Epigenetic drugs, should we be excited?

[Neuroprotection]

for anyone who doesn’t know, Epigenetics refers to processes or changes which alter the way existing genes are expressed without actually changing the DNA sequence. these changes can be short or long-term and very stable, but they are nonetheless reversible. common epigenetic processes include methylation or acetylation of either DNA or histone proteins.
It is now widely believed Epigenetics Play a major role in drug addiction and other psychiatric disorders through regulation of genes and proteins needed for synaptic plasticity. that’s precisely why the histone deacetylase (HDAC) inhibitors are under investigation for treatment of many brain diseases, ranging from mild cognitive impairment to bipolar disorder and schizophrenia. however, HDACIs are already well known and many of their behavioural effects like cognitive enhancement and anti-manic/mood stabilising. I am a bit more excited about drugs modulating DNA and histone methylation as this is just starting to be explored and provides many new opportunities to manipulate useful targets like neuronal receptors, neurotransmitter transporters and even second messenger Systems.
So why are epigenetic drugs exciting?
Well, our neurological and thus psychological States are highly responsive to our environment and whenever stable changes occur to our brain/behaviour, Epigenetics is almost certainly involved. chronic stress and drugs of abuse are two major environmental factors which definitely cause epigenetic changes. therefore, drugs that modulate Epigenetics could be used to remedy or reverse any previously established unwanted alterations, for example, supersensitivity to norepinephrine in PTSD. furthermore, this could be the holy grail for subverting any drug tolerance that relies on processes like receptor desensitisation or internalisation. this is especially relevant to those seemingly long-lasting or irreversible components of opioid and benzodiazepine tolerance. yes, tolerance to these drugs isn’t all about Single receptor classes, as opposing counter-systems and brain circuits are also involved, but Epigenetics could be used to target those as well. we are still in the very early stages of neuronal epigenetic research and it would likely be a very long way before this translates into a marketed drug. however, does anyone else share my optimism?

 

[AlsoTapered]

Use of Epigenetic Drugs in Disease: An Overview

Epigenetic changes such as DNA methylation and histone methylation and acetylation alter gene expression at the level of transcription by upregulating, downregulating, or silencing genes completely. Dysregulation of epigenetic events can be pathological, ...

www.ncbi.nlm.nih.gov

 

[Neuroprotection]

I don’t blame you if the potentials of epigenetics sound unreal, that’s how I felt at first. truth is, Epigenetics is in action all the time, moulding A whole range of biological responses to the environment. personally, I think it has greater potential and far superior safety than traditional Jean therapy in some diseases. yes, epigenetic modulater drugs might not be a cure especially for neurological diseases, but they are much less invasive, their effects are reversible and they don’t involve introduction of a new gene or use of certain vectors which carry their own risks. A good example of Epigenetics Direct relevance to our lives is the importance of beneficial gut bacteria, fibre and most importantly, the short chain fatty acids which arise from fermentation. it is the short chain fatty acids, particularly butyrate, which are thought to contribute to whole body and brain health via inhibiting HDAC enzymes.
Apparently, nicotine is also a very powerful epigenetic modulator which inhibits HDAC enzymes along with histone methyltransferases and DNA methyltransferases leading to a huge range of epigenetic changes. that is one of the reasons why nicotine is a powerful gateway drug to other more addictive stimulants like cocaine. it’s also likely one of the reasons why some people find long-term nicotine administration detrimental to their mental health and performance, whereas others like me find it extremely beneficial especially when used long-term. i’m very excited, not only for all the traditional therapeutic applications of Epigenetics, but also to the possibilities that could open up for well-being enhancement.

 

[polymath]

I think they are trying to develop some type of anti-anxiety drug that erases epigenetic changes caused by psychological trauma and stress. These can also be inherited by someones offspring.

Even phytochemicals like those in curcuma longa and green tea can change gene expression in a way that prevents malignant tumors. And so does the carbohydrate/protein/fat radio in one's typical food intake.

This is a bit like a "lite" version of genetic engineering, and it can't be really controlled if someone decides to chemically cause heritable changes in their gene expression.

 

[vecktor]

All the various epigenetic drugs have a potentially serious drawback, some genes are epigenetically silenced for a good reason. To put it simplistically every cell has the genes to make every part of an organism and to make unlimited copies of itself, some are silenced in development as the cell differentiates and specialises, others are silenced by environmental and other growth factors. Over time and approaching senescence some are silenced and lead to increased prevalence of cancers, some decrease cancers.

It seems clear that the biggest initial potential for epigenetic drugs is to reverse the silencing of anti-cancer regulatory genes and proapoptotic genes in tumors, rather than messing about with expression in neurons, simply because the risk benefit ratio favours using them as chemotherapy prbably in combination with other chemotherapeutic agents. The prevalent view that cancers are always due to genome level mutations is wrong, but most cancers have very altered gene expression profiles. There is a lot of history of epigenome active agents not working as intended for CNS applications.
It has been well known (for decades) that many CNS active drugs interact with the neuronal epigenome, Pharma groups in industry were aware of this at the turn of the century when genetic profiling in vitro became easy. Some leads were developed from this discovery. For example a series of drugs based on the old school antidepressant tranylcypromine have been investigated for multiple applications as lysine specific demethylase inhibitors, irreversible LSD-1 inhibitors mostly, but they have not done particularly well. Almost 20 years ago a selective and very potent brain penetrating LSD1 inhibitor was trialed against dementia and it crashed and burned (no difference from placebo and some tox issues). GSK have since run a few LSD-1 modulators into trials against neurodegenerative conditions and they crashed and burned too. So merely inhibiting histone related enzymes and getting a positive CNS outcome is a not a given.

With LSD1 inhibitors there is a clear complexity to their behavior and some of the initial analogs display pronounced toxicity, perhaps because LSD-1 is very similar to other FAD dependent enzymes and a few of the very toxic varieties hit the Krebs cycle. The mechanism of antidepressant action is not actually known for certain despite 70 years of effort and intense study, a field like neuronal epigenetic modification is interesting but really really unknown territory.

On a pure logical basis, the hereditary nature of neurological epigenetics must be somewhat weak, The environment today is not in anyway stressful in biological terms compared to the past, yet humans still retain the ability to form a diverse array of behavioral archetypes. The papers suggesting detectable inheritable characteristics due to epigenetic alterations are pretty weak, the confounding factor of nature vs nurture, the apple never falls far from the tree and genetic vs epigenetic. The only strong evidence for important inheritable epigenetic modification that I am aware of is the inheritance of increased cancer risk due to exposure to DES in the parent or grandparent. Given that indescriminate altering of gene silencing markers in healthy individuals would likely lead to increased rates of cancer, targeting of the gene silencing and gene upregulation is exceptionally important.

 

[Neuroprotection]

All the various epigenetic drugs have a potentially serious drawback, some genes are epigenetically silenced for a good reason. To put it simplistically every cell has the genes to make every part of an organism and to make unlimited copies of itself, some are silenced in development as the cell differentiates and specialises, others are silenced by environmental and other growth factors. Over time and approaching senescence some are silenced and lead to increased prevalence of cancers, some decrease cancers.

It seems clear that the biggest initial potential for epigenetic drugs is to reverse the silencing of anti-cancer regulatory genes and proapoptotic genes in tumors, rather than messing about with expression in neurons, simply because the risk benefit ratio favours using them as chemotherapy prbably in combination with other chemotherapeutic agents. The prevalent view that cancers are always due to genome level mutations is wrong, but most cancers have very altered gene expression profiles. There is a lot of history of epigenome active agents not working as intended for CNS applications.
It has been well known (for decades) that many CNS active drugs interact with the neuronal epigenome, Pharma groups in industry were aware of this at the turn of the century when genetic profiling in vitro became easy. Some leads were developed from this discovery. For example a series of drugs based on the old school antidepressant tranylcypromine have been investigated for multiple applications as lysine specific demethylase inhibitors, irreversible LSD-1 inhibitors mostly, but they have not done particularly well. Almost 20 years ago a selective and very potent brain penetrating LSD1 inhibitor was trialed against dementia and it crashed and burned (no difference from placebo and some tox issues). GSK have since run a few LSD-1 modulators into trials against neurodegenerative conditions and they crashed and burned too. So merely inhibiting histone related enzymes and getting a positive CNS outcome is a not a given.

With LSD1 inhibitors there is a clear complexity to their behavior and some of the initial analogs display pronounced toxicity, perhaps because LSD-1 is very similar to other FAD dependent enzymes and a few of the very toxic varieties hit the Krebs cycle. The mechanism of antidepressant action is not actually known for certain despite 70 years of effort and intense study, a field like neuronal epigenetic modification is interesting but really really unknown territory.

On a pure logical basis, the hereditary nature of neurological epigenetics must be somewhat weak, The environment today is not in anyway stressful in biological terms compared to the past, yet humans still retain the ability to form a diverse array of behavioral archetypes. The papers suggesting detectable inheritable characteristics due to epigenetic alterations are pretty weak, the confounding factor of nature vs nurture, the apple never falls far from the tree and genetic vs epigenetic. The only strong evidence for important inheritable epigenetic modification that I am aware of is the inheritance of increased cancer risk due to exposure to DES in the parent or grandparent. Given that indescriminate altering of gene silencing markers in healthy individuals would likely lead to increased rates of cancer, targeting of the gene silencing and gene upregulation is exceptionally important.

Thank you for that. Of course, I understand this is unknown territory and undoubtedly, there will be many pitfalls in making an epigenetic drug. however, with the introduction of digital technology into DNA analysis and with the knowledge bass rapidly growing in size, it might not be long before certain targets can be selected and new drugs tested. furthermore, the HDAC inhibitors have shown significant promise in treating some cancers and neurodegenerative diseases, or at the very least acting as disease modifying agents. on a sidenote, do you know anything about the LSD1 enzyme and why it was targeted? i’ve heard about it, but I don’t understand what it does and what was the rationale behind inhibiting it? if you know, please could you share that knowledge with me because it’s been on my mind for a few years now.
Thanks again for your great reply.

 

[Skorpio]

do you know anything about the LSD1 enzyme and why it was targeted

LSD1 is a lysine specific demethylase. Methylation of histone lysines (at a reductive level) makes the dna more accesible for reading. Really there is more nuance, as lysines can accept up to 3 methyl groups and trimethylation seems to be activating, while dimethylation seems to repress transcription.

It is often taught as the opposite effect of histone acetylation, where acetylation represses the chromatin making it harder to read.

This is a big issue with epigenitics and a lot of functions converge on histone methylation/demethylation and acetylation/deacetylation.

Normally these modifications are highly regulated due to signaling processes, so I am wary of broadly altering global levels of histone modifications, as it seems like doing brain surgery with a chefs knife.

I think these drugs have a place in dire conditions, but I am unsure of the risk/reward of using them for psychiatric purposes (which tend to not be short lived and life threatening).