Gene Editing: a hope for Sickle cell anemia

Even after decades of research, Sickle cell anemia (SCA) still has limited treatment options. The recommended care is a palliative treatment based on frequent blood transfusions and medications to relieve the pain. The currently available cure for sickle cell anemia is bone marrow transplantation. However, with Gene editing, scientists have successfully identified different gene therapy applications that will be used as a curative treatment.

Gene editing therapy for Sickle cell anemia is here – and its research is advancing steadily. Genome editing technology, such as CRISPR/Cas9, has revolutionized SCA treatment. CRISPR gave the SCA research a new direction, and we now have multiple CRISPR-based treatments undergoing clinical trials.

CRISPR and Sickle Cell Therapy:

CRISPR involves three steps: collecting hematopoietic stem cells from the patients, modifying the collected cells in the lab, and infusion of the modified cells into the same patient from whom the cells were initially collected. This procedure is being seen as the potential cure for SCD.

It can be used on both adult as well as fetal Hb levels. For adult Hb, the approach is to repair the mutation in the gene responsible for sickle cell disease. First, CRISPR introduces a DNA break to the ß-globin gene. The break site then introduces a correction to the gene via homology-directed repair (HDR). This is also called a gene knock-in. The edited cells, which can now produce normal hemoglobin, are re-implanted/ infused in the patient's bloodstream.

For fetal hemoglobin (Hb F), CRISPR sickle cell gene therapy, commonly known as gene knockout, is used for fetal hemoglobin (Hb F). It involves switching off the gene that suppresses Hb F, which causes Hb F to be expressed, and the mutated adult Hb gets replaced.

Sickle Cell and CRISPR: On-going Human Trials

The U.S. Food and Drug Administration (FDA) has given GPH101, Graphite Bio's investigational gene-editing medicine, fast-track designation for approval in 2022. GPH101 attempts to fix the genetic defect causing sickle cell disease (SCD) and potentially cure the illness. A CRISPR-Cas9 tool is GPH101. It entails the collection of hematopoietic stem cells from patients, laboratory alteration of the obtained cells, and infusion of the transformed cells into the original patient. This method is thought to hold the key to curing SCD.
GPH101's safety and efficacy will be evaluated in the open-label Phase 1/2 CEDAR trial, which currently enrolls up to 15 patients at sites in the United States. It has been forecasted that the proof-of-concept data will be released in 2023.
CTX001 is another CRISPR-based investigational new application, which has been co-sponsored by CRISPR Therapeutics and Vertex Pharmaceuticals to treat sickle cell disease. Patients treated by CTX001 are still under observation. In an interview, one of the recipients, Victoria Gray, said she believes she's now functioning as somebody who does not have sickle cell disease.
CTX001 works on the BCL11A gene (a repressor of fetal Hb production) and works on a fetal Hb level. Bone marrow stem cells are extracted from patients and CRISPR-edited to inactivate BCL11A. The edited stem cells are then introduced back into the patient with the hope that the new red blood cells produced by these edited stem cells would have fetal hemoglobin.

Clinical studies are going on to explore the safety and efficacy profile of CTX001. Scientists believe that CTX001 will become the first gene editing therapy that will be used globally by all SCA patients.

SCA has now become an ideal target for gene therapy. It is because; a single mutation causes the disease, and SCA treatment can also be used in treating Thalassemia. Consequently, the disease has become one of the most competitive fields in gene editing therapy. Apart from the therapies mentioned above, multiple other candidates are undergoing different phases of clinical trials, including:

OTQ923 and HIX763, Novartis Pharmaceuticals: Autologous HSPC transplant; gene disruption to restore Hb F via CRISPR-Cas9
ET-01, Ge Zhang, MD EdiGene, Inc.: Autologous HSPC transplant; gene disruption to restore fetal hemoglobin (Beta-thalassemia) via CRISPR-Cas9
EDIT-301, Editas Medicine, Inc.: Autologous CD34+ HSPC transplant, editing the Haemoglobin Subunit Gamma 1 and 2 (HBG1/2) promoter region to increase fetal hemoglobin production via CRISPR-Cas12a
CRISPR_SCD001, Mark Walters, MD UCLA, UC Berkeley: Autologous HSPC transplant, replacing mutated beta-globin gene via CRISPR-Cas9 knock-in