A new biomedical innovation has effectively enabled the delivery of genetic material aimed at correcting defective genes in the brains of developing fetal mice. This breakthrough could potentially halt the progress of genetic neurodevelopmental disorders before birth.
Recent research reveals that a novel biomedical tool can successfully transmit genetic material to target faulty genes in the brain cells of developing fetuses. This promising technology, tested on mice, may have the capability to prevent the advancement of genetic neurodevelopmental disorders, including Angelman syndrome and Rett syndrome, prior to birth.
“The potential of this tool to address neurodevelopmental conditions is significant. It allows us to possibly rectify genetic abnormalities at a fundamental level during crucial stages of brain development,” stated Aijun Wang, the study’s senior author and a professor of surgery and biomedical engineering at UC Davis.
The research, a joint effort between the Wang Lab and the Murthy Lab at UC Berkeley, was published today in ACS Nano. The research team aims to leverage this technology for treatments of genetic disorders identifiable through prenatal screening. The proposed interventions would take place in utero, helping to prevent further damage as cellular development proceeds.
A sophisticated delivery system with a groundbreaking method
Proteins play a vital role in bodily functions. In certain genetic disorders, genes may produce an excess or insufficient amount of proteins, leading to dysfunction within the body.
The researchers developed a method to deliver messenger RNA (mRNA) to cells, which can then be translated into functional proteins. This technique employs a specialized lipid nanoparticle (LNP) formulation designed to transport mRNA. The aim is to introduce the mRNA into the cells, where it can then provide instructions for protein synthesis.
In a recent publication in Nature Nanotechnology, Wang, Murthy, and their team outlined a new LNP formulation that safely and effectively delivers mRNA. For successful delivery, LNPs carrying mRNA must reach the target cells, where they are absorbed via a process known as endocytosis. Once inside, the cell disassembles the LNP carrier, releasing the mRNA cargo.
“The LNPs developed in this research incorporate a new acid-degradable linker that enables rapid degradation within cells. This new linker also helps in designing LNPs to exhibit lower toxicity,” remarked Niren Murthy, professor of bioengineering at the University of California at Berkeley and co-investigator on this study.
Effectiveness of the delivery method is closely associated with its toxicity. Low uptake efficiency implies the need for increased quantities of nanoparticles, which could necessitate multiple or higher doses, potentially leading to toxic immune reactions.
“The primary obstacle in delivering mRNA to the central nervous system has been the toxicity that triggers inflammation,” Wang noted.
The findings revealed that the LNP approach is more effective in translating mRNA, thereby minimizing the requirement for potentially harmful doses.
Providing instructions to construct the CAS9 enzyme for gene editing
This recent study details the application of LNP technology for delivering Cas9 mRNA aimed at treating genetic disorders within the central nervous system during pregnancy. The team tested its tool on the gene associated with Angelman syndrome, a rare neurodevelopmental disorder.
In genetic disorders, damage accumulates during pregnancy and shortly after birth. Research indicates that treatment is more effective when administered to brain cells before the blood-brain barrier is fully established in infants. Consequently, earlier corrections yield improved outcomes. The intention was to curtail disease progression while still in utero.
The researchers performed injections of LNP carrying mRNA into the brain’s ventricles of mouse models. The mRNA encodes the production of CAS9, a protein that functions as a molecular scissor for gene editing, targeting the gene linked to Angelman syndrome.
“The mRNA serves as the instructional manual, providing the necessary information to assemble functional proteins. The cell possesses all components required to fabricate CAS9; we only need to provide the mRNA sequence, and the cell will utilize it to produce protein,” Wang clarified.
Study Results
The investigation demonstrated that the LNP technology was highly effective in delivering mRNA that translated into CAS9.
Using tracing techniques, researchers tracked the neurons altered within the brain. The findings indicated that the nanoparticles were absorbed by the developing neural stem and progenitor cells in the brain, leading to gene modifications in 30% of brain stem cells in the mouse model.
“Transfecting 30% of the entire brain, especially the stem cells, is a significant achievement. These cells migrate and proliferate throughout the brain as the fetus develops further,” Wang observed.
As fetal development progressed, the study revealed that the stem cells multiplied and migrated to establish the central nervous system. Over 60% of neurons in the hippocampus and 40% in the cortex were successfully transfected.
“This represents a highly promising approach for genetic disorders impacting the central nervous system. Upon birth, many of the neurons could potentially be corrected, leading to the baby being born without symptoms,” Wang explained.
Wang anticipates even greater transfection rates in future studies using diseased mouse models.
“Damaged neurons bearing mutations might perish due to the disease’s impact, allowing healthy neurons to survive and proliferate, enhancing therapeutic effectiveness. A thorough understanding of cellular mechanisms enables us to exploit this knowledge in harmony with the cell’s natural pathways,” he concluded.
