Can new medical approaches repair defective genes?

New research shows that biomedical tools can successfully deliver genetic material to edit defective genes in developing fetal brain cells. The technology, tested in mice, could halt the progression of genetically based neurodevelopmental conditions such as Angelman syndrome and Rett syndrome before birth.

“The implications of this tool for the treatment of neurodevelopmental conditions are profound, with the potential to correct genetic abnormalities at a basal level during critical periods of brain development,” said the study's senior author. Wang Aijun, Professor of Surgery and Biomedical Engineering at the University of California, Davis.

the study, collaboration between Wang laboratory and Mercy laboratory A paper from the University of California, Berkeley, was published today in ACS Nano. The research team hopes to develop this technology as a treatment for genetic diseases that can be diagnosed with prenatal testing. Treatment can be done in utero to avoid further damage to the cells as they develop and mature.

Complex transportation system with innovative shipping methods

Proteins play an important role in the functioning of our bodies. In certain genetic conditions, genes express (produce) more or less protein than the body needs. In such cases, the body may become dysregulated.

Scientists have discovered a way to make it happen messenger RNA (mRNA) into cells where it is translated into functional proteins. This delivery method uses a proprietary lipid nanoparticle (LNP) formulation to carry the mRNA. The purpose is to introduce (transfect) mRNA genetic material into cells. The mRNA then translates the instructions to build the protein.

Recently Nature nanotechnology paper, Wang, Murthy and colleagues described a new LNP formulation for safe and efficient delivery of mRNA. LNPs carrying mRNA must reach cells, where they are taken up through a process known as endocytosis. There, the cell destroys the LNP carrier, thereby allowing the mRNA cargo to be released.

“The LNPs developed in this study use a new acid-labile linker that allows LNPs to be rapidly degraded within cells. The new linker also allows LNPs to be engineered to be less toxic. It will be.” Niren Murthya professor of bioengineering at the University of California, Berkeley, and a co-investigator on this project.

Efficiency is closely related to toxicity. If the uptake efficiency is low, scientists need to use large amounts of nanoparticles. This means multiple doses or high doses that can cause a toxic immune response.

“So far, the biggest obstacle to delivering mRNA to the central nervous system has been the toxicity that causes inflammation,” Wang said.

This study showed that the LNP method has a higher efficiency of mRNA translation, reducing the need for potentially toxic doses.

Delivery of CAS9 enzyme construction manual for gene editing

A new study describes the use of LNP technology for Cas9 mRNA delivery to treat genetic disorders of the central nervous system in utero. The researchers tested the tool for the genes responsible. angelman syndromea rare neurodevelopmental disease.

In genetic disorders, damage accumulates during pregnancy and immediately after birth. Research has shown that it is more efficient to treat brain cells before an infant's blood-brain barrier is fully formed. Therefore, the sooner you fix it, the better. The idea was to halt the progression of the disease in the womb.

The researchers injected the LNPs containing the mRNA into the ventricles of fetal brains in a mouse model. The mRNA is translated into the protein CAS9, which acts like a pair of gene-editing scissors. The resulting CAS9 edits the gene responsible for Angelman syndrome.

“mRNA is like a Lego manual that explains how to put the parts together to form a functional protein. The cell itself contains all the elements to build CAS9. The mRNA sequence You just feed it, and the cells pick it up and translate it into proteins,” Wang explained.

Survey results

In this study, the LNP tool was shown to be highly efficient in delivering mRNA that is translated into CAS-9.

Using tracers, the researchers were able to see all the edited neurons in the brain. Their study showed that the nanoparticles were taken up by neural stem cells and neural progenitor cells during the brain's development. The nanoparticles caused gene editing in 30% of brain stem cells in a mouse model.

“Transfecting the entire brain, especially 30% of the stem cells, is a challenge. As the fetus develops further, these cells migrate and spread to many locations throughout the brain,” Wang said. Ta.

The study showed that as the fetus developed, the stem cells proliferated and migrated to form the central nervous system. The study revealed that more than 60% of neurons in the hippocampus and 40% of neurons in the cortex were transfected.

“This is a very promising method for genetic diseases that affect the central nervous system. When a baby is born, many of the neurons may have been modified. This may mean that the baby is asymptomatic. This means that there is a possibility that the child will be born in the future,” Wang explained.

Wang expects the proportion of transfected cells to be even higher in diseased mouse models.

“Bad neurons with mutations can be killed off by the accumulation of disease symptoms, while good neurons can remain and proliferate. This could improve treatment efficiency. “If we have a good understanding of how this works, we can use this knowledge to work with naturally occurring pathways within the cell,” he said.