Can we fix faulty genes before birth?


A recent breakthrough in genetic research has introduced a tool capable of delivering therapeutic genetic material to developing fetal brain cells, which could potentially prevent genetic neurodevelopmental disorders before birth.

Developed by a collaborative team led by Aijun Wang, professor of surgery and biomedical engineering at the University of California, Davis, the innovative delivery method was successfully tested in mice and can target conditions such as Angelman and Rett syndrome.

“The implications of this device for treating neurodevelopmental conditions are profound. “We can potentially correct genetic anomalies at a fundamental level during critical periods of brain development,” Wang said.

published in journal ACS NanoThe study demonstrates a lipid nanoparticle (LNP)-based delivery system that delivers messenger RNA (mRNA) to fetal cells, facilitating early intervention for genetic disorders identified during prenatal testing.

Delivering materials to fix faulty genes

Central to this new gene editing tool is the use of LNPs to transport mRNA, which carries instructions for making essential proteins. In many genetic disorders, gene mutations cause abnormal protein production, leading to dysfunctional cellular processes.

By providing mRNA that is translated into functional proteins, LNPs provide a way to directly address these genetic defects within developing fetal brain cells.

As Wang and colleagues reported, LNPs carrying mRNA are introduced into cells through endocytosis. Within the cell, an innovative “acid-degradable linker” enables rapid degradation of the LNP, releasing the mRNA payload.

“The LNPs developed in this study use a new acid degradable linker that enables the LNPs to be rapidly degraded inside cells. The new linker also enables LNPs to be engineered for lower toxicity,” said Niren Murthy, professor of bioengineering at UC Berkeley and co-investigator of the project.

Overcoming the challenges of gene repair

This innovation addresses a major hurdle in mRNA-based therapies: toxicity. Without higher efficiency, increased doses would be required, which could trigger a potentially harmful immune response.

“The biggest hurdle so far in delivering mRNA to the central nervous system has been toxicity, which causes inflammation,” Wang said. However, study results showed that LNPs effectively delivered mRNA, reducing the need for toxic doses.

The research team applied the LNP method to deliver mRNA coding for CAS9 – a protein used in CRISPR gene editing technology – into the brain of fetal mice.

quick fix of faulty gene

This approach, focused on Angelman syndrome, aims to intervene before the brain's blood-brain barrier is formed, thereby ensuring greater access and efficiency in quickly correcting genetic defects.

CAS9 acts like molecular scissors, precisely editing DNA to correct specific mutations.

“MRNA is like a Lego manual with instructions on how to put the pieces together to make a functional protein,” Wang explained.

“All the pieces to make CAS9 are present in the cell itself. We just have to supply the mRNA sequence, and the cell will take it and translate it into protein.

High efficiency in brain cell transformation

Through detailed tracking, the researchers observed widespread editing in the developing brain cells of their mouse model. They achieved 30% gene editing in brain stem cells, an important result given that these cells differentiate into different types of neurons in the brain.

“Transfecting 30% of the entire brain, especially stem cells, is a big deal. As the embryo develops further, these cells migrate and spread to multiple locations in the brain,” Wang said.

As development progressed, these stem cells migrated throughout the brain, resulting in more than 60% of hippocampal neurons and 40% of cortical neurons displaying successful gene transfection.

“This is a very promising approach for genetic conditions affecting the central nervous system. When babies are born, many neurons may have been repaired. This means the baby can be born without any symptoms,” Wang said.

Positive result for the faulty gene

Wang and his team estimate that the efficiency of this genetic intervention may be even higher in models where the disease is actively progressing.

“Bad neurons with the mutation may be killed by the accumulation of disease symptoms and good neurons may survive and grow. This may increase therapeutic efficiency,” he explained.

Wang said further understanding of cellular mechanisms could optimize this approach, working in harmony with natural cellular repair pathways.

Ultimately, this study marks an unprecedented step forward in genetic-based prenatal treatments. With further research, this technology could revolutionize the treatment of genetic neurodevelopmental disorders, providing hope for countless families and new avenues for medical intervention early in life.

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