Illustration of a lipid nanoparticle created to deliver mRNA into the body
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The technology used in mRNA covid-19 vaccines can be adapted to deliver genetic material to blood stem cells in bone marrow, according to animal studies. This advancement has the potential to improve and make treatments for a wide range of conditions, including inherited disorders, infectious diseases like HIV, and even aging, more effective and affordable.
Researchers at the Children’s Hospital of Philadelphia, led by Stefano Rivella, believe that this technique has transformative potential. He states, “With a single injection, you can modify the fate of cells. This is the future of medicine. The sky is the limit.”
messenger RNAs (mRNAs) carry instructions for protein production. By delivering mRNAs to blood stem cells, scientists can command the cells to produce any desired protein, including those involved in CRISPR genome editing. This breakthrough opens up a vast range of possibilities in medical research and treatment.
Blood stem cells in bone marrow generate various types of cells, such as red blood cells and immune cells that combat disease. Some inherited blood cell disorders, such as beta thalassaemia and severe combined immunodeficiency, can already be cured by removing blood stem cells, correcting the genetic mutations, and then reintroducing the modified cells into the bone marrow. A CRISPR gene-editing treatment for sickle cell disease is also on the horizon.
However, there are two major challenges associated with this approach. Firstly, the personalized nature of this treatment makes it time-consuming and expensive. Secondly, before reintroducing modified blood stem cells into the body, existing blood stem cells in the bone marrow must be eliminated to create space for the new cells. This process involves using highly toxic drugs that often have severe side effects and can lead to infertility.
One potential solution to overcome these challenges is modifying blood stem cells internally, which has prompted multiple research teams worldwide to focus on this avenue of study.
Rivella and his team started by utilizing lipid nanoparticles, tiny fatty balls present in mRNA vaccines. When injected into muscles, these nanoparticles deliver mRNAs to muscle cells, which then produce the encoded proteins for a short period of time. However, when injected into the bloodstream, most lipid nanoparticles are taken up by liver cells. While this may be useful in treating liver conditions, it becomes problematic for other conditions. To address this issue, the team attached antibodies to the nanoparticles that bind to a protein found on the surface of blood stem cells, ensuring their targeted delivery.
In contrast to viruses used by other researchers to deliver mRNA into cells, lipid nanoparticles have the advantage of carrying larger mRNAs. Hamideh Parhiz at the University of Pennsylvania states, “So far, whatever we wanted to encapsulate, we were quite able to.”
Targeted nanoparticles
Rivella, Parhiz, and their colleagues conducted a series of experiments on mice to demonstrate that antibody-targeted lipid nanoparticles can successfully deliver mRNAs to blood stem cells. When nanoparticles containing mRNAs encoding a protein called luciferase were injected, the bone marrow cells in the mice’s femurs emitted light. Rivella reports that around 60% of the stem cells were modified. Although many liver cells also transformed due to the uptake of antibody-targeted lipid nanoparticles, this does not pose a problem for certain purposes. For instance, fixing sickle cell disease mutations in both the liver and bone marrow is not an issue.
However, there are instances where it does matter. To address this, the team incorporated a “switch” in the mRNAs that is turned off by a molecule found exclusively in liver cells. As a result, the liver stops producing luciferase, while the bone marrow continues to produce it.
Subsequently, the researchers used this approach to deliver an mRNA that triggers cell suicide to selectively eliminate blood stem cells without harming other tissues. This could potentially replace the highly toxic drugs currently used to create space for bone marrow transplants, eliminating their adverse effects. Suk See De Ravin at the National Institutes of Allergy and Infectious Diseases in Maryland, who specializes in gene therapies, states, “This is a coming-together of phenomenal technological advances that will not only improve curative approaches for genetic diseases in well-developed countries but also holds promise for global access.”
Another potential application of this technique is “gene doping” in sports, such as increasing the production of red blood cells to improve oxygen transport throughout the body, a practice that may be challenging to detect.
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