Future Cure for PAS, PFS and PSSD - Also we need more captial

General Discussion
#1

This is a slightly edited version of an old post from another forum I ran a while back - https://www.pasforum.info/threads/plausible-cure-crispr-cas9-gene-editing.21/

It may seem a bit crazy, but I really believe if we are ever to find a working, effective treatment/cure for these conditions, there is a good chance it will come from gene therapy. Luckily for us, the CRISPR gene editing system has arrived and offers the potential to fix this damage.

CRISPR enables fast, cheap, precise and efficient gene editing. This technology is still fairly new but it is advancing quickly and is expected to make medical therapies which target and work at the genetic level much more efficient, cost effective and applicable in clinical practice.

Given the persistent nature of the side effects associated with PAS, PFS and PSSD as well as the seeming lack of any relief, I think there is a very good chance that these conditions relate to some kind of epigenetic effect that these drugs are having on susceptible patients (these are patients with specific genetics or differing levels of drug metabolism). Meaning that Accutane or Finasteride or SSRIs alter gene expression in the body, more specifically the brain which persist beyond treatment. Note that the brain cells do not continuously renew or replace each other as in other parts of the body. Brain cells are non-dividing cells and so Iā€™m fairly sure they would retain any epigenetic effects that developed while taking these drugs. There have already been studies showing strong epigenetic effects of specific SSRIs - https://www.hindawi.com/journals/ijg/2018/8929057/

An exciting aspect of CRISPR is that it is not just capable of inserting or removing genes (this comes with many of the risks associated with gene therapy and insertional mutagenesis such as cancer). CRISPR can also be used to target the epigenetic regulation of genes. This is good news as this kind of epigenetic modification poses far less risk as a potential experimental treatment option than adding or removing genes.

A major problem with gene therapies and CRISPR is the delivery of the gene therapy system into the correct cells in the body such as the brain, a task which is made difficult by the blood brain barrier (BBB). However there are companies such as Ligandal who are working on these problems and given the incentives to get therapies into the brain, its only a matter of time imo before new technologies provide a cheap and effective means of delivering gene therapy products into the brain. There is a strong market demand for more effective therapeutics aimed at the brain.

Some research has focused on more direct approaches such as delivering gene therapy products directly into the brain. Medical research has experimented with the use of MRI guided injections of a gene therapy directly into the brain to treat brain cancer. Showing it can be done, I imagine this kind of technology will become a standard in the future as it removes the complications surrounding the BBB and allows highly targeted delivery. However these technologies may be difficult for us to get access to as they will likely be saved for medically recognized conditions etc.

Who would develop it/How would we be able to use it?

So how or who would develop a treatment such as this? How could we ever get access to this technology. At present, it seems very unlikely that pharma companies will take much notice or interest in treating these conditions. One option may be bio-hacking/self experimentation. Now I donā€™t condone this and recognize that most attempts to bio-hack are both stupid and likely to be mostly ineffective. However bio-hacking/self experimentation is both possible and is likely to become more feasible overtime as the costs, efficiency and effectiveness of these technologies improves in the future.

It sounds like a moon shot but I think its plausible that if genetic research into these conditions could identify an epigenetic effect of Accutane or Finasteride on human cells such as neurons which related to things such as the androgen receptor or 5 alpha reductase or any plausible mechanism that explains PFS, PAS or PSSD i.e. something related to androgen or dopamine signalling. Then provided a delivery technology was available, it would be possible to experiment with CRISPR systems aimed at that specific epigenetic effect. You could theoretically go through a list of the most plausible epigenetic changes related to these drugs, systematically reversing these epigenetic changes with the use of CRISPR until you find one that improves/fixes the major side effects.

Given that this would involve epigenetic changes, there would also be significantly reduced risks associated with this kind of experimentation versus introducing new genes into the body.

I admit this sounds a little far fetched but I think its more than possible. All of these technologies are getting cheaper and more effective over time. This also applies to the ability to study these things in the lab. Anyway its something worth considering if you are feeling like giving up. There is hope on the horizon, these fields and medical technologies are advancing at a rapid rate and likely hold the keys to curing these conditions, but as a community we have to make it happen. You canā€™t rely on anyone else doing it.

As a community the most effective things I think we can do is save money/stack capital as we will need as many funds as possible once an entity gets organized enough to organize this kind of research into the underlying genetic mechanisms etc. I recommended people to buy Bitcoin years ago but never pushed it hard as I knew I would be viewed as a shill and receive all the generic Bitcoin skepticism I have heard over the years but I was correct. Imagine if everyone in this community had bought just $1000 of Bitcoin 5 years ago, we would have enough funds to finance any research project we wanted to. However I still think this holds true into the future as I truly believe bitcoin is worth at least $100T market cap which places it around $5M per coin (note I would not recommend buying any other cryptocurrency, most are scams, I have spent a good deal of my time in this space and have seen/experienced all the nonsense/scams and hype it brings).

But anyway, whichever method or strategy you employ, you should be focused on acquiring money/wealth as this will be very beneficial to this cause. I also think people should try to go into training in the biology/life sciences field if they are unsure what to do. We need a community of wealthy, capable, scientifically minded individuals if we are to have any hope of tackling these incredibly challenging problems.

  • Flynn
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#2

What we first need to do is identify indisputable biomarkers for these syndromes.

Once that is done, we can focus more specifically on a cure. Iā€™ve always said this, but CRISPR IS the only way to solve this issue if indeed there are genetic changes. I am somewhat torn between whether this is genetic or autoimmune, but my view is that it is 100% one of those.

Realistically, CRISPR is the gateway to only one thing. Personalised medicine. The beauty of this is that once CRISPR is perfected (meaning safety, efficacy and potential to pass the BBB) it will be possible to treat any genetic illness (this included).

Regarding bitcoin, you may be right, but you may be horribly wrong. What we need is government and NGO funding. That will guarantee capital to help, though as Iā€™ve previously said, personalised gene editing is on itā€™s way as we speak.

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#3

If we would just do some public outreach then scientists could get public funding to study our condition. At the moment, few even believe our condition exists. Thatā€™s OUR fault and the thing we should fix. The overwhelming majority of medical research is funded by public grants. The reason no one does research for us is that we havenā€™t done enough public outreach.

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#4

There has been some quite recent discoveries in genes linked directly to erectile dysfunction. It focuses on the ā€˜SIM1ā€™ gene. Iā€™m a simple guy - isnā€™t this an obvious to look at? Does Propecia / Accutane / SSRI do anything to mess up the SIM1 gene?

https://about.kaiserpermanente.org/our-story/health-research/news/first-genetic-risk-factor-for-erectile-dysfunction-identified

https://www.pnas.org/content/115/43/11018#abstract-2

#5

Women who have taken SSRIs and/or Accutane have just as much sexual dysfunction as men do. Maybe things that seem to affect only one gender can be ruled out.

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#6

This isnā€™t about erectile dysfunction or at least that misses the main point of these syndromes. Its not a physical problem with the penis. It is a central nervous system problem at the brain level that is resulting in physical problems such as erectile dysfunction as there is a lack of desire/signalling from the brain to the penis. Erectile dysfunction is a secondary effect not the primary/root cause.

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#7

Agree, could be wrong about Bitcoin but given the severity of the situation, its well worth a punt in my opinion. If wrong, you lose a small percentage of your wealth/money. If correct, you achieve massive gains and have the ability to do more about these conditions. Its an asymmetric bet that is worth taking.

#8

One of the big problems here in this forum is that people donā€™t get that the way medical research is performed is not by people funding it themselves or privately. 99% of medical research is funded via public funding sources such as NIH. The way research gets funded is by the affected patients LETTING THE WORLD KNOW THEY EXIST in sizeable numbers. Or in other words, by letting grant administrators know that their medical condition is a REAL PROBLEM in the world (that affects many people).

As long as those patients are just sitting in Internet forums talking among themselves, they effectively do not exist, and their medical condition will never be cured.

So we can talk about investment schemes or private fundraising ideas, but all of that is pissing in the wind and will never even a tiny fraction of the amount of impact as just GETTING THE WORD OUT about our problem will ā€“ until we do that, we will never be cured. Once we do, tens of millions of USD of public funding can be in the pipeline for us.

#9

Yes but the detailed mechanisms of male and female sex drive etc. are still relatively unknown. They both certainly involve dopaminergic signalling etc. so there are many converging systems which affects this kind of signalling such as neurosteroids and androgen signalling etc.

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#10

Guys letā€™s focus on getting started on the first step to ending the last 15 years of utter failure ā€“ public outreach. We can talk about neurosteroids, androgen receptors, TRT, and herbs for another 15, 30, 45 years if you want to after that ā€“ letā€™s just try to actually do something different for once ā€“ like doing the obvious first step to actually accomplishing anything.

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#11

I do agree to some extent however given the nature of these syndromes and the lack of tangible, easily provable symptoms. Its very unlikely that NIH or any organizations will prioritize these conditions or put significant funding into them. Albeit actually try to develop a treatment/cure. We are effectively on our own in that regard.

Of course, everyone should be trying to raise awareness and have these conditions recognized but if you want these things researched and fixed in any kind of meaningful timeframe that is relevant to your life. We need to start amassing capital and funds. Had each member of this community invested $1000 of their money into Bitcoin 4/5 years ago when I first mentioned it, we would not have money to fund multiple studies and run public awareness campaigns. Raising money and having capital matters. Bottom line is, if people donā€™t start stacking capital, we will be in a very similar situation after the next 5 years passes.

We would likely do far better even by making a documentary and raising funds from the public then relying on the NIH etc. Do you really think they would choose to allocate significant funding to these syndromes over the countless other conditions out there which are far more provable and publicly accepted.

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#12

You keep saying things like ā€œaffect many peopleā€. These issues donā€™t affect many people. Thatā€™s the issue man. Letā€™s take dutasteride for instance. 1 million prescriptions in the US alone- only 48 people have said that they suffer adverse effects from dut here.

You see where Iā€™m coming from?

Our best bet is to hope that genetic therapy advances to a stage where it can cure any genetic malfunction (if this is indeed genetic) rather easily.

First, we need to prove this is an actual ailment of course.

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#13

This is pure speculation and there is no evidence to support such strong declarative statements. Please note that our rules explicitly ask to refrain from declarative statements (https://forum.propeciahelp.com/faq):

In fact, there is plenty of anecdotal and some clinical evidence that point to physical causes of (or at least contribution to) erectile dysfunction in some patients. Melcangi, for example, found pudendal nerve neuropathy in 25% of subjects. Penile atrophy is well established among PFS patients. We know that the pudendal nerve, penile smooth muscles and other penile tissues and functions are subject to androgenic signaling, which, of course, is probably disrupted in PFS and may contribute to erectile dysfunction. There is no doubt that desire is important for erections and that it is negatively affected by PFS, but it is not the only factor. PFS is a very complicated disease and too little has been clinically established to make strong statements. So, please be more careful with such statements.

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#14

Between PSSD, PAS, and PFS the number is plenty large enough to get funding. The problem is that WE donā€™t do OUR part. We prefer to read wikipedia articles and steroid abuse forums imagining we have the inside track on the ā€œbest betā€ if only other dudes on the forums would listen to us and see how clever we are. For 15 years. Making no actual progress.

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#16

Iā€™m not trying to break any rules here, Iā€™m also more speaking more about PAS as that is what I have most experience with (I donā€™t have PFS or PSSD) but it seems painfully obvious to me that PAS and likely the other syndromes are primarily related to the central nervous system.

Your sexual desire, sex drive, depression, cognitive issues, anhedonia etc. which characterize these syndromes donā€™t start in regions of the body such as the penis. These are functions of the central nervous system, specifically the brain. Iā€™m sure some patients also struggle with erectile dysfunction and if thatā€™s your only symptom, Iā€™m very happy for you as you dodged a bullet but its not really a primary, base layer, distinctive/distinguishing symptom of these syndromes. There are many conditions/drugs which can affect erectile function, there are few that affect sexual desire, libido and ability to feel pleasure especially from orgasm.

Thereā€™s actually an issue with focusing on erectile dysfunction imo particularly when communicating with people/researchers etc. who donā€™t have these syndromes, as it gives the impression these syndromes are just a form of erectile dysfunction. They are clearly much deeper problems and more severe forms of sexual dysfunction as they involve a loss of libido, desire and pleasure from sex. In many ways it distracts people from the reality of these conditions by making them seem like they are primarily physical issues (maybe they are but I doubt it). This is of course speculation but at some point you have to reason from first principles and try to narrow down the culprits and likely causes of the conditions or you will get nowhere. A focus on erectile dysfunction indicates to me that someone doesnā€™t have a solid understanding of Biology, medicine or how the central nervous system works and affects the peripheral nervous system and peripheral functions.

If it was found that any of these drugs completely destroyed the pudendal nerves or cause 100% penile atrophy. It still fails to explain how these drugs alter affect libido, sexual desire anorgasmia etc. as these processes begin and are formed in the brain and then sent to have their physical effects by signalling from central to peripheral nervous system. i.e. you would still experience libido, sexual desire etc. but you would not get any response from your penis or pleasure from you penis or function from your penis if the peripheral system was completely damaged/destroyed.

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#17

Absolutely nailing it, once again.

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#18

I hope youā€™re both right. My greatest fear is that we are small enough a group to be forgotten by scientists.

#19

Iā€™m almost always right. Please ignore the times when I have been wrong.

@vkg1 is definitely right to continue to make the conversation about everyone playing their part. Waiting for someone else to do everything isnā€™t going to cut it.

Frankly, and I donā€™t mean to talk down to you or to try and make you feel bad, but voicing concerns like ā€œscientists probably wonā€™t care about a small groupā€ is the opposite of productive.

It dissuades people from getting involved in improving their own lives. It also fails to acknowledge that there are ALREADY interested scientists. We donā€™t have to worry if theyā€™d be interested, they are. If we had a higher profile we could qualify for grants and actually move things along.

Instead, weā€™re giving each other a cold dose of reality and putting out the sparks of enthusiasm and hope.

We donā€™t have to do that. You are amazing, you can achieve great things. Letā€™s get this done, we can.

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#20

While I agree that ultimately science (likely epigenetic science) conducted by reputed institutions is a way to discover the root causes of our condition, we should at the same time not discount the very brave and oft foolhardy experimentation that members have undertaken, putting life and limb on the line.

While I donā€™t mean to encourage such risky practices, I wouldnā€™t be surprised if the insight they provide us through spotting patterns in reaction of symptoms to conditions can provide us a useful reservoir of knowledge to draw upon.
Few studies undertaken by universities would be able to expose patients to such an abundance of substances as it would almost certainly not meet contemporary ethical standards.
I wouldnā€™t be surprised if we could garner more information about our condition by well considered investigative research on differential outcomes by members who have tried different substances than by through ill-conducted scientific studies as we have seen time and time again.

As a community we should acknowledge the utility all of the people who have taken chances with their own lives have provided us instead of shunning them and deeming the deranged by default. For all we know the deeper answers to our condition lie in their experiences rather than at an ethically questionable lab in Texas.
At the very least it begs further investigation.

#21

Good. You are welcome to present your ideas as long as you refrain from declarative statements like ā€œIt is a central nervous system problem at the brain levelā€, which are not supported by fact. We ask people to be careful with declarative statements, because a) this condition is highly under-researched, which means there is simply a lot we donā€™t know about this condition, b) it is obviously highly complex and its presentation in patients is highly variable, and c) a lot of people love to make theories while being unfamiliar with the existing literature, which leads to misconceptions.

Well, I think it is painfully obvious that this is incorrect. While the nervous system is certainly affected by this condition, we have plenty of people from all these communities that report penile atrophy, rapid muscle wastage and other symptoms unrelated to the central nervous system. In PFS, we have clear physical evidence from clinical studies that show pudendal nerve neuropathy, androgen receptor overexpression in penile tissue and penile vascular abnormalities, which are unlikely to be driven by issues in the central nervous system. Clearly, the scope of this condition goes beyond the central nervous system.

No, they donā€™t, but nobody said that. However, the symptoms and evidence I mentioned above contradict the notion that this condition originates from the central nervous system. The scope of this condition is broader than that. Any explanation of this condition needs to reflect all the evidence. And focusing on the nervous system just doesnā€™t cut it. The explanation needs to explain physical, nervous system-related and all other symptoms that are frequently reported. And this explanation needs to tie in with the mechanism of the drug that caused them. Fortunately, we already have a decent explanation that can do all that, even though we still have to fill in a lot of blanks.

As someone who is involved in such talks, I can assure on behalf of the staff that it is of utmost importance to us to present to scientists the full scope of symptoms caused by this condition beyond just erectile dysfunction or other narrow views. Thatā€™s why we have conducted a very comprehensive survey that captured pretty much all the symptoms ever reported on this and similar forums.

And on the other hand, you can have all the libido and desire in the world, if your ā€œplumbingā€ does not work, you wonā€™t get an erection either. Thatā€™s the point. Erectile dysfunction can be caused by physical issues, issues with desire or both. And we have evidence for both and, of course, for issues beyond erectile dysfunction, in this condition. It is a complex and multi-systemic condition. And these complexities as well as the many things we still do not know about this condition are the reason why we ask people to be more careful with strong statements.

I hope this puts things into perspective.

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