I think I've hacked it

[Dench57]

I've no idea why somebody who has clearly put a lot of time and effort into figuring out this disease, then sharing his theories with everyone, has been met with such nasty replies. Good going guys.

The more intelligent, diligent, BALDING people from a scientific background we have working on this the better. You can be damn sure nobody else cares about us.

[xyz123]

Original paper is below - it's the Stu1 restriction site. It may not be the functional culprit (it may be tagged to a functional culprit that's yet to be elucidated - and hence the numbers don't work out to exactly 100%). But whatever this tags - it is the gatekeeper for MPB. If you don't have it, you keep your hair. That said - it's necessary, but not sufficient. Even 75% of non-bald guys have it - that's where the MPB disease modifying genes start to play a role.

We need a drug that down-regulates expression of the androgen receptor in the scalp.

http://www.nature.com/jid/journal/v1.../5601004a.html

[Follisket]

Well, he's basically saying that, according to his theory, none of the treatments in development currently would really work, and the one thing he supposedly has figured out is too hard and too expensive to do, and couldn't possibly be out within the next 10 years. Some cure/treatment that is.

And people actually get excited over the prospect of finally having a full head of hair at the age of 70? Jeez, no wonder baldies are screwed.

[xyz123]

No - that's not it at all.

His theory - which I think may actually be correct - accounts for the limited efficacy of current treatments (and that's totally accurate - current treatments have incredibly limited efficacy).

His theory is not that complicated. Yes - there are a million pathways in MPB - but all converge on the androgen receptor. That's why - if you take a drug that affects one pathway - its overall impact is limited because there are multiple other pathways that continue to stimulate the androgen receptor. I think everyone thought that MPB was due to a linear cascade of events - but it's probably not. It's multiple parallel pathways that converge on the androgen receptor.

His insight was driven by work in prostate cancer ,which has recognized that the androgen receptor can be activated by - not just DHT - but multiple other pro-inflammatory factors.

A typical diagram: http://www.carcinogenesis.com/viewim...0_83937_f2.jpg




Honestly - this explains so much. It's why things that create increased scalp inflammation in vulnerable people accelerate baldness - whereas there's no effect in non-vulnerable people. It's why harsh shampoos that contain sodium lauryl sulfate can accelerate baldness in vulnerable individuals (by creating scalp inflammation) - but have no effect on non-vulnerable people. (which led people to say that baldness being caused by harsh shampoos is a myth - which is partially true - but it can definitely accelerate the process).

And this shouldn't be viewed as discouraging. Yes - none of the current treatments will be a definitive cure (as expected) - but if someone can develop a drug that down-regulates the androgen receptor in the scalp - which should not be that hard (the hardest part of this stuff is finding the critical target; which in hindsight was probably right in front of us all along) - then it's conceivable a drug could be developed fairly quickly.

I think this is really encouraging. We're borrowing from discoveries and breakthroughs from another field to break new ground in our area. This happens a lot in medicine - and is often how major breakthroughs occur. Keep the faith

[InBeforeTheCure]

Original paper is below - it's the Stu1 restriction site. It may not be the functional culprit (it may be tagged to a functional culprit that's yet to be elucidated - and hence the numbers don't work out to exactly 100%). But whatever this tags - it is the gatekeeper for MPB. If you don't have it, you keep your hair. That said - it's necessary, but not sufficient. Even 75% of non-bald guys have it - that's where the MPB disease modifying genes start to play a role.

We need a drug that down-regulates expression of the androgen receptor in the scalp.

http://www.nature.com/jid/journal/v1.../5601004a.html

Thanks. As far as I can tell, that's the marker also known as rs6152.

There's also this:

Abstract:

Androgenetic alopecia (AGA) is a common heritable polygenic disorder whose genetics is not fully understood, even though it seems to be X-linked. We carried out an epidemiological survey for AGA on 9,000 people from 8 isolated villages of a secluded region of Sardinia (Ogliastra), and identified a large cohort of affected individuals. We genotyped 200 cases and 200 controls (mean kinship 0.001) with the 500k chip array and conducted case–control association analysis on the X chromosome. We identified Xq11-q12 as strongly associated with AGA. In particular, we found that rs1352015 located 8 kb from the EDA2R gene showed the best result (P=7.77e−7). This region also contains the AR gene, hence we tested both genes in 492 cases and 492 controls. We found that the non-synonymous SNP rs1385699 on EDA2R gave the best result (P=3.9e−19) whereas rs6152 on the AR gene is less significant (P=4.17e−12). Further statistical analysis carried out by conditioning each gene to the presence of the other showed that the association with EDA2R is independent while the association with AR seems to be the result of linkage disequilibrium. These results give insight into the pathways involved in AGA etiology.

Our study shows that AR and EDA2R are significantly associated with AGA. However, there is some LD between the two most associated markers for each gene (rs6152, rs1385699: D′=0.74, r2=0.43). To test if they are independently associated, we conditioned the analysis of each gene to the other one. We used the UNPHASED software (Dudbridge, 2003), which permits the association of a marker to be conditioned to the presence of another marker. The analysis of rs1385699 conditioned to the presence of rs6152 gave a very significant P-value of 6.136e−9, whereas when we conditioned the analysis of rs6152 to the presence of rs1385699 the P-value was 0.04. Again, rs1385699 conditioned to the presence of rs12558842 gave a very significant result (P-value 0.007), whereas rs12558842 conditioned to the presence of the EDA2R variant did not give a significant result (P-value 0.06). These results show that in our population, the EDA2R gene variation causes susceptibility to AGA. The conditioned analysis suggests that markers on the AR gene could be associated because of LD. However, we cannot exclude that other variants in LD with both genes (that is, regulatory elements of either or both genes) could be associated with AGA. Moreover, the functional importance of AR has already been proven by many means, and its involvement in this pathology cannot be excluded. Further functional and genetic studies are needed to clarify the role of these two genes and their possible interactions in the etiology of AGA.

Two receptors for EDA were found that are specific for the two isoforms EDA-A1 and EDA-A2: EDAR and EDA2R, respectively. EDA-A1 and its receptor EDAR are capable of activating the NF-κB pathway and are implicated in hair growth (Botchkarev and Fessing, 2005). EDA2R is capable of activating the NF-κB pathway and also through TRAF3,6, JNK (c-Jun N-terminal kinase) (Sinha et al., 2002), which activates c-Jun. Mutations in EDA and EDAR give rise to ectodermal dysplasia, a clinical syndrome characterized by loss of hair, sweat glands, and teeth, whereas mutations in EDA2R do not (Monreal et al., 1999; Naito et al., 2002; Newton et al., 2004). Recently, a preliminary report suggested that EDAR may influence hair thickness in Asians (A. Fujimoto, R. Kimura, J. Ohashi, U. Samakkarn, W. Settheetham-Ishida, T. Ishida, Y. Morishita, T. Furusawa, M. Nakazawa, R. Ohtsuka, R. Yuliwulandari, L. Batubara, M.S. Mustofa, K. Tokunaga, A scan for genetic determinants of human hair morphology: EDAR is associated with Asian hair thickness, ASHJ Meeting 2007). EDA2R could influence the onset of AGA through the activation of the NF-κB pathway or by c-Jun, which has been shown to be critical for AR transactivation (Bubulya et al., 1996). Moreover, in adult mice, EDA2R is also expressed in the hair bulb and in differentiating hair matrix (Botchkarev and Fessing, 2005). Looking at the human expression data from the UniGene database (http://www.ncbi.nlm.nih.gov/sites/entrez), we noticed that it is expressed during embryonic life and, especially, in the first weeks after birth. Expression then seems to be absent until the 17th year of age, when it recurs in different tissues, including skin. This expression pattern fits very well with the course of AGA, with its onset around puberty.

Source: http://www.nature.com/jid/journal/v1...id200860a.html

I actually have

rs6152 = A (the non-risk allele, present in only 1 of the 54 young balding men in the paper you cited)

rs1385699 = T (the risk allele on the EDA2R gene, associated with baldness)

[trunks]

First of all I want to really thank you FGF11 for your experiment. However some photos as a proof would be gently welcomed (I belive in this theory even without a proof though)

I am posting some studies connected to silencing mutated AR. Probably there is a way to create topical solution with minimal side effects and if your claims are true - that would be a next generation ULTIMATE CURE.

So please FGF11 show us the proof, after that we should try to make this gene therapy happen.

Silencing the androgen receptor: New skills for antiandrogen oligonucleotide skin and hair therapy

Antiandrogen therapeutic oligonucleotides targeting the downregulation of the ARexpression is advantageous because both will be possible to eliminate the only way for androgens to act and simultaneously this strategy allows the medication to be topically administrated.

Control of androgen receptor expression in human keratinocytes and in a reconstituted human epidermis model with selective antisense oligonucleotides

Association of locally increased androgen activity and skin disorders is obvious in acne and androgenetic alopecia in males. In addition, testosterone was unexpectedly found to perturb the epidermal barrier. Blockade of androgen action via androgen receptor (AR) antagonism accelerates wound healing in aged individuals. Androgen activity on skin can classically be inhibited by systemic administration of compounds, which have strong affinity for AR and antagonize androgen binding to AR molecules. In this study we applied a new technology to realize the same purpose: We tested the activity of antisense oligonucleotides against the AR in primary human foreskin keratinocytes, human non-foreskin keratinocytes from young (30 y) and older (60 y) female donors, and reconstituted human epidermis (SkinEthic model). Reconstituted human epidermis is similar to in vivo human epidermis and features a functional permeability barrier. To transfer the antisense oligonucleotides into human keratinocytes an optimum liposome-mediated transfection system with Poly-L-ornithine (12 μg/ml) over 4 h was used. The transfection efficiency was assessed using FITC-labeled (ACTG)5 random oligonucleotides, which were localized in cytoplasmic structures of the keratinocytes. AR expression on the protein level was investigated by Western blotting. Transient transfection of foreskin keratinocytes with phosphorothioate antisense oligonucleotides (PTO) revealed a reduction of AR expression (≈25%) compared to native keratinocytes after 14 h recovery time. The AR knock down in epidermal keratinocytes of the compared women was stronger in the older, more differentiated keratinocytes. After 24 h, AR expression level have returned back to the level of non-transfected cells. The effect could be reestablished by repetition of transfection. PTO and 2?O-methylribosyl (MRO) antisense oligonucleotides decreased AR expression at levels varying between 46% and 70% in the air-lifted reconstituted human epidermis after 18 h recovery time. The successful inhibition of AR expression in human keratinocytes and reconstituted human epidermis is the first step to develop topically efficient compounds with oligonucleotides

[Swooping]

Thanks for your effort.

Inactivation/silencing of AR will most definitely not reverse miniaturization though. I'm extremely sure of this so I automatically put your story into question.

Proof is what I want to see.

[FGF11]

First of all I want to really thank you FGF11 for your experiment. However some photos as a proof would be gently welcomed (I belive in this theory even without a proof though)

I am posting some studies connected to silencing mutated AR. Probably there is a way to create topical solution with minimal side effects and if your claims are true - that would be a next generation ULTIMATE CURE.

So please FGF11 show us the proof, after that we should try to make this gene therapy happen.

Silencing the androgen receptor: New skills for antiandrogen oligonucleotide skin and hair therapy



Control of androgen receptor expression in human keratinocytes and in a reconstituted human epidermis model with selective antisense oligonucleotides

To make more sense out of antisense oligos:

#1 Most of topical solutions act through HFs, what it means is that many of the topical solutions that deliver oligonucleotides pass epithelium into dermis, through the hair shaft (maybe). They concentrate there. Now, most of the studies done in hairless mice with oligo topical solutions (for silencing other genes) do not work (usual topical solutions I mean). However, the same studies work in mice with HFs. Therefore, if the area, is not covered with visible large HFs, the efficiency of Oligo should be extremely low.

#2) The best scientific experiment would be injection (PLEASE DO NOT TRY THIS). But if I were to suggest something, I would say a microneedle semi-auto tattoo gun (they are dermal guns), would probably be the best away to efficiently and vastly introduce oligo every three - four days, fast for a large area. However, it will be inefficient, and more expensive.

3) You should remember, maybe, the physical disruptions, introduced while adding the oligos, were MAYBE HELPING in disrupting the fibrosis (whether it is there or not). Injecting intradermally, makes a gap between dermis and epithelia, for about 30 minutes, every time. By pushing epithelia upward, this may (theoretically) be the reason why the topical would not work.

4) Yes, there are a couple of patents regarding silencing AR that may or may not (I'm not a lawyer) be able to lock the technology. None of them, however, to my understanding, have really tried this, even for ONCE. They did only file the patent, for when such a day would come. Even there are one or two studies trying to silence AR. Those studies are not good studies.

5) This is NOT going to be the ultimate treatment (Please don't use the word cure referring to hair loss - it's an aesthetic condition). This however, will be, extremely more effective treatment with oligo's, and it may actually be very SAFE.

6) Triple repeats in AR do not only correlate with AGA but they also correlate with rheumatoid arthritis (RT). Pointing toward a role for AR in AGA and RT.

I appreciate when you share intelligent comments. Please contribute intelligently, otherwise, don't.

[uzumakinaruto]

Hi sorry for the noob question- does that mean, if im reading it right- that ablating the AR receptor in the hair follicles on the hairless scalp will resolve hair loss and regrow hair?

[xyz123]

Thanks for your effort.

Inactivation/silencing of AR will most definitely not reverse miniaturization though. I'm extremely sure of this so I automatically put your story into question.

Proof is what I want to see.

Agree - proof is critical.

But how can you be certain that silencing of AR won't reverse miniaturization? As highlighted - this is not the same as complete androgen deprivation (like what happens with trans-genders). As we know, trans-genders with pre-existing baldness do not regrow most of their - but as he indicated, this may be secondary to continued activation of the AR through non-androgen dependent pathways.

I don't think we have any evidence to indicate that silencing of AR will not regrow hair - has this ever been done/tried before? If his theory is correct, the AR is the final common pathway - everything converges on the AR to trigger and maintain baldness. If you reduce/eliminate AR, follicles should be released and able to grow again - regardless of how much PGD2, TGF-beta, etc. that you have floating around your scalp.