Gene Therapy: Potential to Reduce Depression and Addiction

Researchers at the Icahn School of Medicine at Mount Sinai reported in Nature Neuroscience that adjusting the activity of one specific gene, in a brain region tied to both addiction and depression, can be enough to blunt the body's response to drugs and to stress. The work draws on epigenetics, the study of how our genes change in their behavior. These changes don't come from altering the DNA code we inherit. They come from molecules that control when a gene switches on, where it does so, and how strongly.

Addiction and depression turn out to share a close relationship with epigenetic control, and that pattern holds across both human patients and animal models. Part of what drives the control comes from transcription factors, proteins that attach to particular stretches of DNA and then either push a gene toward expression or silence it. DNA sits inside every cell and carries the genes plus the instructions an organism needs to develop and keep going. Certain DNA sequences get translated into messages telling a cell which proteins to assemble, which in turn sets what that cell actually does.

Every cell holds the full genetic code, yet the genes are not all switched on at any given time. Whether a gene fires or stays quiet depends on those transcription factors, which shape how the DNA is organized inside the cell. The transcription factors themselves respond to epigenetic mechanisms that chemically modify either the DNA or the histones, the proteins the DNA wraps around. Once prompted, a transcription factor changes the DNA's shape so that a stretch becomes reachable by the machinery that builds proteins.

The team worked with mouse models of depression, stress, and addiction. They delivered synthetic transcription factors into the nucleus accumbens, a reward-related area, targeting a single gene called FosB that has been tied directly to both addiction and depression. By acting on that one gene, the transcription factors made the mice more resilient to stress and less prone to becoming addicted to cocaine. In nerve cells, FosB expression is central to how mice react to drugs and to stress. Turning that expression up has been shown to raise drug sensitivity while also strengthening resistance to stress. And in both mouse brains and the brains of people dealing with addiction or depression, FosB shifts in response to these same triggers.

Eric J. Nestler, MD, PhD, who led the study and chairs the Department of Neuroscience and directs the Friedman Brain Institute at Icahn, explained that his lab had already seen various transcription factors and downstream epigenetic changes respond to drugs or stress, and seen those changes steer gene expression. The problem, he noted, was scale: epigenetic regulation happens across hundreds or thousands of genes at once, so separating a modification that merely exists from one that actually matters for neuropsychiatric disease had been out of reach until now.

Elizabeth Heller, the paper's lead author, built a new way to steer FosB's epigenetic regulation. She used synthetic transcription factors known as Zinc Finger Proteins, engineered to land on just one gene among roughly 20,000, packaging them into a virus and injecting that virus into the reward region of the brain. Once the FosB-ZFPs bound to the target, they altered the histones near FosB to either switch its expression on or shut it off.

Heller pointed out that although addiction and depression are inherited conditions that affect gene expression in the brain, the field still hasn't pinned down the relevant mutations in gene sequence behind them. That is why her team looked instead at changes in gene structure as a route to understanding how drug and stress sensitivity shift. The implications reach the roots of both conditions. She called the findings a first step toward new treatments for these neuropsychiatric diseases, and added that engineered transcription factors could matter well beyond neuroscience, since epigenetic gene regulation sits underneath many illnesses, including most cancers.

The upshot: altering the action of a single gene could leave mice more resilient to stress and less likely to get hooked on cocaine.