A new gene-editing technology to address sickle cell disease has recently been approved by the FDA, opening doors for further CRISPR research (Braňo, Unsplash)
Approved by the U.S. Food and Drug Administration (FDA) on December 8, 2023, Casgevy and Lyfgenia recently made history as the first CRISPR-based gene therapies for treating sickle cell disease (SCD). These treatments involve modifying the patient’s blood stem cells with CRISPR-Cas9 technology.
History of Gene Editing
The idea of gene therapy first emerged in scientific circles in the 1960s, but the first successful use of a virus to insert genes into stem cells was demonstrated in the 1980s. This was an important step in gene editing research. In 2003, the Human Genome Project was completed, which provided a comprehensive genetic blueprint of the human body and helped provide more info about gene editing.
Then CRISPR-Cas technology came into light as the next powerful gene editing tool. In 2012, Jennifer Doudna and Emmanuelle Charpentier co-invented CRISPR-Cas9, revolutionizing gene editing due to its efficiency and ease of use.
What is CRISPR?
CRISPR, or Clustered Regularly Interspaced Short Palindromic Repeats, is a gene editing technology that originates from bacterial immune systems. It can modify DNA sequences in cells and organisms with high precision. The CRISPR/Cas system operates by utilizing guide RNA molecules that are programmed to target specific DNA sequences. Once guided to the target, the Cas enzyme cuts the DNA, allowing for various modifications such as inserting, deleting, or replacing genetic material.
This technology can be used for both biomedical research and clinical applications. Right now, CRISPR is being studied for potential treatments of genetic disorders, including sickle cell disease and beta-thalassemia, as well as infectious diseases. CRISPR has also been used to create animal models for studying human diseases and has advanced our understanding of gene function. However, it is not perfect, and there are still problems to solve such as off-target effects and efficient delivery methods.
Ethical and Moral Issues Around CRISPR
CRISPR technology has raised many ethical and moral concerns and therefore is not widely implemented at the moment. Firstly, CRISPR’s potential use in manipulating the human germline raises concerns about unforeseen mutations, informed consent, and long-term hereditary effects. Studies have revealed that CRISPR-Cas9 editing can lead to unexpected mutations and may cause unforeseen off-target effects. Informed consent remains an issue as well, because research participation should include clear communication about the technology’s potential risks, including off-target editing, to ensure ethical guidelines. Research has also shown that CRISPR-Cas9 can introduce unanticipated changes in DNA that may be heritable by future generations, which could lead to unwanted effects and long-term consequences.
CRISPR’s ease of accessibility and potential for exploitation also raises concerns regarding the technology's misuse for eugenics purposes, which has warranted strict regulations, global debate, and public awareness.
Introducing Casgevy and Lyfgenia
Recently, gene therapies Casgevy and Lyfgenia were approved for treating sickle cell disease (SCD) in patients 12 years and older.
Casgevy, developed by Vertex Pharmaceuticals and CRISPR Therapeutics, employs CRISPR-Cas9 genome editing technology to modify the patient’s hematopoietic stem cells, increasing the production of fetal hemoglobin (HbF). This prevents the sickling of red blood cells, a distinctive feature of sickle cell disease. The therapy involves a hematopoietic stem cell transplant and can involve weeks to months of hospitalization. A preparatory treatment with busulfan, a chemotherapy drug, is also needed.
Lyfgenia, developed by Bluebird Bio, works by adding a functional β-globin gene to the patient's hematopoietic stem cells, resulting in the production of adult hemoglobin with anti-sickling properties. This modified gene produces hemoglobins with similar oxygen-binding capacity as wild type hemoglobin, reducing sickling of red blood cells.
Lyfgenia has shown significant effectiveness as it has eliminated severe vaso-occlusive events (VOEs), a group of acute complications associated with SCD, in 94 percent of patients and resolved all VOEs in 88 percent of patients between 6 and 18 months post-infusion. Lyfgenia is expected to be available in many qualified treatment centers, but has a clear warning of potential development of blood cancers, which emphasizes the need for careful monitoring.
What Does the Future Hold for CRISPR?
The future holds significant promise for CRISPR-based therapies with the approval of Casgevy and Lyfgenia. The FDA’s stamp of approval will likely lead to further research into different types of CRISPR-based therapies, potentially leading to application past SCD into other genetic disorders and cancers. The introduction of therapies like Casgevy and Lyfgenia may also lead to long-term safety and efficacy studies, helping pave the way into a more affordable and accessible era for future treatments.
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