Gene Therapy:  
Potential to Reduce Depression & Addiction

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According to a study conducted at the Icahn School of Medicine at Mount Sinai, and published in the journal Nature Neuroscience, regulation of a single, specific gene in a brain region related to drug addiction and depression is sufficient to reduce drug and stress responses.

Epigenetics is the study of changes in the action of human genes caused, not by changes in DNA code we inherit from our parents, but instead by molecules, which regulate when, where, and to what degree our genetic material is activated. Epigenetic regulation and the diseases of both drug addiction and depression have shown that they are closely linked in both human patients and animal models. This regulatory action stems partly from the function of transcription factors - specialized proteins that bind to specific DNA sequences - that either encourage or shut down the expression of a given gene.

DNA, which is found in every cell of the body, is composed of genes and the genetic instructions necessary for organisms to grow and survive. Specific DNA sequences are converted into messages that communicate to the cells which proteins to make. Hence, dictating the specific function of a particular cell. And although all cells contain DNA with the genetic codes necessary for every gene, they aren’t always expressed. This genetic expression depends on the transcription factors - proteins that regulate the structure of DNA within the cell, which regulate which genes will be activated or repressed.  Transcription factors are triggered by epigenetic mechanisms that either chemically alter the DNA itself, or the histones (proteins surrounding the DNA).  When triggered, these transcription factors alter the DNA’s shape making sections of the DNA available for the protein building machinery.  

The Study

Using mouse models of human depression, stress, and addiction, researchers introduced synthetic-transcription factors into a brain region called the nucleus accumbens (an area of the brain associated with rewards) at a single gene called FosB. This particular gene has been directly connected to both addiction and depression. They found that transcription factors could bring changes to this single gene and inevitably cause the study mice to become more resilient to stress and less likely to become addicted to cocaine, a highly addictive substance. 

Expression of the FosB gene in nerve cells is essential for drug and stress responsiveness in mice. In particular, activation of FosB expression has been shown to increase both drug sensitivity and resilience to stress. It has also been proven that, in the brains of mouse models and in drug-addicted and depressed human patients, FosB is altered by exposure to such stimuli.  “Earlier work in our laboratory found that several transcription factors and downstream epigenetic modifications are altered by exposure to drugs or to stress and that these changes, in turn, control gene expression,” says Eric J. Nestler, MD, PhD, Nash Family Professor, Chair of the Department of Neuroscience and Director of the Friedman Brain Institute at the Icahn School of Medicine at Mount Sinai, who led the study.  “But because such epigenetic regulation occurs at hundreds or thousands of genes, until now it had been impossible to determine the difference between the mere presence of an epigenetic modification and its functional relevance to neuropsychiatric disease.”

The Results

Elizabeth Heller, lead author on the paper, developed an innovative method to control epigenetic regulation of FosB. Heller introduced synthetic transcription factors called Zinc Finger Proteins (ZFPs), designed to target only a single gene out of 20,000, by incorporating them into a virus and injecting that virus into the reward-related brain region. Study results indicate that upon binding to that one gene, the FosB-ZFPs modified histones in the vicinity of the FosB gene, in order to either activate (turn on) or repress (turn off) expression.  Heller states that, “While drug addiction and depression are hereditary diseases that regulate gene expression in the brain, the field has yet to uncover relevant mutations in gene sequence that underlie these disorders. Therefore, we focused on changes in gene structure to probe the mechanism of action of such changes in drug and stress sensitivity.” 

This study has enormous implications for treating both depression and drug addiction at their very foundation.  “Our data is a critical first step towards developing novel therapeutics to combat these neuropsychiatric diseases,” says Heller. She also added that, “The use of engineered transcription factors has broad implications outside of neuroscience because epigenetic gene regulation underlies many diseases, including most forms of cancer.”  

Conclusion:  Gene therapy could cause mice to become more resilient to stress and less likely to become addicted to cocaine.

- Laura A. Wells

Heller, E., Cates, H., Peña, C., & Sun, H., et. al. (2014, October 27). Locus-specific epigenetic remodeling controls addiction- and depression-related behaviors. Retrieved November 25, 2014, from http://www.nature.com/neuro/journal/v17/n12/full/nn.3871.html

Mount Sinai Medical Center. (2014, November 10). Changes in single gene's action can control addiction- and depression-related behaviors. ScienceDaily. Retrieved November 24, 2014 from www.sciencedaily.com/releases/2014/11/141110150845.htm