The United Kingdom's Medicines and Healthcare products Regulatory Agency (MHRA) has marked a significant milestone in medical history by approving the world's first CRISPR-based therapy, Casgevy, developed by Vertex Pharmaceuticals and CRISPR Therapeutics.
This groundbreaking decision allows the treatment of patients aged 12 and older with sickle cell disease or transfusion-dependent beta thalassemia, two inherited blood disorders.
CRISPR, which stands for "clustered regularly interspaced short palindromic repeats," is a sophisticated gene-editing tool initially discovered in bacteria. Bacteria use CRISPR sequences as a defense mechanism against viruses, with the Cas9 enzyme acting as a molecular scissor to chop up the DNA of invading viruses. Scientists have harnessed this natural system to edit genes in other organisms, turning CRISPR into a powerful tool for genetic engineering.
The CRISPR/Cas9 system operates by using a guide RNA molecule to locate a specific DNA sequence in the nucleus of a cell. Once the target DNA is found, the Cas9 enzyme binds to the DNA and makes precise cuts. The cell then repairs these breaks, which can result in the disabling or repair of a gene, or the insertion of new genetic material. Newer forms of CRISPR, known as base editors, can edit genetic material one nucleotide at a time without cutting the DNA, offering even more precision.
In the context of Casgevy, the therapy involves collecting a patient’s stem cells from the bone marrow and using CRISPR to edit a gene in those cells to produce high levels of fetal hemoglobin. The modified stem cells are then infused back into the patient, where they take up residence in the bone marrow and start producing red blood cells with the correct form of hemoglobin. This treatment is aimed to be a one-time procedure, potentially providing a long-term solution for these blood disorders.
Clinical trials for Casgevy have shown promising results. In a trial for sickle cell disease, almost all patients were free of severe pain crises for at least 12 months post-treatment. Similarly, in the beta thalassemia trial, a significant majority of patients did not require a red blood cell transfusion for at least 12 months following treatment. Side effects reported were comparable to other autologous stem cell transplant procedures, with no serious adverse effects reported.
The approval of Casgevy is a landmark not only for patients with these specific blood disorders but also as a validation for CRISPR technology's potential in treating a wide range of genetic diseases. The technology's ability to make precise changes at the molecular level opens up new avenues for understanding and potentially curing genetic diseases. CRISPR/Cas9 and related tools are now being explored for various applications, including turning genes on or off, and modifying single nucleotide bases.
The future of CRISPR-based treatments looks promising. Following the UK's approval, regulatory decisions in the U.S. and other regions are anticipated. The success of Casgevy and ongoing advancements in CRISPR technology signify a new era in genetic medicine, offering hope for treatments that were once thought to be beyond reach.
References
Wang, S., Su, J.H., Zhang, F., et al. (2016). An RNA-aptamer-based two-color CRISPR labeling system. Scientific Reports, 6, 26857. https://doi.org/10.1038/srep26857
Komor, A., Kim, Y., Packer, M., et al. (2016). Programmable editing of a target base in genomic DNA without double-stranded DNA cleavage. Nature, 533(7603), 420–424. https://doi.org/10.1038/nature17946
MedCity News. (2022, August). Bluebird bio gene therapy wins first FDA approval for rare blood disorder. https://medcitynews.com/2022/08/bluebird-bio-gene-therapy-wins-first-fda-approval-for-rare-blood-disorder/