User:Dburke11/Epigenetic therapy

With exposure therapy for fear, anxiety, and trauma[edit]
Traumatic experiences can lead to several mental illnesses including post-traumatic stress disorder. It was previously thought that PTSD could be treated with advances in cognitive behavioral therapy methods like Exposure therapy. In exposure therapy, patients are exposed to stimuli that provoke fear and anxiety. In theory, repeated exposure can lead to a decreased connection between the stimuli and the anxiety. While exposure therapy helps many patients, many patients do not experience improvement in their symptoms while others may experience more symptoms.

The biochemical mechanisms underlying these systems are not completely understood. However, brain-derived neurotrophic factor (BDNF) and the N-methyl-D-aspartate receptors (NMDA) have been identified as crucial in the exposure therapy process. Successful exposure therapy is associated with increased acetylation of these two genes. Acetylation is a biochemical modification that affects how tightly DNA is wound around histone proteins, thereby influencing gene expression. When the genes encoding BDNF and NMDA receptors experience increased acetylation, they become more "accessible" for transcription, the first step in protein production. So, enhanced expression of BDNF and NMDA receptors seems to bolster neural plasticity, facilitating the brain's capacity to form new connections and adjust its responses to anxiety-provoking stimuli. For these reasons, increasing the acetylation of these two genes has been a major area of recent research into the treatment of anxiety disorders.

N-methyl-D-aspartate receptors (NMDA receptors) play a crucial role in synaptic plasticity and learning, including fear extinction, which is a core mechanism targeted in exposure therapy. These receptors are involved in the consolidation of new memories and the extinction of fear responses by regulating the strength of synaptic connections. Exposure therapy aims to reduce the fear response to specific stimuli by repeated exposure to those stimuli in a safe environment. During exposure therapy, the process of fear extinction occurs, where individuals learn that the feared stimuli no longer predict harm. NMDA receptors are implicated in this fear extinction learning process through their involvement in synaptic plasticity mechanisms, such as long-term potentiation (LTP) and long-term depression (LTD), which underlie the formation and extinction of fear memories. Research has shown that pharmacological manipulation of NMDA receptors can influence fear extinction learning and enhance the efficacy of exposure therapy. For example, drugs that enhance NMDA receptor function, such as D-cycloserine, have been used as adjuncts to exposure therapy to facilitate fear extinction in individuals with anxiety disorders. The article "Effects of D-cycloserine on extinction: translation from preclinical to clinical work" (Davis et al., 2006) discusses the preclinical and clinical studies investigating the effects of D-cycloserine, a partial agonist at the glycine site of the NMDA receptor, on fear extinction and its translation to clinical applications in exposure therapy for anxiety disorders.

In relation to epigenetic therapy, modulating NMDA receptor-related pathways and enhancing fear extinction learning. By targeting epigenetic modifications of NMDA receptor genes, such as promoting DNA demethylation or histone acetylation, it may be possible to enhance NMDA receptor function and facilitate fear extinction processes. This could involve adjunctive treatments with epigenetic-modifying agents, tailored to individual genetic and epigenetic profiles, to optimize exposure therapy outcomes in individuals with anxiety disorders.

Going deeper into BDNF as well, utilizing BDNF as more than a mere marker in exposure therapy and integrating it into epigenetic therapy to target BDNF-related pathways could serve as a valuable addition to complement exposure therapy.

The relationship between BDNF, exposure therapy, and epigenetic therapy can be elucidated by considering the role of BDNF in fear extinction learning, which is a core mechanism targeted in exposure therapy, and the potential for epigenetic mechanisms to modulate BDNF expression and function.

BDNF plays a pivotal role in fear extinction learning, crucial for exposure therapy, by facilitating synaptic plasticity and consolidating safety memories. Individuals with BDNF dysfunction, like those with the Val66Met SNP (The Val66Met single nucleotide polymorphism (SNP) of BDNF), may exhibit impaired fear extinction, potentially leading to treatment resistance in exposure therapy. Consequently, strategies aimed at enhancing BDNF function or expression could enhance the efficacy of exposure therapy interventions. Moreover, epigenetic mechanisms, such as DNA methylation and histone modifications, dynamically regulate BDNF expression and function. Environmental factors and genetic variants like the Val66Met SNP can influence BDNF epigenetic marks, impacting its transcriptional activity. Targeting epigenetic modifications of BDNF presents a novel approach to modulating fear extinction processes, potentially improving exposure therapy outcomes. Epigenetic therapy could complement exposure therapy by targeting BDNF-related pathways, such as demethylating the BDNF gene promoter or altering histone acetylation patterns to facilitate BDNF transcription. Integrating genetic information, such as BDNF polymorphisms, with epigenetic profiles and clinical data allows for personalized treatment approaches. Identifying individuals likely to benefit from targeted epigenetic interventions could enhance fear extinction learning and improve treatment outcomes in exposure therapy. This interplay between BDNF, exposure therapy, and epigenetic regulation holds promise for optimizing treatment outcomes and advancing personalized medicine approaches for anxiety disorders.

HDAC inhibitors are also a topic that can be discussed in this area. Exposure therapy's effectiveness in rodents is increased by the administration of Vorinostat, Entinostat, TSA, sodium butyrate, and VPA, all known histone deacetylase inhibitors. Several studies in the past two years have shown that in humans, Vorinostat and Entinostat increase the clinical effectiveness of exposure therapy as well, and human trials using the drugs successfully in rodents are planned. In addition to research on the effectiveness of HDAC inhibitors, some researchers have suggested that histone acetyltransferase activators might have a similar effect, although not enough research has been completed to draw any conclusions. However, none of these drugs are likely to be able to replace exposure therapy or other cognitive behavioral therapy methods. Rodent studies have indicated that administration of HDAC inhibitors without successful exposure therapy worsens anxiety disorders significantly, although the mechanism for this trend is unknown. The most likely explanation is that exposure therapy works by a learning process, and can be enhanced by processes that increase neural plasticity and learning. However, if a subject is exposed to a stimulus that causes anxiety in such a way that their fear does not decrease, compounds that increase learning may also increase re-consolidation, ultimately strengthening the memory.

Psychotherapy can be linked to alterations in epigenetic markers. An example of the growing evidence that indicates that successful psychotherapy can be linked to alterations in epigenetic markers, particularly DNA methylation, and could serve as a potential indicator of treatment efficacy is a research paper titled "Epigenetics of traumatic stress: The association of NR3C1 methylation and posttraumatic stress disorder symptom changes in response to narrative exposure therapy" by Wilker et al. (2023). This study explored the relationship between DNA methylation at the glucocorticoid receptor gene (NR3C1) and the success of psychotherapy in treating Posttraumatic Stress Disorder (PTSD) among conflict survivors in Northern Uganda. The researchers used Narrative Exposure Therapy (NET) on a sample of 153 individuals with PTSD and conducted diagnostic interviews and saliva sampling before treatment and at 4 and 10 months after treatment completion. They found that changes in methylation at a specific CpG site (cg25535999) were associated with PTSD symptom development. Treatment responders showed an increase in methylation at this site after therapy, while lower methylation levels before treatment predicted greater symptom improvement. These findings suggest that epigenetic changes at NR3C1 may play a role in the success of trauma-focused therapy, highlighting the importance of glucocorticoid signaling in PTSD treatment.

-I am going to look at this section, lots of grammar issues but also missing information... going to ask for other thoughts though

Background[edit]
Epigenetic therapy is the use of drugs or other epigenome-influencing techniques to treat medical conditions. Many diseases, including cancer, heart disease, diabetes, and mental illnesses are influenced by epigenetic mechanisms. Epigenetic therapy offers a potential way to influence those pathways directly. - old lead

Epigenetic therapy: Epigenetics refers to the study of changes in gene expressions that do not result from alterations in the DNA sequence. This results in the heritable silencing of genes without a change in the coding sequence. As such, Epigenetic therapy is using drugs or other techniques to influence the epigenetic basis of certain medical issues. Many diseases, including diabetes, cancer, heart disease, and mental illnesses are influenced by epigenetic mechanisms. Diabetic retinopathy is known to be associated with a number of epigenetic markers, including methylation of the Sod2 and MMP-9 genes amongst others (9). One of the most common epigenetic mechanisms that can be targeted in cancer is the epigenetic activation of oncogenes. (21) Epigenetic therapy for heart disease is an emerging field, focusing mainly on regeneration of affected tissues. Epigenetic treatments for schizophrenia focus on reducing the symptoms of the disease as it cannot be eradicated. Epigenetic therapies are medicine designed to effect the underlying epigenetic molecular pathways that cause disease. - new lead

Main article: Epigenetics

Epigenetics, a term coined in 1942 by CH Waddington, refers to the study of changes in gene expressions that do not result from alterations in the DNA sequence'. Altered gene expression patterns can result from chemical modifications in DNA and chromatin, to changes in several regulatory mechanisms. The structure of chromatin can lead to epigenetic changes, euchromatin is decondensed and epigenetically accessible region while heterochromatin is condensed and epigenetically repressed region. Epigenetic markings can be inherited in some cases and can change in response to environmental stimuli over the course of an organism's life.

Many diseases are known to have a genetic component, but the epigenetic mechanisms underlying many conditions are still being discovered. "Epigenetic profiling" is now possible due to increases in genetic sequencing (ChIP-Seq). This has allowed for the mapping of the epigenome at near base pair levels, showing the importance of DNA mechanisms such as promotor regions. The combination of sequencing data and analysis have given great insight into the epigenetic reasons for disease. (Cite2016.59 ) A significant number of diseases are known to change the expression of genes within the body, and epigenetic involvement has been shown to be a avenue for this. These changes can be the cause of symptoms of the disease. Several diseases, especially cancer, have been suspected of selectively turning genes on or off, thereby resulting in a capability for the tumorous tissues to escape the host's immune reaction.

Known epigenetic mechanisms typically cluster into three categories. The first is DNA methylation, where a cytosine residue that is followed by a guanine residue (CpG) is methylated. In general, DNA methylation attracts proteins which fold that section of the chromatin and repress the related genes. The second category is histone modifications. Histones are proteins which are involved in the folding and compaction of chromatin. There are several different types of histones which can be modified in a number of ways. Acetylation of histone tails typically leads to weaker interactions between the histones and the DNA, which is associated with gene expression. Histones can be modified in many positions, with many different types of chemical modifications, but the precise details of the histone code are currently unknown. The final category of epigenetic mechanism is regulatory RNA. MicroRNAs are small, noncoding sequences that are involved in gene expression. Thousands of miRNAs are known, and the extent of their involvement in epigenetic regulation is an area of ongoing research. Epigenetic therapies that modify chromatin are reversible (cite), unlike gene therapy. This means that they are druggable for targeted therapies.

-I am going to go through one section at a time and edit for clarity and professionalism. ( quick grammar edits and potential source id written later than 2015) Sources for wiki

Epigenetic therapy: Autism

Causes of Autism from article tandf

https://www.tandfonline.com/doi/full/10.3109/1547691X.2010.545086

Moos, W.H., Maneta, E., Pinkert, C.A., Irwin, M.H., Hoffman, M.E., Faller, D.V. and Steliou, K. (2016), Epigenetic Treatment of Neuropsychiatric Disorders: Autism and Schizophrenia. Drug Dev. Res., 77: 53-72. https://doi.org/10.1002/ddr.21295

Genetics of autism - scincedirect

https://www.sciencedirect.com/science/article/pii/S0166432813003562

better - https://www.sciencedirect.com/science/article/pii/S1098360021001155

Judith H. Miles,Autism spectrum disorders—A genetics review, Genetics in Medicine, Volume 13, Issue 4,2011,Pages 278-294, https://doi.org/10.1097/GIM.0b013e3181ff67ba.

( https://www.sciencedirect.com/science/article/pii/S1098360021001155 )

https://www.nature.com/articles/nrg.2017.4#Sec2

Vorstman, J., Parr, J., Moreno-De-Luca, D. et al. Autism genetics: opportunities and challenges for clinical translation. Nat Rev Genet 18, 362–376 (2017). https://doi.org/10.1038/nrg.2017.4

Epigenetics and therapies - mdpi

https://www.mdpi.com/1660-4601/10/9/4261

Siniscalco D, Cirillo A, Bradstreet JJ, Antonucci N. Epigenetic Findings in Autism: New Perspectives for Therapy. International Journal of Environmental Research and Public Health. 2013; 10(9):4261-4273. https://doi.org/10.3390/ijerph10094261

https://analyticalsciencejournals.onlinelibrary.wiley.com/doi/full/10.1002/ddr.21295

Moos, W.H., Maneta, E., Pinkert, C.A., Irwin, M.H., Hoffman, M.E., Faller, D.V. and Steliou, K. (2016), Epigenetic Treatment of Neuropsychiatric Disorders: Autism and Schizophrenia. Drug Dev. Res., 77: 53-72. https://doi.org/10.1002/ddr.21295

https://link.springer.com/article/10.1007/s40291-022-00608-z#citeas

Williams, L.A., LaSalle, J.M. Future Prospects for Epigenetics in Autism Spectrum Disorder. Mol Diagn Ther 26, 569–579 (2022). https://doi.org/10.1007/s40291-022-00608-z

https://www.annualreviews.org/content/journals/10.1146/annurev-pharmtox-061008-103102

Journal Article

Szyf, Moshe Epigenetics, DNA Methylation, and Chromatin Modifying Drugs. 2009, Annual Review of Pharmacology and Toxicology, Volume 49, 2009 ,43-263 (2009). https://doi.org/10.1146/annurev-pharmtox-061008-103102

https://analyticalsciencejournals.onlinelibrary.wiley.com/doi/full/10.1002/ddr.21295

Szyf, Moshe, Epigenetics, DNA Methylation, and Chromatin Modifying Drugs. Annual Review of Pharmacology and Toxicology, Volume 49, 2009 243-263 (2009). https://doi.org/10.1146/annurev-pharmtox-061008-103102

https://pubmed.ncbi.nlm.nih.gov/30093643/

Deverman BE, Ravina BM, Bankiewicz KS, Paul SM, Sah DWY. Gene therapy for neurological disorders: progress and prospects. Nat Rev Drug Discov. 2018 Sep;17(9):641-659. doi: 10.1038/nrd.2018.110. Epub 2018 Aug 10. Erratum in: Nat Rev Drug Discov. 2018 Oct;17(10):767. PMID: 30093643.

Autism

Autism or autism spectrum disorder (ASD) is a neurodevelopmental disorder discovered in 1943. It is part of a growing group of disorders called pervasive developmental disorders (PDDs), which are becoming increasingly common up to 1 in 110 in the United States and 1 in 64 in the United Kingdom.

While there are many causes for Autism spectrum disorder to manifest (viral infection, encephalitis, or an auto immune reaction, but the primary reasons are genetic or epigenetic. in the 1970s karyotyping allowed for the understanding of chromosomes, over time techniques such as fluorescence in situ hybridization (FISH)) we began to be able to analyze chromosomes with more resolution. Chromosome microarray and single nucleotide genotyping, and even whole genotype sequencing allow resolution at the gene level. One issue that possibly leads to autism is copy number variation in a gene the most studied of which is the 15q multiplication from the maternal chromosome. A database of genes (AutDB) has over 800 potential targets for study as a cause for autism. While not an exhaustive list a few examples are NLGN4X, PAH, PEX7,and SYNE1 .

The heterogeneity of autism causes and symptoms has lead to research in epigenetic factors. Maternal health during pregnancy, including taking folic acid, has been shown to affect the chances of not having ASD through epigenetic means. DNA methylation and histone modification are the two leading causes for epigenetic causes for autism. Targets for research for DNA methylation in relation to autism are oxytocin receptor, SHANK3, and BCL-2. Oxytocin is a hormone that partially controls social interactions, this has been epigenetically linked to autism. Methylation controls SHANK3 levels, which in turn activate CpG- island genes, which can lead to autism. BCL-2 is involved in cell death, and an event that misfires could contribute to brain development in that region. Histone modification also potentially leads to autism. Histone modification contributes to brain development. Modification of lysine residues on the H3 histone effect brain development. histone deacetylase inhibitors sodium butyrate and trichostatin A are regulators of oxytocin and vasopressin which are linked to autism symptoms.

Epigenetic therapies are a new emerging medical field. There are a number of potential therapies to treat ASD, using various methods. While the research into potential therapies is still in its infancy one of the positives of epigenetic therapy is it is reversible, this leads to many less potential side effects.While there are no current therapeutics approved for epigenetic use in autism there are a number of potential categories, histone decacetylase inhibitors (HDACis), and DNA methyltransferases. While there is great hope for epigenetic therapy for autism and some powerful research, there is currently no available drugs in clinical trials.

Histone acetlytion is a standard way to measure gene activity, HDACS remove histones thereby lowering the gene activity at that site. HDACi drugs are being tested and used as cancer theraputics, but are showing potential for neurodevelopmental disorders such as ASD. Valproic acid, commonly called Vorinostat, is an HDACi that helps with mood stabilization, this shows that is has potential for other neuro applications. MGCD0103 is a drug that is in preclinical trials as a cancer drug. Is mechanism is to affect HDAC1. HDAC1 has a large impact on many functions in the body, including many neuro regions, this makes it a good candidate for a potential Autism therapy.

DNA Methyltransferases (DNMT) have the potential to silence specific genes. As we learn more about genes related to ASD such as PAH (see above) these compounds become more relevant as therapies. There are three types of DNMT's. DNMT1 is a maintenence DNMT whereas DNMT3a and DNMT 3b are a de novo factor. There are currently two therapeutics being tested for this process, azacitidine and decitabine.