Sickle cell disease is an inherited blood disorder that causes red blood cells to deform and become sickle (or crescent) shaped. These misshapen blood cells clump together and get stuck in blood vessels, blocking blood flow and depriving tissues and organs of oxygen-rich blood. This leads to a variety of problems including severe pain, infections, and organ damage, and can lead to premature death. Gene therapy and gene editing may offer a one-time treatment that addresses the genetic cause of sickle cell disease.
Genetic Cause
Sickle cell disease occurs when a person inherits a faulty beta-globin gene, also known as the HBB gene. In adults, this gene controls how red blood cells produce hemoglobin, a protein that helps red blood cells carry oxygen throughout the body. Without enough functional hemoglobin, the red blood cells become stiff and take on a sickle shape. This causes the red blood cells to break apart easily, which leads to inflammation and damage to the blood vessels. The symptoms can impact a person’s everyday life by limiting their ability to do regular activities and can result in frequent hospital visits.
While in the womb, humans produce fetal hemoglobin, which comes from a different gene than the adult form. Typically, the fetal hemoglobin gene switches off shortly after birth. While most people switch to making healthy adult hemoglobin during infancy, people with sickle cell disease transition to making the abnormal form of adult hemoglobin because of the mutation in their HBB gene.
Gene Therapy Approaches
The gene therapy approach that is used is ex vivo, which means cells are removed from the body, modified with new genetic instructions, and then returned to the body to begin producing healthy blood cells. Chemotherapy is administered before gene therapy, as it eliminates existing stem cells that are still carrying the faulty gene. The cells removed from the body (through a blood draw) are hematopoietic stem cells, or HSCs, which are versatile cells that can turn into any type of blood cell the body needs. In one approach, referred to as gene addition, the HSCs can be instructed to produce more healthy adult hemoglobin by delivering (or adding) a working HBB gene. In another approach, referred to as gene silencing, a gene would be delivered that silences the BCL11A gene (or prevents it from working. The BCL11A gene typically acts as an “off” switch in our body and stops production of fetal hemoglobin after we are born. Silencing this gene allows the body to once again produce fetal hemoglobin. Fetal hemoglobin is similar to healthy adult hemoglobin in that it is able to carry oxygen effectively in the red blood cells to the tissues.
Using Viral Vectors
In the approaches mentioned above, the gene with its new instructions is delivered to the cell using a vector, which are often derived from viruses. But don't worry, the viral genes are removed so only therapeutic genes are delivered. Let’s try to understand viral vectors a bit more:
- It's important to know that viral vectors have been studied for many years and have shown great success in safely treating diseases that otherwise have little to no options such as rare genetic diseases and certain forms of cancer.
There is a common misconception that using a virus to deliver therapeutic genetic material could then infect the person with that virus, but this is not the case because the infection-causing viral parts have been removed.- Think of a virus as having two parts—an envelope and a message. Researchers take the harmful message out of the envelope and they put a new helpful message (a specific gene) into the envelope. Because they removed the old harmful message, the envelope cannot cause disease in the person. Instead, the envelope delivers the new message (the new gene) with the goal of treating the disease. In this case, the modified stem cells are returned to the patient’s body and begin producing healthy fetal hemoglobin or normal adult hemoglobin, depending on which gene therapy the patient received.
Sickle Cell Disease and Gene Editing
Gene editing is a type of gene therapy that removes, disrupts, or corrects faulty elements of DNA within a gene by using an enzyme that cuts the DNA at one specific location. The specific DNA cut allows changes to the sequence with high precision. There are various gene editing technologies under research, including ZFNs (zinc finger nucleases), and CRISPR-Cas variants (clustered regularly interspaced short palindromic repeats and CRISPR-associated protein 9.
As an example, the CRISPR-Cas9 system is a type of gene editing approach in which a small piece of RNA is created in a lab and attached to an enzyme (in this case, an enzyme called Cas9). The piece of RNA attaches to the target sequence of DNA, and the Cas9 enzyme will then cut the cell's DNA at that targeted location. Researchers add a new piece of DNA that instructs cells to founction properly.
Similar to the gene addition and gene silencing approaches, gene editing removes from the body hematopoietic (blood-forming) and progenitor cells (cells that give rise to mature cells). Then gene editing technology is used to either edit a portion of the BCL11A gene, which acts as the “off” switch to fetal hemoglobin production, or to directly edit the faulty HBB gene that causes sickle cell disease. The edited cells are then infused back into the patient as part of a stem cell transplant, helping them produce normal adult hemoglobin or fetal hemoglobin.
Treatment Pipeline
Gene therapy and gene editing approaches are currently being researched in many clinical trials. This is a necessary step to establish safety and effectiveness in treatments. Development of these therapies is being pursued by companies such as Bluebird Bio, Vertex Pharmaceuticals, CRISPR Therapeutics, Sanofi, Aruvant Sciences, and Editas Medicine. Researchers at academic medical centers—Donald Kohn, MD (UCLA) and David Williams, MD (Boston Children’s Hospital)—are also sponsoring early trials.
To stay up to date on active and recruiting clinical trials in the U.S. and globally, visit the ASGCT Clinical Trials Finder and search for sickle cell disease in the “diagnosis” filter.
Existing Treatments
A bone marrow transplant is a one-time, potentially curative option for sickle cell disease. However, less than one quarter of people with the disease are eligible for these transplants, as they would need to have a matching donor. The bone marrow transplant procedure and the medical care that follows it have potential complications, including infection and organ damage. To find out more visit the National Marrow Donor Program. Alternatively, pain relievers or blood transfusions can help manage the symptoms of sickle cell disease. Blood transfusions are typically administered once or twice a month for people with the disease. In contrast, gene therapy uses the person's own cells, eliminating the need for a donor while treating the cause of the disease. Gene therapy aims to be administered only one time and has the potential to be curative as well.
Availability
There is currently no FDA-approved gene therapy for sickle cell disease. People with sickle cell disease may consider participating in a clinical trial for gene therapy if they meet the strict eligibility criteria and the trial is accepting patients. Inclusion and exclusion criteria are an important way for researchers to understand if the treatment is working and to maximize participant safety. These criteria usually include age—typically the minimum age for participants is 18 and the maximum is 40 years old for sickle cell disease trials. Also, medical history is important to consider. Many clinical trials require participants to have no history of gene therapy treatment or organ transplants, and their sickle cell disease must be considered “severe.”
Participating in a clinical trial provides an investigational drug at no cost, but typically at least a portion of routine patient care costs are charged to the patient's health insurance. These trials offer an opportunity to support the scientific community and others who also have the disease. It is important to discuss eligibility, risks, and benefits with your treating physician or hematologist.
Get Involved
Getting involved with patient advocacy organizations is a great way to connect with other families and people affected by sickle cell disease. These organizations can provide useful resources, guidance, and advocacy for treatment research. Sickle cell disease affects millions of people around the world, and is the most common inherited blood disorder in the U.S. You and your family are not alone, and there are resources to help.