Gene editing, particularly with CRISPR-Cas9 technology, has shown potential to revolutionise medicine by offering cures for a range of genetic disorders, especially blood disorders such as sickle-cell anaemia.
Sickle-cell anaemia, a genetic blood disorder, causes chronic pain and life-threatening complications for millions of people in India and worldwide. In this disease, red blood cells become crescent or sickle-shaped, which not only reduces their oxygen-carrying capacity but also makes it difficult for them to pass through blood vessels. A patient suffering from sickle cell disease may suffer from severe anaemia, sudden pain crises, organ damage and an increased risk of infection.
In most cases, these patients are offered blood transfusions, pain management, and hydroxyurea as treatments, which provides some degree of relief. But it does not relieve them of the pain and various other associated complications. Bone Marrow Transplant has so far been the only curative treatment option.
But now gene editing, an innovative treatment in which we can repair or replace the defective gene that causes the disease, is a new hope for millions suffering from the disease. Sickle-cell anaemia is caused by a mutation in the HBB gene, which encodes the beta-globin subunit of haemoglobin. Haemoglobin is the protein in red blood cells responsible for transporting oxygen throughout the body. The mutation leads to the production of abnormal haemoglobin, known as haemoglobin S (HbS). Under low oxygen conditions, HbS molecules tend to stick together, forming rigid rods that distort the shape of red blood cells into a sickle form. These deformed cells can block small blood vessels, causing painful episodes called vaso-occlusive crises and damaging organs due to restricted blood flow.
Gene editing, using the CRISPR-Cas9 technology, the new promising treatment for genetic disorders , directly targets and corrects the underlying genetic defects. CRISPR, which stands for Clustered Regularly Interspaced Short Palindromic Repeats, is a revolutionary tool that allows scientists to make precise, targeted changes to the DNA of living organisms. The Cas9 protein acts as molecular scissors, guided by RNA sequences that match the target gene, to introduce cuts at specific locations. Once the DNA is cut, the cell's natural repair mechanisms can be harnessed to correct or replace the faulty gene.
In the case of sickle-cell anaemia, researchers have employed gene editing to either correct the mutation in the HBB gene or reactivate fetalhemoglobin (HbF) production. Fetalhemoglobin, which is naturally produced during fetal development, prevents sickling of red blood cells. Normally, HbF production ceases shortly after birth, replaced by adult haemoglobin (HbA). However, reactivating HbF can compensate for the defective HbS, mitigating the symptoms of sickle-cell anaemia. Another promising approach involves editing the BCL11A gene, which suppresses HbF production. By disrupting this gene, researchers can restore HbF production in red blood cells, bypassing the effects of the sickle-cell mutation. Early clinical trials have shown that this method can significantly increase HbF levels, reducing the frequency and severity of pain crises and improving overall patient health.
During a clinical trial, a patient named Victoria Gray, who was then 33 years old, was treated for sickle-cell anaemia using CRISPR-Cas9 at TriStar Centennial Medical Center in Nashville in the United States. During the treatment, Gray's bone marrow cells were harvested and then edited to disrupt the BCL11A gene. Edited cells were then reinfused back into her body. The results were remarkable – her HbF levels increased significantly, and she experienced a dramatic reduction in pain episodes and hospitalisations. Gray is not the only one, many other patients have been cured of this painful disease during the clinical trials.
Another approach, developed by researchers at St. Jude Children's Research Hospital, involves directly correcting the sickle-cell mutation in the HBB gene using CRISPR. This method has shown promise in preclinical studies and is currently undergoing clinical trials. Early results indicate that edited cells can be engrafted in the bone marrow and produce healthy red blood cells, offering a potential one-time cure for the disease.
In the case of thalassemia, which occurs due to mutations in the genes responsible for haemoglobin production, CRISPR-Cas9 can be used to either correct the defective gene directly or induce the expression of foetal haemoglobin in the gene, much like in the treatment for sickle cell anaemia. Early clinical trials have shown promising results.
While the initial focus of gene editing has been on blood disorders due to the relative accessibility of hematopoietic stem cells, it is now being explored to treat various other kinds of genetic defects such as cystic fibrosis, which is caused by mutations in the CFTR gene, leading to the production of thick, sticky mucus that clogs the lungs and digestive tract, muscular dystrophy, particularly Duchenne muscular dystrophy (DMD), which is caused by mutations in the DMD gene, which encodes dystrophin, a protein essential for muscle function. While still in the early stages of research, gene editing could one day offer a cure for a neurodegenerative disorder such as Huntington's disease, which is caused by a mutation in the HTT gene, leading to the production of a toxic protein that damages brain cells.
Researchers across the world are exploring various strategies to treat or even cure many debilitating conditions with gene editing.
While gene editing has the potential to cure genetic blood disorders, the experience of treating sickle-cell anaemia has shown that there are several challenges that need to be addressed. One major challenged is the delivery of the gene-editing machinery to the target cells. Most current approaches involve ex vivo editing, where cells are removed from the patient, edited in the lab, and then reinfused. This process is complex, expensive, and requires specialised facilities, limiting its accessibility.
The second major challenge is the cost of therapy. For lower-middle-income countries like India, developing these tools and therapies indigenously is essential. Interestingly, India is at an advanced stage of launching its own gene-editing therapies. When available, these therapies will provide its people with an affordable and reliable treatment for this complex and painful disease.
The author is a Pediatric Hematologist and Oncologist with an active interest in Cell and Gene therapy.