Have you ever heard of base editing? This relatively new technology within the field of genome editing offers the potential opportunity to treat a variety of genetic conditions. According to Medical XPress, researchers tested base editing as a potential treatment for sickle cell disease (SCD). Although the researchers were unable to test this on humans, they did evaluate the efficaciousness using mice models. Discover the full study findings published in Nature.
According to an unrelated article published in Nature Reviews Drug Discovery:
Base editing — the introduction of single-nucleotide variants (SNVs) into DNA or RNA in living cells — is one of the most recent advances in the field of genome editing. As around half of known pathogenic genetic variants are due to SNVs, base editing holds great potential for the treatment of numerous genetic diseases, through either temporary RNA or permanent DNA base alterations.
In prior studies, researchers have attempted to treat SCD by editing defective HBB genes or attempting to treat HBB gene mutations. Normally, HBB provides instructions for the production of beta-globin, which is part of the structure of hemoglobin. But in patients with SCD, this gene is defective, causing the creation of malformed red blood cells and preventing oxygenated blood from moving throughout the body. Current gene-editing techniques usually require slicing the DNA helix. However, this can cause gene editing mistakes and spur additional health issues.
Thus, researchers wanted to take a different approach: base editing. Unfortunately, there have been some difficulties with base editing and SCD in the past. For example, base editing has been unable to edit SCD-related gene mutations to allow them to mimic healthy cells, creating “wild-type” variants.
So in this study, researchers developed a novel approach. As described in the article, the team:
used a custom adenine base editor (ABE8e-NRCH) to convert the SCD allele (HBBS) into Makassar β-globin (HBBG), a non-pathogenic variant.
Non-pathogenic means that those with these gene mutations typically do not have symptoms relating to SCD or any additional conditions. Thus, it seemed like a safe choice. To begin, researchers altered hematopoietic stem cells (HSCs), changing them from a valine base into an alanine base. Next, researchers inserted a Cas9 protein. As a result, the treatment avoided impacting cells outside of its target range.
Once the researchers had created this specific technique, they tested it on mice models of SCD. To begin, the researchers extracted HSCs from the mice models. Next, they isolated and treated the HSCs. Finally, the HSCs were allowed to grow. Ultimately, the researchers determined that 80% of SCD cells turned into Makassar β-globin.
More so, researchers also transferred treated cells back into the mice models of SCD. They determined that these treated cells reduced symptoms associated with SCD, such as anemia and fatigue. Although this base editing technique still requires eventual human testing, it does show promise for treating SCD.
Sickle Cell Disease (SCD)
Altogether, HBB gene mutations cause sickle cell disease (SCD), a group of inherited blood disorders. These mutations create malformed, sickle-shaped blood cells. Because of the shape of these cells, they have difficulty moving throughout the body. The cells cause blockages, restricting blood flow. SCD is inherited in an autosomal recessive pattern, meaning patients must receive one defective gene from each parent to inherit the condition. An estimated 70,000-100,000 Americans have SCD. Those of African American descent have a higher risk of inheriting this condition.
Typically, SCD symptoms appear in early childhood. In fact, symptoms can be apparent as early as 5 months old. Symptoms include:
- Jaundice (yellowing of the skin and eyes)
- Anemia (low red blood cell count)
- Pain crisis
- Pulmonary hypertension
- Swelling of the hands and feet
- Frequent and/or repeated infections
- Delayed growth
- Organ damage
- Note: The most frequently damaged organs include the bones, joints, skin, lungs, heart, spleen, kidneys, liver, eyes, and brain.