April 13, 2024

FDA approves first gene-editing therapy

The Food and Drug Administration (FDA) recently approved Casgevy (exagamglogene autotemcel), the first cell-based gene-editing therapy to utilise the CRISPR/Cas9 system (CRISPR) in history, to treat transfusion-dependent beta thalassemia.

In December last year, the FDA also approved Casgevy for the treatment of life-threatening forms of sickle cell disease. This means that adult patients in the US with this red-blood-cell disorder – or ‘hemoglobinopathy’ – will be able to access this as a one-time treatment.

However, Casgevy raises serious ethical questions.

The FDA approved Casgevy to treat patients who are 12 years and older with sickle cell disease (SCD) involving recurrent vaso-occlusive crises (VOCs), as well as patients aged 12 and older with beta thalassemia that requires blood transfusions. The agency’s decision to approve Casgevy was highly anticipated, as it marks the first time the FDA has approved any product utilising the CRISPR genome-editing technology. 

This therapy is given as a one-time, single-dose infusion. But Casgevy is also “personalised” for every patient, because it uses the patient’s own blood stem cells as the treatment’s raw material. In fact, the treatment involves a series of steps, as summarised below.

A patient is given prophylactic blood infusion for 8 weeks (to reduce bleeding risks during the procedure). Then, the patient is given a drug (plerixafor) to “mobilise” the patient’s haematopoietic stem cells, that is, to make them available in the blood stream. Once mobilised, the cells expressing the cell marker CD34+ (which indicates they can divide and replicate indefinitely) are extracted from the patient by apheresis – through a machine that separates the so-called CD34+ stem cells from the other cells. This process is less invasive than bone-marrow harvesting and does not require anaesthesia.

Once these cells are collected, they are transported to a manufacturing site, where the CRISPR/Cas 9 system is applied to them. A CRISPR is a naturally occurring segment of DNA that defends and destroys viral bacteria that invades DNA. The Cas9 is an endonuclease that causes double strand breaks in DNA. With the help of a “guide RNA,” the Cas9 can make targeted modifications to the cellular genome in the extracted cells. This CRISPR-Cas9 system is applied to the haematopoietic stem cells so that they produce foetal haemoglobin (HbF), which enhances oxygen availability in the cells. This is therapeutic because it means the cells go from sickle shaped to spherical. Specifically, the editing process disrupts the expression of the BCL11A gene, which results in increases HbF protein production. 

The edited cells are then engrafted into the patient’s bone marrow. However, before they are engrafted into the patient, the patient undergoes a regimen of myeloablative conditioning using the chemotherapy drug bulsafan, which ensures that the edited cells dominate over the original cells in the patient’s body.

The ethical issues

While the clinical trial data were promising, with a 93.5% elimination of VOCs, several serious ethical issues are associated with CRISPR gene-editing therapy. 

Germline modification. It will be recalled that the global scientific community responded with shock and disgust when it was revealed that at least two babies had been born with genome modifications. During the Second International Summit on Human Genome Editing, Dr He Jiankui claimed that twins Lulu and Nana had their genomes edited by CRISPR to confer resistance to HIV, which it was said could lead to AIDS. While the male partner was HIV positive, the female partner was negative. 

Using IVF to make the embryos, the twin babies were genetically modified by disabling the CCR5 (C-C motif chemokine receptor 5) gene – a gene which makes a receptor that enables the virus to enter and infect cells – during the single-cell phase. Dr He’s controversial work raises concerns regarding scientific practice and ethical accountability. But Casgevy is distinguished from this experiment as the DNA alterations only affect the patient and cannot be passed to their offspring.

Equity. There are also costs and equitable distribution issues. Gene therapies are expensive. Casgevy treatment costs about US$2.2 million. While its approval will have benefits for the disease, there are serious questions regarding accessibilityHemgenix, manufactured by CSL Behring for treating haemophilia B, is currently the world’s most expensive drug at around $3.5m.

This equity issue is especially relevant in egalitarian societies such as Australia. Insurance companies could be unwilling to pay this innovative treatment’s exceptionally high up-front cost. Gene-editing therapies will inevitably only be available to some members of society, leading to increased social inequities. While some wealthy patients may afford it, many may not. 

Risks. Moreover, there are risks involved with gene therapies. It is possible for the CRISPR-Cas9 system to break the DNA in the wrong place, causing a so-called off-target effects. Neither the FDA nor researchers are aware of the prevalence or effects of off-target effects of CASGEVY. Dr Daniel E Bauer explained that the use of Casgevy involves hundreds of millions of cells being edited; if even one DNA break was off target, it could theoretically cause leukemia. 

Although CRISPR technology has improved on older techniques (such as ‘TALENS’), it is neither perfect nor well-established. Safety is a primary concern. In the second international summit on genome editing, there was broad agreement among the experts that the risks of all genome editing remain high. Currently, there are studies directed at this critical issue. 

Durability. The long-term durability of gene-editing therapies is still a concern, with long-term data often limited. Thus, patients receiving the treatments will be followed in a long-term study, up to 15 years, to evaluate each product’s safety and effectiveness.

The FDA’s approval for these dreadful diseases is a massive step in the right direction, but these significant ethical issues must be addressed.


Dr Christopher Rudge is a lecturer at Sydney Law School as a member of Sydney Health Law. His research examines the ethical, social and legal implications of health professional practice, therapeutic goods regulation, health technology innovation and related social policy, such as social security and welfare.

Dr Patrick Foong is a senior law lecturer at Western Sydney University. His research interests are bioethics and health law.

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