Scientists Take Steps Toward Gene-Editing Therapy In Adults

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Geneticists are able to manipulate the genomes of a variety of organisms, starting when the embryo is a single cell. Once the organism becomes more developed, it becomes more difficult to make those changes. That difficulty prevents scientists from replacing disease-causing gene variants with healthy copies as a means of treating genetic disorders. David Liu of Harvard University led a team of researchers in developing a technique that is able to use specialized proteins to edit the genome of living animals. The paper has been published in Nature Biotechnology.

“Current drugs that treat genetic diseases cannot address the root cause of the disease,” Liu explained in a press release. “Unlike infectious diseases, for example, which we treat by killing the disease-causing agent, in the case of diseases that come from mutations in our own genes, one has to go into the cells and do surgery on our genomes to fix the root cause. Thanks to recent discoveries by scientists around the world, we now have genome-editing proteins that can do the surgery. But the challenge is that these proteins, like virtually all proteins, do not enter cells spontaneously.”

Previous methods for getting gene-editing proteins inside of cells rely on cationic lipids, which are hydrophobic molecules with one positively-charged end. After the proteins are attracted to the negatively-charged molecules on the surface of mammalian cells, they are shuttled inside by small bubbles known as endosomes.

“The key difficulty, which has been known for decades, is that getting cargo out of endosomes is very difficult,” Liu continued. “The efficiency with which a protein will spontaneously escape an endosome is very low—maybe as low as one in a million under normal circumstances.” In essence, the protein is trapped.

The new method devised by Liu’s team takes the opposite approach, using proteins with a high negative charge, similar to the charge of DNA and RNA. These proteins are then put in the center of a sphere called a liposome, which is attracted to the cell surface. The proteins enter the cell directly via the liposome, or the entire unit is carried inside with an endosome just like traditional methods. The difference is, the liposome fuses with the endosome, allowing the inner proteins to escape into the inside of the cell.

These proteins have been designed so they only work for a short amount of time. This minimizes the risk of them further altering the genome and potentially causing problems once the target gene has been edited.

“We hope this approach to protein delivery will help connect where genome editing is now to where the field needs to be in order to realize the therapeutic potential of these proteins to address genetic diseases,” Liu added.

These proteins—like all non-viral vectors—cannot be used to treat every type of condition, but it could be used on those affecting blood, muscles, eyes, and ears, which Liu’s team has decided to attack first. The hairs of the inner ear, which bend and convert sound waves into impulses that the brain recognizes as auditory signals, can become damaged through overexposure to loud noises or due to genetic causes. The team successfully targeted and edited genes within the inner ear of living mice, making it quite promising that this technique could be used to treat certain genetic disorders in the future. 

[All images via Harvard University]

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