Sickle cell disease is a genetic blood disorder that is caused by mutations in the hemoglobin protein, resulting in red blood cells taking on a sickle shape instead of the normal round shape. Currently, the only curative treatment for sickle cell disease is a bone marrow or blood stem cell transplant. However, these procedures can be risky and have potential complications.
Researchers at the University of Pennsylvania have been investigating a new method to correct the pathogenic genes that cause sickle cell disease. They have been exploring the use of mRNA technology, which involves using lipid nanoparticles to deliver genetic information to targeted cells. In this case, the researchers used lipid nanoparticles decorated with an antibody that detects a protein called antigen CD117 on the surface of blood stem cells. Once the nanoparticle is engulfed by the stem cell, it releases the desired mRNA, which instructs the cell to produce proteins that activate a cellular response.
In their experiment, the researchers used mRNA that encodes a Cas9 adenine base editor fusion protein or a single-guide RNA that targets the sickle cell mutation. The Cas9 protein is part of the CRISPR-Cas9 gene editing system and can convert a single DNA base to another base. In this case, the researchers aimed to convert pathogenic hemoglobin DNA into a harmless variant.
The results of the study showed that the editing levels and the increase in nonpathogenic hemoglobin were directly correlated. Even the highest dose of lipid nanoparticles did not inhibit the growth and function of the blood stem cells. These findings suggest that base-editing mRNA, when paired with single-guide RNA, has the potential to neutralize the threat of sickle red blood cell mutations.
This research is still in its early stages, but it holds immense therapeutic potential. If clinically translated, a single injection of mRNA lipid nanoparticles could potentially cure patients with sickle cell disease, offering a safer and simpler alternative to bone marrow transplants.