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Fixing Genes Before Birth: Innovative mRNA Delivery for Prenatal Therapy

Overview of the Breakthrough

Recent research demonstrates a biomedical tool capable of delivering genetic material to edit faulty genes within developing fetal brain cells. Tested in mice, this technology may prevent the onset of neurodevelopmental conditions, including Angelman and Rett syndromes, before birth.

Quote: "This technology has far-reaching implications for neurodevelopmental therapy," said Aijun Wang, UC Davis professor of surgery and biomedical engineering. "We may be able to correct genetic issues fundamentally during vital brain development windows."

Collaborative Research Efforts

This study, a collaboration between the Wang Lab and UC berkeley's Murthy Lab, was published in ACS Nano. The researchers hope to refine this technology to treat genetic conditions diagnosed prenatally, enabling early intervention within the womb to reduce developmental cell harm.

Advanced mRNA Delivery Mechanism: A New Approach to Gene Editing

Role of Proteins and mRNA

Proteins play a vital role in body's functions, assembled in cells following instructions from messenger RNA (mRNA). In some genetic disorders, genes may overproduce or underproduce proteins, leading to imbalances that may require gene silencing or protein supplementation.

Insight: "Due to their large and intricate structures, proteins are difficult to deliver," Wang noted. "Effective delivery is a major challenge, and overcoming it is key to advancing disease treatment."

Lipid Nanoparticle (LNP) Technology for mRNA Delivery

Scientists identified a method to deliver mRNA to cells, enabling them to produce functional proteins directly. This involves a unique lipid nanoparticle (LNP) formulation that carries mRNA, transfecting the cells with the instructions needed for protein synthesis.

Delivering mRNA through LNP technology is advancing disease treatments, playing crucial roles in vaccine development, gene editing, and protein therapies. The Pfizer and Moderna COVID-19 vaccines have highlighted its potential and increased its use.

Enhancing mRNA Delivery with Lipid Nanoparticles (LNPs)

Increasing Efficiency with Acid-Degradable Linkers

In a recent paper published in Nature Nanotechnology, researchers Wang and Murthy outlined an innovative lipid nanoparticle (LNP) formulation that ensures safe and efficient mRNA delivery. To achieve this, LNPs must successfully reach the cells, where they undergo endocytosis. This process enables the cell to dismantle the LNP, thereby liberating the mRNA payload.

An individual mRNA molecule measure approximately 100 nanometers in diameter, whereas a typical sheet of paper has a thickness of about 100,000 nanometers.

According to Niren Murthy, a bioengineering professor at the University of California, Berkeley, and co-investigator on this project, the lipid nanoparticles (LNPs) created in this study incorporate a novel acid-degradable linker that facilitates rapid degradation within cells. This innovative linker also allows for the engineering of LNPs with reduced toxicity.

Wang explained that when cells internalize the lipid nanoparticles (LNPs), the particles undergo degradation in the acidic environment of the endosome. This process facilitates a more efficient and timely release of mRNA into the cytosol—the liquid matrix within the cell where mRNA is translated into proteins. This localization is crucial for the mRNA to exert its intended effect.

The relationship between efficiency and toxicity is critical. Thus, understanding the quantity of lipid nanoparticle (LNP) carries required for a cell to uptake sufficient amounts of proteins is essential. If the uptake efficiency is inadequate, researchers may have to administer a higher number of nanoparticles, which could result in multiple doses or elevated doses that risk eliciting a toxic immune response.

Wang stated that the primary challenge in delivering mRNA to the central nervous system has been the toxicity that induces inflammation.

The study demonstrated that the lipid nanoparticle (LNP) approach enhances the efficiency of mRNA translation, thereby decreasing the requirement for potentially toxic dosages.

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Issuing the documentation necessary to develop the CAS9 enzyme for gene editing techniques

Utilizing LNPs to Deliver CAS9 Enzyme for Genetic Editing

Targeting Genetic Disorders with CAS9 mRNA

In the study, the authors descirbe how LNP technology can be leveraged for delivering CAS9 mRNA to treat genetic conditions affecting the central nervous system during fetal development. The researchers focused their tests on the gene responsible for Angelman syndrome, a rare neurodevelopmental condition.

In genetic conditions, damage can accumulate during gestation and shortly after birth. Research indicates that delivering therapies to brain cells is more effective before the blood-brain barrier is fully developed in infants. Therefore, the sooner the intervention occurs, the more beneficial it is. The goal is to halt disease progression in utero.

The research team administered the LNP containing mRNA directly into the ventricles of the fetal brain in a mouse model. The mRNA is translated into CAS9, a protein that functions as molecular scissors for gene editing. The resulting CAS9 protein will target and edit the gene associated with Angelman syndrome.

Wang described mRNA as akin to a Lego assembly guide, detailing the instructions for forming functional proteins. The cell is equipped with the components to construct CAS9; our contribution is to deliver the mRNA sequence, allowing the cell to translate it into proteins.

The research demonstrated that the LNP tool exhibited exceptional efficiency in delivering mRNA, which translated into CAS9.

Visualization and Efficacy in Neural Cells

The researchers utilized tracers to visualize all neurons that had been edited within the brain. Their findings showed that the nanoparticles were incorporated by the developing neural stem and progenitor cells, leading to genetic modifications in 30% of the brain stem cells in the mouse model.

Key Findings and Future Potential

Transfection Efficiency in Brain Cells

• "Transfecting 30% of the entire brain, particularly the stem cells, is significant. As the fetus continues to develop, these cells migrate and distribute throughout various regions of the brain," stated Wang.
• As fetal development progressed, the study demonstrated that stem cells proliferated and migrated to establish the central nervous system. Notably, more than 60% of the neurons in the hippocampus and 40% in the cortex were successfully transfected.

Future Outlook: Wang noted that this approach is highly promising for genetic disorders affecting the central nervous system. If successful, many neurons may be corrected by the time the baby is born, possibly leading to a symptom-free outcome.

Wang expects to find a significantly increased rate of transfection in cells from a mouse model affected by disease.

"Neurons affected by mutations my be eliminated due to the buildup of disease symptoms, while healthy neurons may survive and proliferate, potentially enhancing therapeutic efficacy. By understanding cellular mechanisms, we can harness this knowledge to align with the cell's natural pathways," he explained.

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