Gene editing therapies signal a medical revolution

The approval of Casgevy and Lyfgenia signifies a remarkable leap forward in the treatment of sickle cell disease, offering hope for patients seeking one-time, curative treatments. This historic medical milestone signals the beginning of a new wave of personalized medicine and indicates a transformative shift in the global approach to how we will treat genetic disorders and diseases in the years ahead.

On November 16, 2023, the UK approved the world's first CRISPR-based gene therapy, Casgevy, for treating sickle cell disease (SCD) and transfusion-dependent beta thalassemia (TDT). The US followed suit shortly after, and on December 8, 2023, Casgevy, along with lentiviral-based Lyfgenia, were granted approval from the US Food and Drug Administration (FDA) for treating SCD. Prior to these new therapies, the options for SCD treatment were limited to rare and risky stem cell or bone marrow transplants. As a result, these pioneering gene therapies have emerged as transformative, curative treatments for patients with SCD.

CRISPR-Cas9 gene editing

A simple CRISPR system relies on the protein Cas9, which operates as a four-component system, involving two small molecules: crRNA and trans-activating CRISPR RNA (tracrRNA). In 2012, Jennifer Doudna and Emmanuelle Charpentier streamlined the CRISPR system from the four-component Cas9 endonuclease into a more manageable two-component system which earned them the 2020 Nobel Prize in Chemistry.

Doudna and Charpentier also found that CRISPR-Cas9 could be programmed with RNA to edit genomic DNA. This technology works by combining Cas9 with a custom guide RNA, allowing scientists to precisely edit any gene. The guide RNA directs Cas9 to the target gene, where its molecular scissors snip the DNA. This process triggers the cell's repair mechanism and, by introducing a separate sequence of template DNA, scientists can guide the repair process to fix a defective gene or insert a new one. This development enabled CRISPR to be used as a gene-editing tool.

Casgevy – CRISPR-based gene editing

Casgevy (exagamglogene autotemcel) was developed by CRISPR Therapeutics and Vertex Pharmaceuticals and is the first ever approved CRISPR-based gene-editing therapy. Casgevy presents a potential one-time transformative therapy for eligible patients with either SCD or TDT. In the US, it has only been approved for treating SCD in patients who are upwards of 12 years old and experience recurrent vaso-occlusive crises (VOCs), a painful complication of SCD.

CRISPR-Cas9 technology is used to modify the genome of a patient's own hematopoietic (blood) stem cells, specifically targeting autologous CD34+ hematopoietic stem cells (HSCs) at the erythroid-specific enhancer region of the BCL11A gene. Following transplantation into the patient, these genetically modified blood stem cells engraft, attaching and multiplying within the bone marrow. The objective of this modification is to decrease BCL11A expression in erythroid lineage cells, fostering increased production of fetal hemoglobin (HbF) and, consequently, a reduction or elimination of VOCs. This blood stem cell transplant is a one-time, single dose infusion.

In a clinic study investigating Casgevy's efficacy in treating adult and adolescent SCD patients with a history of at least two VOCs in the two years prior, 93.5% of the 31 evaluable patients achieved freedom from severe VOC episodes for a minimum of 12 consecutive months during the 24-month follow-up period¹. These promising results demonstrate the potential of Casgevy in successfully managing the disease.

Casgevy is currently undergoing US investigation for treating TDT, with Vertex Pharmaceuticals having submitted a Biologics License Application to the FDA. The anticipated approval decision is expected by March 30, 2024.

Lyfgenia – cell-based gene therapy

Lyfgenia (lovotibeglogene autotemcel), developed by Bluebird Bio Inc., has also been approved for the treatment of SCD for patients 12 years and older with a history of VOCs. It is a cell-based gene therapy that employs a traditional gene therapy approach, utilizing a virus to deliver a gene into cells, rather than relying on CRISPR. Lyfgenia uses a lentiviral vector for genetic modification, this works by altering the patient's blood stem cells to produce a modified HBB gene capable of producing a form of hemoglobin, called HbAT87Q, with anti-sickling properties. After modification, these cells are returned to the patient in a one-time infusion as part of a hematopoietic stem cell transplant. Before the transplant takes place, the patient must undergo high-dose chemotherapy to remove the faulty blood cells and allow the modified cells to repopulate the blood with hemoglobin-producing blood cells. This effectively reduces the risk of sickling, blood flow issues, and VOCs.

Like Casgevy, Lyfgenia involves a one-time, single-dose infusion as part of a hematopoietic stem transplant. Findings from a 24-month study showed that 88% of 32 patients achieved complete resolution of VOCs in the following 6 to 18 months after infusion with Lyfgenia².

Treatments in the pipeline

Looking ahead, the landscape of gene therapies holds great promise for treating various diseases, with several treatments currently in the pipeline awaiting FDA approval. The imminent approvals are anticipated to make a substantial impact on modern medical care. This collective progress in gene therapies signifies a significant leap forward in advancing medical treatments, instilling hope for more curative treatments and improved outcomes across various health challenges.

Despite the unknown long-term effects of these therapies, ongoing research and the development of additional gene therapies hold the promise of continued progress in the field, bringing us closer to curing more genetic disorders with each approval. The coming years hold the potential for a paradigm shift in how we approach and treat genetic disorders, paving the way for more personalized therapies and an improved quality of life for individuals affected by disease.

References

FDA (2023) FDA Approves First Gene Therapies to Treat Patients with Sickle Cell Disease. [Online] FDA

bluebird bio, Inc (2023) bluebird bio Details Plans for the Commercial Launch of LYFGENIA™ Gene Therapy for Patients Ages 12 and Older with Sickle Cell Disease and a History of Vaso-Occlusive Events. [Online] bluebird bio