Science & Technology (Commonwealth Union) – Researchers have shown a method that could pave the way for gene therapies with fewer side effects, researchers successfully altered several types of human cells using protein nanoparticles developed at the University of Michigan Engineering and Michigan Medicine.
Gene therapy has shown remarkable success in treating blood-related disorders such as sickle cell disease and leukemia. However, many current approaches rely on viruses to deliver therapeutic genes, which can lead to unintended consequences including secondary cancers or excessive immune responses. The research team hopes that protein nanoparticles will provide a safer alternative for delivering gene-based treatments.
As a proof-of-concept, the scientists used the nanoparticles to modify different human cell types. Liver cancer cells, kidney cells and immune cells were engineered to emit a green glow after receiving genes that produce green fluorescent protein. Once the cells absorbed and broke down the nanoparticles, the DNA or messenger RNA contained within them was released, enabling the cells to activate the newly introduced genes.
According to Joerg Lahann, Wolfgang Pauli Collegiate Professor of Chemical Engineering, director of the U-M Biointerfaces Institute and the study’s corresponding author published in Advanced Materials, many diseases arise when a single mutation causes a protein to be absent or malfunction. In such cases, introducing a functional gene could potentially correct the problem.
“Typically, this is done with viruses, but the viruses can be toxic and activate the immune cells. So there has been a push in the field to replace virus-based gene editing strategies.”
The National Institutes of Health backed the study to seek out alternatives.
Gene editing has already become a key element of several treatments approved by the U.S. Food and Drug Administration for conditions such as blood and bone marrow cancers, sickle cell disease and beta-thalassemia.
Doctors take immune cells or blood-forming stem cells from patients and change them using a genetically modified version of the Human Immunodeficiency Virus (HIV). This virus naturally mixes its genetic material with immune cells. Scientists change the virus so that it sends helpful genes instead. For example, these genes can make it easier for the blood to carry oxygen or help immune cells find and kill cancer cells. Then, the modified cells are put back into the patient.
About 80% of adults and children who get CAR T-cell therapy, a common treatment, have their cancer go away completely. Gene-editing therapies work for about 88% of people with sickle cell disease and 89% of people with beta-thalassemia.
However, a small number of cancer patients later develop a second immune-cell cancer, and some people treated for sickle cell disease have also developed blood cancers. Research indicates these secondary cancers may occur when the modified virus disrupts tumour-suppressing genes as it inserts its genetic material into the genome.
Other viruses approved by the U.S. Food and Drug Administration are injected directly into the body to treat illnesses such as skin cancer, congenital blindness and spinal muscular atrophy. Yet these viral treatments can sometimes trigger infections or severe immune reactions.
Scientists believe the newly developed nanoparticles could reduce these risks. Their ring-shaped plasmid DNA or RNA remains separate from the patient’s genome, meaning it does not interrupt or damage existing genes. In addition, the protein-based outer shell of these nanoparticles may prove safer than currently used lipid nanoparticles, which in some cases can lead to inflammation, fever and liver injury.
The nanoparticles are produced using a printing method known as electrohydrodynamic (EHD) jetting. In this process, proteins are first combined with DNA or RNA in water and loaded into a syringe positioned above an aluminum plate. An electric field is then applied, propelling the charged mixture of protein, genetic material, and water out of the syringe at high velocity.
