World’s first CRISPR therapy greenlit

DNA double helix

Just three years after Charpentier and Doudna won the Nobel Prize for their development of CRISPR, it has been approved for use in therapy, but not without ethical concerns. Photo credit: Sangharsh Lohakare via Unsplash


The UK’s Medicines and Healthcare products Regulatory Agency (MHRA) and the US Food and Drug Administration (FDA) have approved the world’s first CRISPR-based gene editing treatment. Following scrutiny of two ongoing clinical trials to assess its safety, quality, and effectiveness, the new treatment titled Casgevy has been authorised to treat sickle-cell disease and transfusion-dependent beta-thalassaemia. Both are debilitating genetic diseases rooted in errors in the gene that encodes for haemoglobin, the critical protein in our red blood cells responsible for transporting oxygen throughout our body.

Casgevy harnesses the potential of the CRISPR-Cas9 gene editing tool, which won its inventors the 2020 Nobel Prize in Medicine. The technology is based on a bacterial antiviral defence system. CRISPR itself refers to sequences of DNA known as Clustered Regularly Interspaced Short Palindromic Repeats, which guide Cas (CRISPR-associated protein) to recognise viral DNA. Cas proteins act as “molecular scissors”, cleaving foreign DNA and protecting bacteria from viral infections. Among the many kinds of Cas proteins, Cas9 from Streptococcus pyogenes is the most widely used in research today.

In research applications, scientists have made this system programmable to efficiently edit genomes in any organism. A specially designed piece of guide RNA directs the Cas9 protein to cut any site desired by the researcher. The cell’s repair mechanisms are imperfect, often introducing mutations at the cut site. Scientists can also introduce an extra piece of DNA which enables the cell to make highly specific edits like insertions, deletions, and single-base mutations.

While other genome editing techniques like Zinc Fingers and TALENs have been available for decades, CRISPR-Cas9’s competitive cost, efficacy, and ease of design have rapidly made it a mainstay in genetic engineering research. Its unparalleled ability to introduce specific mutations has expedited our understanding of gene function, accelerating research into diseases like cancer.

Sickle-cell disease & beta-thalassaemia

Both sickle-cell disease and beta-thalassaemia involve mutations in the beta-globin chain, a component of adult haemoglobin. While treatment options are available to manage symptoms, the only permanent solution is a bone marrow transplant, which carries the risk of life-threatening side effects.

In sickle-cell disease, genetic mutations cause haemoglobin to form polymers under low-oxygen conditions, resulting in the characteristically sickle-shaped red blood cells. Not only do these cells have a shorter lifespan than normal red blood cells, but they also have a propensity to clog small blood vessels, cutting off oxygen supply to nearby tissues. These vaso-occlusive episodes, or pain crises, are often excruciating and can potentially be fatal.

Beta-thalassaemia is a group of blood disorders where mutations cause reduced or absent synthesis of the beta-globin chain. Consequently, the body is not able to produce sufficient adult haemoglobin, leading to anaemia. Many patients require blood transfusions every few weeks to manage the resulting anaemia, but this also elevates the risk of iron toxicity.

Administration, trials & results

To administer Casgevy, clinicians take blood stem cells from the patients’ bone marrow and edit them in the lab using CRISPR-Cas9 technology. Instead of directly editing the problematic beta-globin gene, Cas9 is targeted to the BCL11A gene. This encodes a transcription factor which normally suppresses production of foetal haemoglobin soon after birth. When Cas9 cuts and thus disables BCL11A, the brakes on foetal haemoglobin production are released. This is crucial as foetal globin does not have the problematic beta-chain mutated in sickle-cell disease and beta-thalassaemia.

After being edited, the stem cells are then infused back into the patient’s bone marrow, where they will start to produce foetal haemoglobin. By transporting oxygen using foetal haemoglobin instead of adult haemoglobin, the patient’s red blood cells bypass the faulty beta-globin gene.

Promising results have emerged from two clinical trials. 12 months after treatment, 16 of 17 patients treated for sickle-cell anaemia were free of severe pain crises, and 24 of 27 patients treated for beta-thalassaemia did not require blood transfusions. All patients in the trials are now enrolled in a separate trial with the aim of evaluating safety and efficacy up to 15 years after infusion.

Ethics—accessibility, unknowns & the possible future of germline editing

While the news is a breakthrough for the future of CRISPR-based therapies, genome editing has been fraught with ethical and regulatory complexities since its inception. For one, being the first approved CRISPR-based treatment, little information on its long-term safety exists, which may limit its widespread adoption. Additionally, the risk of off-target effects, where guide RNA misdirects Cas9 to unintended genomic sites, presents a challenge in both laboratory and clinical settings. The solutions to these issues are already underway and are relatively straightforward: closely monitor those being treated with Casgevy and improve the specificity of the Cas9 system.

…haemoglobin disorders are most prevalent in tropical regions, where low income and the high cost of treatment mean that many can hardly afford basic health services, let alone revolutionary new gene therapies.

Besides safety, there is also the issue of cost and equitable access. Gene therapy costs millions of dollars, in part reflecting the costly research of development and their one-time nature. Existing treatments like Zolgensma and Zynteglo, priced at $2.1 million and $2.8 million respectively, set a precedence for the price of Casgevy. While Casgevy’s developers have not announced a price, a report by the Institute for Clinical and Economic Review suggests that a cost of $2.05 million would make the drug cost-effective. For many, access to such treatments will depend on coverage by the NHS or insurance companies in the US. But when it comes to sickle-cell disease and beta-thalassaemia specifically, most will never have this option—haemoglobin disorders are most prevalent in tropical regions, where low income and the high cost of treatment mean that many can hardly afford basic health services, let alone revolutionary new gene therapies.

As our understanding of the efficacy and safety of gene editing expands, we eventually must question if it should be used as a tool to completely eradicate debilitating diseases. Casgevy and all other currently approved gene therapies modify only specific cells relevant to the disease. Also known as somatic cell gene editing, the changes made will only occur in the patient and will not be passed onto future generations. On the other hand, human germline gene editing (HGGE), which modifies cells like eggs, sperm, and embryos, induces heritable changes such that persons born from these edited cells will never be afflicted with the disease.

HGGE opens a new can of worms—germline editing for reproductive purposes is banned in all countries, given the unclear distinction between prevention of disease and genetic enhancement. Even as more somatic gene therapies are approved, clinical use of HGGE remains a distant reality, with many scientists calling for a global moratorium. In 2018, Chinese scientist He Jiankui’s claim of having created the first genetically engineered babies was met with international outcry, leading to tightening of regulations by the Chinese government. International efforts to develop standards have since been set in motion. In its 2020 report, the International Commission on the Clinical Use of Human Germline Genome Editing recommended a cautious, incremental approach and proposing criteria for the usage of HGGE.

HGGE opens a new can of worms—germline editing for reproductive purposes is banned in all countries, given the unclear distinction between prevention of disease and genetic enhancement.

CRISPR-based therapy holds transformative potential, promising breakthroughs in treating debilitating diseases. However, we must tread carefully, acknowledging the safety, ethical, and financial considerations that accompany such scientific advances. Navigating this ground-breaking frontier necessitates a conscientious approach, ensuring that the paradigm-shifting CRISPR-based gene therapy aligns with ethical responsibility.