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, potentially halting genetic neurodevelopmental disorders before birth. 

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

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

Published in the journal ACS Nano, the study showcases a lipid nanoparticle (LNP)-based delivery system that transmits messenger RNA (mRNA) to fetal cells, facilitating early intervention for genetic disorders identifiable during prenatal testing.

Delivering material to fix faulty genes

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

By delivering mRNA that translates into functional proteins, the LNPs offer a way to directly address these genetic faults within developing fetal brain cells.

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

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

Overcoming challenges to fix genes

This innovation addresses a major hurdle in mRNA-based therapy: toxicity. Without high efficiency, increased doses would be required, potentially triggering a harmful immune response. 

“The biggest hurdle to deliver mRNA to the central nervous system so far has been toxicity that leads to inflammation,” Wang said. However, the study’s results showed the LNPs effectively delivered the 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 – to the brains of fetal mice. 

Fixing faulty genes early

This approach, focused on Angelman syndrome, aimed to intervene before the brain’s blood-brain barrier formed, ensuring greater accessibility and efficiency in correcting genetic faults early.

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

“The mRNA is like the Lego manual that has instructions to put the pieces together to form functional proteins,” Wang explained. 

“The cell itself has all the pieces to build CAS9. We just have to supply the mRNA sequence, and the cell will take and translate it into proteins.”

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, a significant outcome given that these cells differentiate into various types of neurons across the brain.

“Transfecting 30% of the whole brain, especially the stem cells, is a big deal. These cells migrate and spread to many places across the brain as the fetus further develops,” Wang said. 

As development progressed, these stem cells moved throughout the brain, resulting in over 60% of hippocampal neurons and 40% of cortical neurons exhibiting successful gene transfection.

“This is a very promising method for genetic conditions affecting the central nervous system. When the babies are born, many of the neurons could have been corrected. This means the baby could be born with no symptoms,” Wang explained.

Positive outcomes for faulty genes

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

“Bad neurons with mutation may be killed by the accumulation of disease symptoms and good neurons may stay and proliferate. This could lead to amplified therapeutic efficiency,” he explained.

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

Ultimately, the study marks a groundbreaking step in genetic-based prenatal therapies. With further research, this technique could revolutionize treatment for genetic neurodevelopmental disorders, offering hope for countless families and new pathways for medical intervention at the earliest stages of life.

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