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In a landmark decision last week, the US Food and Drug Administration (FDA) approved two treatments involving cell-based gene therapies. 

An agency within the US Department of Health and Human Services, the FDA assures the safety, effectiveness, and security of human and veterinary drugs, vaccines, and other biological products for human use, as well as medical devices. 

The two milestone treatments approved by the FDA are Casgevy and Lyfgenia, which represent the first-ever cell-based gene therapies in treating sickle cell disease (SCD) in patients aged 12 and older.

Sickle cell disease is a rare, painful, inherited blood disorder that affects more than 100,000 people in the US — most commonly African Americans and Hispanic Americans, with about 20 million people worldwide suffering from this disease.

In this condition, the main problem is a mutation in hemoglobin (Hb), a protein found in red blood cells that is responsible for delivering oxygen to your entire body’s tissues. Red blood cells normally are disc-shaped but the mutation causes them to develop a “sickle” or crescent shape. 

These sickled red blood cells do not move easily and tend to stick together, restricting the flow in blood vessels and limiting oxygen delivery to the body’s tissues. This then leads to severe pain and problems like stroke, infections, and organ failure.

Sickle cell disease is not only a lifelong illness but is also life-threatening and could lead to early death. Currently, the only cure for this disease is a bone marrow transplant from a donor. However, it carries the risk of rejection by the immune system and the difficult process of finding a matching donor. Now, gene therapy is being looked into to offer a possible cure for this potentially fatal disease.

In both of the recently approved genome editing approaches, patients’ own blood stem cells are used, meaning the patient themselves is the donor. These cells are then modified and finally given back to the patient. 

This blood stem cell transplant involves a single dose, one-time infusion. In this process, stem cells are collected before the treatment. Subsequently, the patient undergoes myeloablative conditioning, which removes cells from the bone marrow. These cells are then replaced with the modified cells in Casgevy and Lyfgenia.

Patients receiving either of the treatments will be followed in a long-term study to evaluate the safety and effectiveness of the products and whether they actually help patients get better and live longer, as well as any complications. 

Both these approvals of cell-based gene therapies are seen as an “important medical advance” in targeting potentially devastating diseases and improving public health.

“Gene therapy holds the promise of delivering more targeted and effective treatments, especially for individuals with rare diseases where the current treatment options are limited.” 

– said Nicole Verdun, MD, director of the Office of Therapeutic Products within the FDA’s Center for Biologics Evaluation and Research.

The Innovative Gene Editing Tech

One of the therapies recently approved by the FDA, Casgevy, is the first treatment to utilize a novel genome editing technology, marking a significant advancement in the gene therapy field. This technology, known as CRISPR/Cas9, earned Jennifer Doudna and Emmanuelle Charpentier the Nobel Prize in 2020. Employing these ‘genetic scissors,’ researchers and scientists can precisely alter the DNA of animals, plants, and microorganisms, a technique that holds breathtaking potential.

Genome editing or gene editing is a group of technologies allowing changes to an organism’s DNA. These tools allow for targeting particular locations in the genome and adding, removing, or altering the DNA accurately. While several approaches to genome editing have been developed, CRISPR-Cas9 is a popular one, which is short for clustered, regularly interspaced, short palindromic repeats.

This unique type of genome editing technology, CRISPR/Cas9, enables editing parts of the genome by adding, removing, or modifying sections of the DNA sequence. This gene-editing tech has been creating a lot of buzz in the science world thanks to being a simple, precise, cheaper, more efficient, and versatile way of genetic manipulation.

In CRISPR/Cas9, there are two essential components — a guide RNA to match a desired target gene and CRISPR-associated protein 9 or Cas9, which causes a double-stranded DNA break to allow for any changes to the genome.

This gene editing technology is an adaptation to the genome editing system that naturally occurs in our body and is used by bacteria as an immune defense. So, what happens is when we get infected with viruses, its DNA pieces are used by the bacteria to position themselves into their own to create CRISPR arrays. These CRISPR arrays are particular patterns that allow the bacteria to remember the viruses.

Consequently, when the viruses attack again, the bacteria produce segments of RNA (Ribonucleic acid that is present in most living organisms and viruses and is essential for most biological functions) from CRISPR arrays that recognize the DNA of viruses and get attached to their specific regions. At this stage, the bacteria then use molecular scissors Cas9 to edit the DNA, thereby disabling the virus. 

Now, this immune defense system is adapted to edit DNA. Here, a small piece of polymeric molecule RNA is created with a “guide” sequence that affixes to a specific target sequence in both the cell’s DNA and to the Cas9 enzyme. So, when it is initiated into the cells, the guided RNA recognizes the planned DNA sequence, and the Cas9 (CRISPR-associated protein 9) then splits the DNA at the particular location. At last, using the DNA repair machinery of the cell itself, changes are made to the DNA.

So, gene editing is of great interest in the prevention and treatment of human diseases with scientists working to determine whether this approach is safe and effective for use in people. 

Currently being explored in research and clinical trials for diseases like cystic fibrosis, hemophilia, and sickle cell disease, this approach shows promise for treating and preventing more complex illnesses such as cancer, heart disease, diabetes, Alzheimer’s, and HIV infection. However, due to ethical and safety concerns, germline cell and embryo genome editing is illegal in many countries.

Effectiveness of the Cell-based Gene Therapies

Developed by Boston-based CRISPR Therapeutics and Vertex Pharmaceuticals, the CRISPR treatment is a one-time intervention designed to provide lifelong symptom relief. In this treatment for sickle cell disease, aimed at patients 12 years and older who experience recurrent vaso-occlusive crises, the CRISPR/Cas9 technology is employed to alter the blood stem cells of patients through genome editing.

The patient’s DNA is accurately cut in targeted areas, and then altered blood stem cells are transferred back. Inside the patient, these cells attach and multiply within the bone marrow and increase the production of a special type of hemoglobin (fetal hemoglobin or HbF) that facilitates oxygen delivery to prevent the sickling of red blood cells.

Data reveals that 44 adult and adolescent patients with sickle cell disease (SCD) with a history of two several vaso-occlusive crises (VOCs) in total were treated with Casgevy in the trial, and 31 of them had sufficient follow-up time to be evaluable. Out of this 93.5%, 29 patients got rid of severe VOC episodes for at least 12 consecutive months. Meanwhile, all the treated patients had successful engraftment, with no graft rejection or failure reported in any of the patients.

Meanwhile, the most common side effects recorded were mouth sores, nausea, vomiting, headache, and itching. Low levels of platelets and white blood cells, musculoskeletal pain, abdominal pain, fever, and low white blood cell count were other side effects of the Casgevy treatment.

Lyfgenia is another cell-based gene therapy approved by the FDA for drugmaker Bluebird Bio Inc. This treatment, unlike CRISPR-based therapies, makes use of a gene delivery vehicle; a lentiviral vector for genetic modification. In this more conventional form of gene therapy treatment, the blood stem cells of patients with SCD and a history of vaso-occlusive events are genetically modified to produce HbAT87Q.

HbAT87Q is a gene-therapy-derived hemoglobin that functions similarly to the normal adult hemoglobin A produced in persons not affected by sickle cell disease. Modified stem cells, which contain this special hemoglobin and have a lower risk of sickling and blocking blood flow, are then delivered to the patient. 

When it comes to the safety and effectiveness of Lyfgenia, based on the analysis of data from a single-arm, 24-month multicenter study in patients, 88% of 32 patients, which is 22 patients, achieved complete resolution of vaso-occlusive events (VOEs) during this time period. 

As for the side effects, low levels of platelets, red blood cells, and white blood cells, along with mouth sores of the lips, mouth, and throat, are some of the most basic ones. Fever and low white blood cell count have also been recorded, consistent with chemotherapy and the underlying disease. Additionally, hematologic malignancy or blood cancer has occurred in patients treated with Lyfgenia. Therefore, patients receiving this product should have lifelong monitoring for these malignancies. 

Limitations With the New Therapies

Eagerly awaited by patients, families, providers, and physicians, these two therapies essentially change things significantly, with SCD to be potentially seen as a curable disease instead of a painful and debilitating one. 

Reflecting on this shift, Dr. Alexis Thompson, chief of the division of hematology at Children’s Hospital of Philadelphia, said in an interview:

“I think this is a pivotal moment in the field. It’s been really remarkable how quickly we went from the actual discovery of CRISPR, the awarding of a Nobel Prize, and now actually seeing it being an approved product.”

However, these new therapies are not without their issues. Firstly, they are very expensive. As stated by Vertex, the cost is an eye-watering $2.2 million per patient, putting it out of reach for most, if not many, families. This figure doesn’t even account for the full price, as the cost of care associated with the treatment, like chemotherapy or a prolonged hospital stay, drives this number even higher. These treatments have multiple phases involving months of follow-up care and a recovery period. In fact, not just Casgevy, but the wholesale price of Lyfgenia is also just as expensive at $3.1 million.

Addressing these concerns, advocates point out that living with the disease itself incurs immense costs. For those with commercial insurance, the average lifetime cost is around $1.7 million. Consequently, the high initial price of treatment could be offset by the savings from avoiding the lifetime complications of the SCD disease. Another significant challenge is insurance coverage. Treatment can only commence once the patient’s insurer agrees to pay, and this process can take months.

On top of the cost challenges, most hospitals are not authorized to offer these breakthrough treatments. Currently, only nine centers are permitted by Vertex to offer Casgevy treatment, with plans to eventually expand to about 50. Similarly, Bluebird has authorized 27 centers for Lyfgenia and intends to increase this number as well.

But even then, genome editing requires rigorous and complicated procedures that many hospitals simply cannot provide. Not only do countries with the majority of sickle cell patients lack sophisticated medical centers, but even in the US, accessing this complicated treatment may not be straightforward and widespread.

These are not the only issues, though. Many patients might find the treatment daunting, and there are additional worries about the treatment itself, such as potential long-term health issues caused by editing errors, which remain uncertain. The FDA is particularly cautious about the risks of “off-target” effects, where the gene-editing tool might alter the non-targeted DNA, resulting in unintended health consequences in the future. In light of this, the agency has added a boxed warning to Lyfgenia that, in some cases, it may cause certain blood cancers. This strongest safety warning label was given after two patients in the clinical trial died from a form of leukemia.

At the same time, these treatments are showing promise for treating other illnesses. For instance, CRISPR-based treatments have the potential to treat familial hypercholesterolemia, an inherited form of high cholesterol, and a rare liver condition called amyloidosis. So, it is a huge moment for those whose lives are severely disrupted by this painful and life-threatening sickle cell disease and the potential for much more. 

Having said that, it is evident that gene-editing treatments have a considerable journey ahead to become more accessible. However, this is just the beginning of a transformative era in medical science.

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