A New Formula Provides Spatially Precise Gene Editing in the Brain
Post by Shannon Kelly
The takeaway
Gene editing drugs can be used to change the DNA of brain cells and alter their function. The current study found that a newly developed light-activated gene editing formula allows researchers to control the exact location of gene editing in the brain.
What's the science?
Gene editing is a technology that modifies cells’ DNA and is used both to study gene function and as a therapeutic technique to treat genetic disorders. One of the major limitations to current gene editing techniques is a lack of control over which cells are affected. Previous research examining light-activated gene editing formulas in order to target certain cells has shown limited efficacy and requires invasive techniques. This week in Nature Communications, Rebelo and colleagues demonstrated that a new gene editing formula allows researchers to control where in the brain gene editing occurs using non-invasive near-infrared light waves.
How did they do it?
The authors developed a new gene editing method in which gene editing enzymes are attached to nanoparticles which deactivate the enzymes until they are triggered by near-infrared light (NIR; invisible light waves that can safely pass through the skull into the brain). After the formula is injected into the brain and absorbed into brain cells, the researchers selectively exposed some cells to NIR light. If the nanoparticles are exposed to NIR light, they convert it to blue light which breaks their connections to the enzymes. Then, with the help of hydroxychloroquine (a malaria drug), the gene editing enzyme is released from the vesicle which formed as it entered the cell and is free to move to the nucleus where it can modify the cell’s DNA. The authors tested the effects of their gene editing method in the brains of live mice by (1) injecting the drug into the subventricular zone (an area where new brain cells are formed after birth), (2) injecting the drug into the ventral tegmental area (a key component of the reward pathway) and observing mouse behavior, and (3) administering the drug non-invasively through the nose.
What did they find?
In the first experiment, the authors examined stem cells from the subventricular zone after administering the gene editing drug and found that gene editing occurred only in the cells that were exposed to NIR light, demonstrating that NIR light can be used to activate the gene editing formula in select brain cells. In their second experiment, they showed that using the gene editing formula in combination with optogenetics (a method of externally activating brain cells) in the ventral tegmental area affected mouse behavior during a preference test. This finding suggests that the authors were able to influence the mouse’s experience of reward by triggering reward-related brain cell activity. In the final experiment, they found that when the drug was administered intranasally, it dispersed throughout the brain and could be activated in select brain areas using NIR light, suggesting that the drug may be administered effectively using a non-invasive route.
What's the impact?
This study found that a novel technique could provide spatial control of gene editing within the brain. This gene-editing formula may improve the ability of researchers to study brain function at the level of brain cells and circuits. This research also may pave the wave for the development of a new gene therapy technique that could be used to treat brain disorders including those affecting the reward pathway, such as substance use disorder, as well as genetic disorders, such as Fragile X Syndrome.