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Gene Therapy For Depression: A Futuristic Treatment

Despite the fact that pharmaceutical companies continue to promote the concept of “chemical imbalances” as the root cause of depression, this is a vast oversimplification of an infinitely more complex condition.  While a chemical imbalance may be one of the primary contributing factors to a person’s depression, what causes the chemicals (neurotransmitters) to become imbalanced in the first place?  Certainly a person’s lifestyle and dietary intake can influence neurotransmission and promote favorable epigenetic expression, but they cannot correct maladaptive genetic mutations.

Many people with depression are thought to have maladaptive genes that affect a multitude of processes including: neural activation, neurotransmission, hormone levels, arousal, and personality development.  As a result, an individual’s hedonic set point (or baseline level of wellbeing) is thought to be largely predetermined by genetic inheritance.  Certain people that hit the inheritance lottery (as a result of favorable genes) tend to have an inclination to feel happy – even if they don’t know why.

It is certainly not helpful to go through life blaming your genes if you’re depressed, as complaining accomplishes nothing and only promotes “learned helplessness.”  However, assuming you’ve continued to try therapeutic interventions without symptomatic relief – it is important to consider that faulty genes may be holding you back.  One futuristic intervention for depression that may emerge within the next 50 years is that of gene therapy.

What is Gene Therapy? How it could treat depression.

Gene therapy is a scientific technique (currently in experimental stages) that alters genes to prevent various diseases.  In the future, it is thought that gene therapy could allow medical professionals to treat depression via modification (insertion) of a specific gene.  In theory, this would target maladaptive genes that contribute to depression, and correct them via insertion of the more favorable genes.

The technique of gene therapy uses a vector (most often viral) to transport a gene to specific cells where the gene is required.  After the gene has been successfully inserted, the gene is processed by the cells, and proteins are manufactured.  The manufactured proteins then follow specific orders (as dictated by their programming) within cells.

Assuming you were receiving gene therapy for your depression, you may require: replacement of a mutation, deactivation of a gene, and/or addition of new genes.

  • Replacement of genetic mutations: One approach of using gene therapy is to replace a genetic mutation (responsible for depression) with a healthy copy of the gene.
  • Deactivation of genes: In some cases, gene therapy could be used to essentially deactivate certain genes that are contributing to a person’s depressive symptoms. While techniques like RNAi for depression inhibit expression of genes, gene therapy could permanently disable genetic mutations.
  • Adding a new gene: Someone with depression may be lacking a specific gene associated with mitigating depression. Gene therapy could insert a new gene into the individual’s body to permanently prevent depressive symptoms.

Therapeutic Targets of Gene Therapy for Depression: P11 & PDE11A

There are a variety of therapeutic targets to be considered in depression.  Many of these genetic biomarkers already have been documented as targets for novel antidepressant drugs.  That said, if we look into the future, gene therapy may prove more effective with less side effects than pharmaceuticals.

The most obvious therapeutic target for depression is that of p11.  Low levels of p11 expression within the nucleus accumbens is associated with depressive behavior in rodents.  Further, low levels of p11 have been confirmed in the brains of humans with depression – making it a logical first target for gene therapy.

Another possible target of correction would be PDE11A halpotype GAACC.  This phosphodiesterase gene is associated with major depression and is predictive of antidepressant responses.  Other possible genetic polymorphisms that warrant further investigation include: 5-HTTLPR, STin2, PDE9, and PDE1A polymorphisms.

Gene Therapy for Depression (Scientific Research)

There is increasing evidence suggesting that specific genetic abnormalities contribute to major depressive disorder.  While gene therapy hasn’t yet been studied in humans for the treatment of depression, preliminary rodent studies highlight its efficacy.  Included below is a synopsis of the research, much of which focuses on the protein p11 (S100A10).

2015: It is well-documented that major depressive disorder is problematic for those with the condition, but it also takes a significant toll on the economy.  As of now, there aren’t any objective assessments to determine whether someone is depressed.  Since most reports of depression (and its severity) are subjective, psychiatrists prescribe medications based on their interpretation of the condition.

While psychiatry can be effective for certain individuals, many fail to attain sufficient symptomatic relief.  Fortunately with scientific advancement, researchers are now able to determine how specific genes and other biomarkers may contribute to depression.  Moreover, companies like GeneSight attempt to predict antidepressant responses and blood tests for depression are being investigated.

A review published in 2015 discussed how genes influence depression, and how RNA biomarkers derived from blood cells may aid in the diagnosis of depression.  It appears as though researchers are attempting to use the entire human genome and uncover specific genetic underpinnings responsible for major depression.  Assuming all contributing genetic abnormalities associated with depression were discovered, this would provide pharmaceuticals with new pharmacological targets, and allow for further testing of targeted gene therapy in animals.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/25708651

2013: Current evidence suggests that a specific protein involved in the pathogenesis of depression is known as p11 (S100A10).  This protein is involved in modulating the signaling of serotonin.  In a report from 2013, researchers documented that p11 levels are regulated among individuals with depression following administration of antidepressants.  Moreover, p11 seems to dictate whether an individual will respond to antidepressants, and the individual’s depressive behaviors.

Specifically, a person’s susceptibility to depression may be related to interactions between p11 and serotonin.  The protein p11 interacts with an array of serotonergic receptors, and is necessary for antidepressants to improve mood.  In rodent studies, mice that are lacking p11 fail to respond to antidepressants, suggesting cases of refractory depression.

Researchers are currently working to devise novel new antidepressants that target different serotonergic receptors such as “serotonin 4” – found primarily within the gut.  It appears as though p11 has a significant interaction with “serotonin 4.”  Therefore, perhaps targeting “serotonin 4” in the future may provide faster-acting antidepressants.

In addition, it is important to consider the role that gene therapy could play in the treatment of depression.  By specifically inserting the p11 gene, a person may not require antidepressant medications and/or may achieve a better response to pharmaceutical interventions.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/24002251

2013: Researchers published a report suggesting that gene therapy could be an effective futuristic intervention for the treatment of various psychiatric disorders, including major depression.  It is known that most individuals with psychiatric abnormalities often have dysfunctional circuitry within regions of the brain.  As a result of dysfunctional circuitry, researchers speculate that gene therapy may normalize the circuitry and ultimately provide substantial benefit to recipients.

They discuss the fact that the modality of delivery for gene therapy would require the same surgical procedures that are currently being used for deep brain stimulation.  It was noted that neurosurgeons would be necessary for implantation of the genes.  Despite the surgical technicality associated with gene therapy, it may be promising for a variety of psychiatric conditions (not limited to depression), including: OCD, addiction, and schizophrenia.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/23268195

2012: It is clear that not everyone derives benefit from the same antidepressant.  A drug that is effective for one person, may be ineffective (or make things worse) for another.  Many researchers believe that those with depression may exhibit similar overt symptoms, but the specific genetic underpinnings of major depression may be subject to significant individual variation; this explains why responses to medications vary.

An article published in 2012 highlights the fact that specific genes and their interactions with the environment likely contribute to depression.  Further, it was suggested that genes also likely predict whether a person is likely to respond to antidepressant treatment.  Researchers believe that by investigating genetic differences among those with depression, they’ll be able to predict treatment responses and elucidate root causes.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/22198824

2011:  There are many problems of psychiatry, one of which is that the field fails to consider individualization when it comes to a specific diagnosis.  For example, two people could be diagnosed with depression, yet one may be depressed as a result of low serotonin and the other could be depressed as a result of low dopamine and norepinephrine.  Despite these individual differences, there is no way of knowing the root cause of depression for each individual.

Not only are psychiatrists unable to measure neurotransmitter levels in the brains of those that are being treated, they aren’t usually able to understand what caused those chemical imbalances.  In some cases, a person with depression may not even have a specific chemical imbalance – it could be caused by another factor.  An article published in 2011 suggested the need for understanding how genetic variation and gene-environment interactions may contribute to depression.

They discuss specific genetic polymorphisms that modulate DNA methylation, noting that methylation differences (undermethylation vs. overmethylation) could predict a more specific subtype of depression based on individual biochemistry.  Assuming psychiatrists could account for patient-specific genetic abnormalities (contributing to depression), they could prescribe individualized treatments with greater efficacy.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/21631158

2011: Despite the fact that many individuals desperate for relief from depression would try gene therapy, it is a long ways from being perfected.  One such target that may provide therapeutic efficacy is targeting the p11 gene.  P11 is considered a protein that binds to serotonin receptors.

Suboptimal levels of p11 in the nucleus accumbens of rodents promotes depression in rodents.  On the other hand, increasing expression of p11 in the nucleus accumbens attenuated the depression.  Therefore it could be speculated that gene therapy interventions aimed at increasing the p11 gene in humans would also improve mood.

Despite early promise of gene therapy targeting p11 in the brains of rodents, there are numerous concerns that need to be addressed before human trials will take place.  More rodent research is necessary to determine the side effects, long-term effects, and adverse reactions.  In addition, various regulatory issues need to be addressed before gene therapy could be tested in humans with depression.

  • Source: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3394098/

2010: One theory regarding the cause of depression is that serotonin signaling becomes dysfunctional.  Dysfunctional serotonin signaling may be caused specifically by inadequate levels of the gene p11.  It has been determined that P11 functions as protein that binds to 5-HT1B and 5-HT4 receptors.

Researchers have noted that mice with a knockout of p11 tend to be highly prone to depressive behaviors.  As a result, researchers hypothesized that p11 plays an important role in regulating mood.  Additionally, scientists were able to pinpoint the nucleus accumbens as a prominent region of action for p11.

Upon administration of RNA interference with an adeno-associated virus (AAV), they were able to specifically inhibit p11 in the nucleus accumbens of adult mice.  It was this specific inhibition (of p11 in the nucleus accumbens) that promoted depressive behaviors.  Authors highlighted the fact that gene therapy (using an adeno-associated virus) to increase p11 in the nucleus accumbens may provide therapeutic benefit to those with depression.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/20962330

2010: Another publication documented the fact that p11 expression in the nucleus accumbens of animals can modulate depressive behaviors.  Those with greater expression of p11 in the nucleus accumbens tend to exhibit normal behaviors and less depression.  On the other hand, those with p11 knockout or inhibition (in the nucleus accumbens) tend to exhibit depressive behaviors.

Researchers also investigated the levels of p11 among 17 humans diagnosed with major depressive disorder and compared the levels to 17 humans without any mood disorders.  They discovered that those with major depression had significantly lower levels of p11.  This suggests that aiming to increase p11 in the brains of humans with depression may effectively ameliorate symptoms.

It is believed that enhancement of p11 in the brains of humans with depression would reverse the condition.  It is unknown as to whether increasing p11 beyond normal levels would enhance an individual’s hedonic set point.  That said, it appears as though insufficient levels of p11 prevent neurons from properly responding to serotonin.

Remember that p11 is just one promising genetic target to consider among those with depression.  It is responsible for transporting 5-HT receptors to the surface of the neuron, allowing them to communicate with the serotonin.  Targeting p11 may be a viable intervention in the future for those with treatment-resistant cases of depression.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/20962329

2009: In a publication from 2009, researchers suggest that current-market antidepressants have numerous problems.  These include: delayed onset of action, poor response rates, and an array of unwanted side effects.  For this reason, it is important to focus on other potential targets for the treatment of depression.

Authors proposed investigating phosphodiesterases (PDEs), enzymes that are known for metabolizing cAMP (cyclic adenosine monophosphate) and cGMP (cyclic guanosine monophosphate).  Both animal and human research suggests that PDEs can contribute to depressive moods and anxiety.  In addition, various PDE genes have been discovered among those with depression and various other psychiatric conditions (e.g. schizophrenia).

Recently, it was also discovered that PDE4B inhibition in mice resulted in super intelligence (cognitive enhancement) as well as potent anxiolytic effects.  While no improvement in mood was noted as a result of this inhibition, it is thought that other PDE targets may enhance wellbeing and/or offset depression.  Assuming PDE genes (or lack thereof) associated with depression can be discovered, this may pave the way for gene therapy, RNAi, or a combination of the two techniques.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/18932104

2009:  A study published in 2009 documented that up to 50% of those with depression and 25% of individuals with anxiety disorders do not respond to antidepressants.  These responses are likely due to individualized genetics.  For example, “Person A” may derive significant benefit from a drug because it is correcting neurotransmission resulting from a genetic abnormality.

Another individual (“Person B”) may have the same condition as “Person A,” but a completely different underlying genetic cause.  “Person B” may feel significantly worse on the drug that improves the mood of “Person A.”  For this reason, it is important to consider the role of genetics in psychiatry and the treatment of mood disorders.

Researchers discuss a variety of genes that likely influence whether someone responds to an antidepressant, as well as other genes that may contribute to the underlying etiology of depression.  In large-scale studies of individuals with depression, two polymorphisms of SERT (serotonin transporter gene) including 5-HTTLPR and STin2 are thought to play a role.  Moreover, other genes that may be involved in depression and responses to antidepressants include: specific 5-HT receptor genes, BDNF, P-glycoprotein, G-proteins, TPH1, TPH2, MAOA, NET (norepinephrine transporter), FKBP5, and CYP450.

For example, it is understood that CYP450 is involved in metabolism of antidepressant drugs – thus influencing responses to specific drugs and doses.  Researchers hope to use specific genes to predict responses to antidepressants in the future.  It could also be suggested that certain genetic abnormalities could futuristically be targeted with gene therapy and/or RNAi rather than pharmaceuticals.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/19738481

2007: Many people notice that taking antidepressants increases depression and suicidality.  This may be due to the fact that the drug is altering neurotransmitters that don’t warrant altering.  Individual genetic variation is thought to distinguish those who will respond to a specific antidepressant from those who end up feeling worse as a result of the intervention.

Researchers are still unsure as to what causes some individuals to become increasingly suicidal while taking antidepressants.  As a result, they decided to investigate various genetic biomarkers that may contribute to medication-induced suicidal ideation.  DNA samples were collected from 1,915 participants in the STAR*D (Sequenced Treatment Alternatives to Relieve Depression) study.

These DNA samples were analyzed for 768 SNPs (single nucleotide polymorphisms) within 68 specific genes.  The alleles and genotype frequencies were assessed among 120 individuals that experienced antidepressant-induced suicidal ideation.  Results indicated that medication-induced suicidal ideation is associated with genetic biomarkers GRIA3 and GRIK2 – both of which produce ionotropic glutamate receptors.

Assuming more studies confirm these findings, it may be possible to determine individuals that may have suicidal reactions to antidepressant interventions.  Therefore increased monitoring and/or alternative therapies may be advised for these individauls.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/17898344

2006: A study from 2006 shed light on the possibility that PDE (phosphodiesterases) genes may play a role in the etiology of major depression.  It is known that PDEs are enzymes that function by degrading cAMP and cGMP within the brain.  Cyclic adenosine monophosphate (cAMP) is a messenger derived from ATP and is associated with learning, memory, and mood, and cyclic guanosine monophosphate (cGMP) regulates processes within the CNS influenced by nitric oxide.

Researchers investigated whether specific genetic biomarkers of PDEs influences the likelihood of major depression.  They collected DNA data from 284 individuals with depression (all of whom were Mexican Americans) and compared it to 331 non-depressed controls.  A total of 21 genes within the PDE family were analyzed to determine whether there were notable differences between those with depression and the controls.

Results indicated that specific polymorphisms of PDE9A and PDE11A were associated with increased likelihood of depression.  Those who derived significant therapeutic benefit from antidepressants had polymorphisms of PDE1A and PDE11A.  It was noted that specific PDE genes were predictive of depression and responses to pharmaceuticals.

Authors concluded that PDE11A halpotype GAACC is associated with major depression and antidepressant responses.  This conclusion was later confirmed by research conducted in 2009.  Therefore it may be useful to consider various PDE targets for gene therapy or RNA interference.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/17008408
  • Source: http://www.ncbi.nlm.nih.gov/pubmed/19557111

Potential Benefits of Gene Therapy for Depression

There are several potential benefits of using gene therapy for the treatment of depression.  The most prominent benefit is that it could be used to essentially vaccinate and/or prevent depression from ever occurring in certain individuals, and permanently correct depression in others.  Gene therapy would be correcting genetic abnormalities at the source rather than serve as a temporary fix like pharmaceutical antidepressants.

  • Genetically engineered prevention: In the future, depression could be prevented with genetic engineering in embryos. While some may dislike the idea due to ethical concerns of “playing god” – this could prevent a person from dealing with a lifetime disability of depression.  Many would argue that the engineering of genes prior to birth would be of substantial benefit to the individual as well as the rest of society.
  • Individualized targeting: Assuming scientists are able to isolate specific genetic abnormalities responsible for causing depression, they’ll likely find individual differences. Two people with severe depression may have different genetic correlates responsible for the depression.  Therefore gene therapy may be used on an individual basis to correct abnormalities and optimize personal performance.
  • Minimal side effects: In the future, gene therapy techniques will be refined and have minimal likelihood of significant side effects. Many people with depression dislike taking medications due to side effects (e.g. weight gain, sexual dysfunction, dry mouth, etc.).  With gene therapy, these side effects associated with ingestion of pharmaceuticals won’t occur.
  • Permanent cure: Some believe that gene therapy will eventually ameliorate all psychiatric conditions, possibly serving as a permanent cure. Adding a corrected copy of a maladaptive gene may normalize neural functioning.  This is different from standard treatment with pharmaceutical drugs which may mitigate symptoms of depression, but not the underlying genetic causes.

Potential Pitfalls of Gene Therapy for Depression

Despite the fact that gene therapy appears to be a promising new therapeutic intervention for depression and other neurological conditions, there are a number of concerns associated with the procedure.  Specifically, gene therapy isn’t yet considered a safe option for human trials among those with depression.  The technique’s efficacy isn’t well-established, and the long-term effects remain unclear.

  • Cost: At this stage, the costs associated with gene therapy would make it unaffordable for most individuals with major depression. Various gene therapy interventions may cost well over $1 million per individual.  Until costs are lowered, safety is established, and efficacy is proved – gene therapy remains an unrealistic treatment.
  • Delivery methods: It is still unknown as to how gene therapy for depression would be delivered. Assuming the genes were inserted with viral vectors, it is important to consider the risk of inflammation and toxicity.  Scientists will need to perfect delivery methods of gene therapy, establishing both safety and efficacy before it can be tested in humans.
  • Efficacy: Currently it is unknown as to how effective gene therapy would be for the treatment of depression in humans. While it may sound promising to target specific genes to treat depression, the degree of therapeutic benefit remains unclear.  Assuming genes are inserted via a viral vector and multiple treatments are required, the immune system may learn to attack the foreign material quickly – thus minimizing gene therapy’s efficacy with subsequent administration.
  • Ethical concerns: There are a variety of ethical concerns that people have with gene therapy. Some may be using gene therapy for blatant mood enhancement, whereas others would be using it to treat depression.  Some may perceive high-priced gene therapy as an option for the wealthy with limited or no availability for the poor.  These ethical concerns need to be addressed for gene therapy to emerge as a viable treatment for depression.
  • Safety concerns: Preliminary evidence suggests that gene therapy may pose significant safety risk for the recipient. Upon insertion of new DNA, a number of adverse reactions stemming from mutations could occur.  This could result in tumor growth, leukemia, and/or possibly death.  While gene therapy doesn’t appear unsafe based on clinical trials, there are certainly some health risks to consider.
  • Short-term results: In order for gene therapy to serve as a “cure,” the insertion of DNA into specific cells will need to retain functionality. The cells with the inserted DNA must be stable, otherwise it will only provide short-term benefits.  This will require continuous short-term treatments and won’t serve as a cure.
  • Side effects: Whenever something foreign is introduced to the body, it is attacked by the immune system. Assuming you were to insert a new gene into your brain, your immune system may attack it, making you sick with numerous side effects.  In other words, you may end up feeling sicker after gene therapy than you do after taking an antidepressant.
  • Therapeutic targets: As of 2015, various therapeutic targets for gene therapy remain unclear. While enhancing p11 in the nucleus accumbens seems like a viable option, more research is necessary to understand its effect.  In addition, many individuals have abnormalities with multiple genes that cause depression.  It may be difficult to target several genes simultaneously with gene therapy.

Do you think gene therapy will eventually be used to treat depression in humans?

It appears as though insertion of P11 within the nucleus accumbens may alleviate depressive symptoms in humans.  As of now, there aren’t any preclinical trials involving gene therapy for depression, and until many ethical, safety, efficacy concerns are addressed – there aren’t likely to be any for awhile.  Perhaps within the next several decades we will see gene therapy emerge as a potential treatment for depression.

In its early stages, it may provide short-term relief with minimal side effects.  As the method is perfected, researchers should theoretically be able to insert genes to permanently offset depression, improve mood, and/or shift hedonic set point.  A number of ethical concerns will emerge as people turn to gene therapy as a cosmetic procedure for improving mental performance and mood.

If you think gene therapy will be used to treat depression in your lifetime, share your thoughts in the comments section below.  Discuss how long you think it will take for scientists to devise a safe and effective gene therapy intervention for depression.  Do you think the gene therapy will be based on a universal “antidepressant” protocol or personalized to fit a person’s unique genetic variation?

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