and lead a normal life.
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