CRISPR Therapy For Sickle Cell Disease Faces FDA Scrutiny Amid Safety Concerns
CRISPR–Cas9 genome editing system-based therapy is on the verge of gaining approval from the US Food and Drug Administration (FDA). On Wednesday, external advisers to the FDA will meet to deliberate on the DNA-altering therapy designed to combat sickle-cell disease. Sickle cell is a genetic condition that can lead to malformed blood cells and excruciating pain in patients. The discussions during this meeting are expected to be primarily focused on the safety data submitted by the developers of the treatment, Vertex Pharmaceuticals based in Boston, Massachusetts, and CRISPR Therapeutics in Zug, Switzerland.
Mark Walters, a paediatrician at the University of California, San Francisco, who has been part of a steering committee advising the two companies on the clinical development of the treatment, known as exagamglogene autotemcel (exa-cel), emphasised the paramount importance of safety. He noted that safety data remains somewhat limited and that this crucial aspect could significantly influence the decision-making process.
Sickle-cell disease results from abnormal forms of haemoglobin, the protein responsible for transporting oxygen in red blood cells. The altered haemoglobin causes blood cells to become misshapen and adhesive, leading to the clumping of cells and potential blockages in blood vessels. This deprivation of oxygen can cause long-term damage and severe episodes of pain referred to as vaso-occlusive crises.
Exa-cel aims to mitigate these issues by reactivating the production of another form of haemoglobin typically present only in developing fetuses. The BCL11A gene typically shuts down the production of fetal haemoglobin shortly after birth. Exa-cel effectively disables BCL11A, enabling the resumption of fetal haemoglobin production. This provides a source of normal haemoglobin, alleviating the effects of the abnormal form.
In their clinical trial, Vertex and CRISPR Therapeutics reported that, nine months after treatment, 39 out of 40 participants had not experienced a single vaso-occlusive crisis. Prior to treatment, they had, on average, suffered from around four crises each year.
The process involves collecting blood-producing stem cells from individuals with sickle-cell disease, followed by treatment with a genome editor. This editor includes the Cas9 enzyme, which cuts DNA, and a guiding molecule directing the enzyme to the specific stretch of DNA within the BCL11A gene. Cas9 cuts both DNA strands at that region, and the cell's natural DNA-repair mechanisms mend the strands. However, these repairs are prone to errors, often introducing mutations in the DNA sequence that disable BCL11A and allow fetal haemoglobin production to resume.
One critical concern with CRISPR–Cas9 therapies is that Cas9 can sometimes mistakenly cut DNA at other regions in the genome that resemble its target. Repairs to this 'off-target' DNA can lead to unwanted mutations. The FDA has identified this as a crucial issue in the case of exa-cel and is expected to discuss it extensively during the upcoming meeting.
The FDA has raised concerns about the assays used by Vertex and CRISPR Therapeutics to assess exa-cel's risk of causing off-target changes. One assay involved searching a genome database for regions similar to exa-cel's CRISPR–Cas9 target site that could be mistakenly cleaved by the Cas9 enzyme. The genetic diversity of populations predominantly affected by sickle-cell disease, notably people of African descent, was not adequately represented in these genome searches, according to the FDA. This implies that there may be genetic sequences in these populations that could be targeted by Cas9 but were missed during the analysis.
Additionally, the FDA has expressed unease that the companies' assays for detecting off-target effects in live cells did not include a sufficient number of cells from people with sickle-cell disease.
One significant concern, beyond off-target edits, is that two participants in a clinical trial involving a different gene-altering therapy for sickle-cell disease developed blood cancers afterwards. This trial, conducted by Bluebird Bio in Cambridge, Massachusetts, used a virus to deliver non-sickled haemoglobin into blood stem cells. Subsequent investigations determined that the cancers were not caused by the virus, raising speculation that similar cases might occur with other therapies like exa-cel, which modify blood stem cells and reinfuse them. Some studies suggest that individuals with sickle-cell disease may be more susceptible to malignant blood cancers. If precancerous cells were reintroduced, the therapy might inadvertently support their growth into cancerous cells.
In response to these concerns, Vertex and CRISPR Therapeutics have proposed a 15-year follow-up of trial participants to monitor the potential long-term impacts of the treatment. Advocates stress the importance of physicians informing patients about the associated risks, given the uncertainties surrounding these therapies.
