A new technique for controlling gene expression could make gene therapy as easy as switching a light.
Researchers at Children’s Hospital Boston and Harvard Medical School in Massachusetts have created a simpler and safer system for controlling how and when a gene’s information is converted into proteins.
“Ultimately, the system should also enable the ‘release’ of a therapeutically useful protein in response to changing concentrations of chemicals in cells,” says Richard Mulligan, director of gene therapy research at Children’s Hospital Boston and director of the Harvard Gene Therapy Initiative. “For instance, it may be possible to develop a gene therapy whereby cells are engineered to secrete insulin in response to a rise in glucose. Such ‘biological sensing’ could have a wide range of applications.”
Cutting communication
Currently, gene regulation for therapeutic purposes involves a complicated system that is risky because it can trigger the immune system and cause side-effects such as leukemia.
The new technique works by inserting a special DNA sequence into a patient’s cells. In this sequence is a ribozyme, a sequence of RNA that can spontaneously cut itself in half.
The ribozyme becomes part of a therapeutic gene’s messenger RNA (mRNA), which carries DNA information to ribosomes, which construct proteins. In effect, mRNA is like a telephone line, connecting DNA and cellular factories to convey instructions for protein construction.
The inserted ribozyme can affect this process by not only cutting itself in half but also cutting mRNA in half, severing the telephone line and disabling a gene’s message.
Likewise, inhibiting the ribozyme from splitting allows messages to travel freely from the gene to the cell, turning the gene’s message back on. Ribozymes can be prevented from splitting using any number of drugs.
“Perhaps the most exciting aspect of the new work is that, in conjunction with other technologies, we will likely be able to ‘tailor’ gene regulation systems to respond to any drug or chemical,” says Mulligan.
Animal proof
To find ribozymes that functioned well within human cells, the researchers had to evaluate hundreds of known samples. When they discovered one that was especially prone to cutting itself in half, they tweaked it to make it even more efficient for their purposes.
Next they found two compounds that inhibit ribozyme self-cutting and demonstrated that they could be used to turn on genes in cells and induce cells to make desired proteins.
The final step was to prove the technique worked in live animals. The researchers introduced the gene for a protein called luciferase along with a ribozyme into the retinas of mice. When they treated the mice with a ribozyme-inhibiting drug, the gene turned on and the mice’s retinas began producing luciferase. Without the drug, the gene remained off.
The research is reported in the journal Nature.
From Better Humans