Restoring a vital gene in a small part of the brain could well reverse major depression in humans after animals studies demonstrated considerable promise, say researchers from NewYork-Presbyterian Hospital/Weill Cornell Medical Center in an article published in Science Translational Journal, October 20 issue. The scientists say their data indicates that gene therapy would be able to treat patients who have not benefited from traditional medication treatment for major depression.
The next step will be to carry out a human trial using a gene therapy similar to the one researchers created for treating Parkinson’s disease; trial results soon to be published.
Lead researcher, Dr. Michael Kaplitt said:
Given our findings, we potentially have a novel therapy to target what we now believe is one root cause of human depression.
Current therapies for depression treat symptoms but not underlying causes, and while that works for many patients, those with advanced depression, or depression that does not respond to medication, could hopefully benefit from our new approach.
The authors wrote that p11, a brain protein, located at the nucleus accumbens, a minute part of the brain, plays a major role in our sensations of reward and pleasure – two features which patients with major depression lack. Addiction research scientists commonly investigate this part of the brain. A person who has been diagnosed with depression suffers considerably, to the point of disability because of their inability to find satisfaction with positive life experiences.
The investigators emphasize that several brain areas and neural circuits are involved in the development of depression – it is a complex disorder. However, they are convinced that if they restore p11 the course of a person’s depression would change.
Dr. Kaplitt says:
Applying molecular neurobiology and gene therapy to depression could dramatically alter the approach to psychiatric diseases. Our results provide further evidence that the underlying causes of psychiatric disorders are due to molecular changes in key brain circuits, so that they are much more similar to common neurological disorders — such as Parkinson’s disease – that might be helped by restoring molecular function.
In this study, human and animal data was gathered and studied by scientists at NewYork-Presbyterian/Weill Cornell, Rockefeller University, Karolinska Institute in Sweden, the University of Texas Southwestern Medical Center and Neurologix in Fort Lee, N.J.
This new investigation can be traced back to a conversation between Dr. Paul Greengard, Rockefeller University, a Nobel Prize winner in 2000 for research into neurotransmissions between brain neurons, and Dr. Kaplit, NewYork-Presbyterian/Weill Cornell, a pioneering gene therapy scientist.
Dr. Greengard and team discovered that the p11 gene fault is a major factor in the development of depression. The p11 protein is required to bring serotonin, a neurotransmitter, to the surface of brain cells (nerve cells). Serotonin has many functions, including regulating our sleep, mood, and appetite. In fact, the majority of drugs for treating depression (antidepressants) aim to regulate serotonin.
Dr. Kaplitt said:
In the absence of p11, a neuron can produce all the serotonin receptors it needs, but they will not be transported to the cell surface and therefore won’t stick out and latch on to the neurotransmitter.
In this latest animal study, the investigators aimed to disable the p11 gene’s function in mice. They used a virus which produced siRNA (small bits of double-stranded RNA) that stopped the gene doing what it was supposed to do (blocked its expression). They carefully targeted the p11 genes in the nucleus accumbens part of the brain. According to previous MRI studies, this part of the brain is especially affected in patients with major depression.
Dr. Kaplitt said:
Focusing exclusively on this area is fairly novel because it had been thought to be mostly involved in behaviors that are tied to addiction.
They found that the mice whose p11 gene had been disabled had behaviors closely linked to depression, prompting them to adapt a gene therapy treatment they had carried out in 2007 for Parkinson’s disease and published in The Lancet. An inert “smart” virus gets into the brain cells and deposits a genetic payload into the neuron’s genome – Trojan-horse style. The new genes produce the desired protein – p11.
The mice which received this ‘gene therapy’ soon lost their depression-like signs and symptoms.
Put simply – some normal and non-depressed lab mice had the p11 protein (gene) stopped in a tiny part of the brain. Consequently they became depressed. With gene therapy the p11 protein was restored, and they got better.
Autopsies of humans who had severe depression typically reveal very low levels of p11 protein in the nucleus accumbens, the authors add.
Dr. Kaplitt said:
Together, these studies provide strong evidence that maintaining adequate levels of this particular protein, p11, in this pleasure-reward area of the brain may be central to preventing or treating depression.
Gene therapy to restore p11 could eventually evolve into identifying a small molecule to do it, the scientists say.
The authors wrote (conclusion):
Normalization of p11 expression within this brain region with AAV-mediated gene therapy may be of therapeutic value.
Brian Alexander, Jennifer Warner-Schmidt, Therese Eriksson, Carol Tamminga, Margarita Arango-Llievano, Subroto Ghose, Mary Vernov, Mihaela Stavarche, Sergei Musatov, Marc Flajolet, Per Svenningsson, Paul Greengard and Michael G. Kaplitt
Sci Transl Med 20 October 2010: Vol. 2, Issue 54, p. 54ra76
DOI: 10.1126/scitranslmed.3001079
Written by Christian Nordqvist