Follica - Good News!

[bobs]

Got this of other forums. What is promising is that their procedure wont need to go through the FDA so no xx years of trials. Other good thing is that they got funding now.


http://www.puretechventures.com/content ... nPage=news

http://www.xconomy.com/2008/01/04/gone- ... treatment/

 

[phish]

interesting, if the trials show good regrowth, we could see this in less then 2 years. lets pray its safe and shows good hair.

 

[hairsucks]

Good stuff, another treatment in the pipline. Lets hope it's good.

I't only a matter of time before one is the real deal.

 

[elguapo]

This part of the second link is interesting:

The doctor can then use this newly created therapeutic window to inject drugs that push the cells to develop along one pathway or another and grow hair or skin. Zohar won’t reveal what drugs Follica is using, except to say that they are small molecule drugs normally taken orally for purposes with no relation to hair growth.

I wonder what oral drug they are using.

Good post.

 

[Charly]

Speaking of which...I'm sure you've heard people say that if you shave your head more will grow and thicker. I know this doesn't work know with the advent of clippers, but maybe it did when they used a straight razor to do it and did it often lets say every two weeks, cause in essence you might of been removing the top layer of skin. Not old enough to know how a straight razor shaves. What do you guys think?

 

[elguapo]

I think shaving doesn't remove enough of the skin to regenerate the kind of regrowth that these articles are talking about. Not a bad question, but when they menion dermabrasion, they are talking about going pretty deep into the skin.

These articles touch on the idea/observation mentioned a few months ago, that skin wounds, if deep enough, stimulate hair growth. Actually, I forgot the "hole" in this idea, which is that even if this procedure does work, the hair that might grow in could be vulnerable to DHT just like the hairs before them that were lost to baldness in the first place.

Now I am wondering if the best approach would be a hybrid between this would-stimulus that Follica seems to be working on, and the HM procedure that Intercytex is working on. Do what ICX is doing with HM, which is taking dermal papilla cells from follicles of the back of the head, which are resistant to DHT, multiplying those cells in the lab, and before injecting them into the bald scalp/donor area, first use dermabrasion to remove a layer of the skin. Who knows, maybe this is what ICX is already doing, with their stumulation technique which proved more effective for the second group of cohorts in their current Phase II trials of TRC.

 

[michael barry]

Bobs,

In an interview with Costarialis, Costarialis let slip that Arthur Klingman noted that he'd seen de noveau hairs show up in dermabrasion patients with acne scars.


Do you understand the signifigance of this statement?


Although Follica (and Costarialis) maintain that wounds have to be 5 mm or cm (I forget which) deep and have to be left open (even though he claimed dermabrasion might be a part of the treatment, and that wnt protiens (the "proprietary step) would have to be administered, apparently Klingman (still at the Penn dermatology department with Costarialis at 91 years of age) seen otherwise.



Ive held my tounge on this bit of info, but I suspect that if someone had some lithium chloride, which mimics wnt in human skin, and some sandpaper........................................and were willing to NOT DRESS the dermabrated area or cover it for a couple of weeks, they just might be able to "make" hair.


In experiments the scientist were able to have the mice always grow hair by wounding the critters skin and applying wnt-protiens AND they were able to make the mice have thicker hair by adding more wnt protiens. These mice were genetically HAIRLESS, so we know that they were not "rejuvinating" hairs.





My question: if someone did this and got hairs in the frontal cortex of the scalp, would those hairs be/not be male pattern baldness hairs? If the formed with an adult males level of testosterone, it would seem that they could be like donor hairs and more or less very tolerant of androgens...............................or would androgens suppress their formation at all? Questions, questions.


What I do know is this....................if dermabrasion "made" hair on acne scar victims like Klingman said it did, do we really need Follica's WNT protiens? Would wnt-mimetics like Lithium Chloride do?



At the very worst, if this thing only produces "permanent" hair in the wreath area (donor area in hairtransplant parlance), then a man could simply get hair transplants and then regenerate donor area's (or re-thicken them) with follica's treatment, thus "making" new good hair for the front.



Its interesting.

 

[michael barry]

http://www.sciencefriday.com:80/newsbriefs/read/117


You can listen to Costarialis speak about Klingmant noticing the de noveau growth in dermabrasion patients in that link. You can also see a picture of hair growing white on a mouse (new hair isn't pigmented in the mice, lets hope its not the same way on humans or it would be wise to buy alot of stock in Clairol, but I digress). The article explains a great deal.




Parting note: The new Costarialis patent has microdermabrasin with a prostaglandin B-2 inhibitor. Green tea has been shown to inhibit prostaglandin B-2, and lithium chloride mimics wnt in the skin..............

 

[cal]

Hmmm . . .

So who's got the lithium chloride?


Okay, seriously, I'm assuming there must be some reason not to run out & try this or someone already would have done so. Right?

 

[elguapo]

Too funny... I'm laughing at myself, that is...

Step one in logic is to agree that growing new hair might be achieved by introducing a wound to the bald area of the scalp. Step two is to say "wait, if you do that, sure, new hair might grow, but it could be susceptible to DHT just like the hairs that were once there, but went away in the first place."

Step three, as introduced my Michael (and lost no me=), was this snippet:

At the very worst, if this thing only produces "permanent" hair in the wreath area (donor area in hairtransplant parlance), then a man could simply get hair transplants and then regenerate donor area's (or re-thicken them) with follica's treatment, thus "making" new good hair for the front.

Thanks for chiming in.

-elnotsoguapowithouthair=(

 

[Charly]

So then in theory it should work.....I recently read about a study in mens health that stated that our skin stayed younger under our beard cause of daily shaving and compared shaving to the expensive dermabrasion treatments women get.

 

[RaginDemon]

dont get your hope too high.

 

[harold]

Too funny... I'm laughing at myself, that is...

Step one in logic is to agree that growing new hair might be achieved by introducing a wound to the bald area of the scalp. Step two is to say "wait, if you do that, sure, new hair might grow, but it could be susceptible to DHT just like the hairs that were once there, but went away in the first place."

Step three, as introduced my Michael (and lost no me=), was this snippet:

At the very worst, if this thing only produces "permanent" hair in the wreath area (donor area in hairtransplant parlance), then a man could simply get hair transplants and then regenerate donor area's (or re-thicken them) with follica's treatment, thus "making" new good hair for the front.

Thanks for chiming in.

-elnotsoguapowithouthair=(

From the second link in the original post....

David Steinberg
1/4/08 2:12 pm

I am with the company. While we have not tested this in humans yet we fully expect that hair will persist. There are multiple reasons for this. First of all, consider hair transplants - while they have other flaws, the hair does indeed persist despite the presence of circulating DHT. In a distinct, but similar way, the Follica treatment changes the microenvironment of the follicles. Further, a single hair cycle lasts several years, and at the very least the new hair should last one full cycle (because of the underlying physiology of the condition). Also, circulating levels of DHT actually drop over a man’s life. We have seen numerous clinical reports of patients showing sustained hair cycling when exposed to conditions similar to the treatment Follica is pursuing (in a carefully directed and controlled way).

So it seems they are confident that the hairs produced have agood chance of being androgen independent. Barring that as they say the hair is going to last at least a good few years before it deteriorates.
hh

 

[harold]

http://www.sciencefriday.com:80/newsbriefs/read/117


You can listen to Costarialis speak about Klingmant noticing the de noveau growth in dermabrasion patients in that link. You can also see a picture of hair growing white on a mouse (new hair isn't pigmented in the mice, lets hope its not the same way on humans or it would be wise to buy alot of stock in Clairol, but I digress). The article explains a great deal.




Parting note: The new Costarialis patent has microdermabrasin with a prostaglandin B-2 inhibitor. Green tea has been shown to inhibit prostaglandin B-2, and lithium chloride mimics wnt in the skin..............

Michael do you have a link to that new patent?
hh

 

[bobs]

M.B,

I did not know that, very very interesting. Seems like the body has some fantastic abilities of regenerating.

As for the DHT discussion, I have read some dubious posts, I think no one really can know at this point what to expect.
Even if they are vulnerable to DHT you have some options, either go with Transplants/Re-generate or do one Follica-session
each 2-6 years. Besides, DHT levels drop as you age.

I find the shaving-discussion interesting too. Most people I speak with say that when they shave their hair it grows back thicker and fuller. However, I have read that it does not, I have never tried to shave my head with a razor so I dont know.
I did read one story about an old man who made small cuts with a razor on his head and then applied some sort of garlic-potion on it for some time and regrew some hair, but that sounds very odd indeed

Anyway, this is all very exciting. I had thought that Follica would at the best come out with something in ten years but IF all goes very well we might have something on the market much sooner.

And also, Michael Barry, thank you for your posts, I find them very interesting to read even if the scientific level most times exceeds my own understanding but I learn much from them.

 

[harold]

This is from one Costarelis patent (I dont know if it is the new one mentioned by Michael) and it shows that they seem to have solved the pigmentation issue by using dickkopf-1 at a certain stage in the process.
http://www.wipo.int/pctdb/en/wo.jsp?wo= ... SPLAY=DESC

[000196] At 25 and 45 days after wound induction, wound sites contained new hairs (Figure 11 „ left and right panels, respectively). New hairs appeared to lack pigmentation, except when the wnt pathway was inhibited, using Dkk-1 (Dickkopf-1) during the first nine days after wounding (see Example 10).

EXPRESSION OF WNT-I INHIBITORS DURING THE FIRST NINE PAYS

AFTER WOUNDING CAUSES PIGMENTATION OF NEW HF

MATERIALS AND EXPERIMENTAL METHODS

[000222] In this Example, doubly transgenic mice expressing both tetO-Dkkland K5-rtTA were utilized. When these mice are fed chow formulated with 1 g/kg doxycycline (BioServ, Laurel, MD), they express DkId , under the control of the K5 promoter, in the basa? epidermis. The control mice also received doxycycline, but they were K5-rtTA negative and thus did not express Dldd.

RESULTS

[000223] A 1 cm2 wound was induced on the lower back of the doubly transgenic mice at 21 days or 50 days old. Mice were placed on doxycyc?me-containing chow immediately after wounding to induce Dldd expression, and then doxycycline was discontinued after completion of the re- epithelialization at 9 days after wounding. Dkkl expression inhibits Wnt activity, which in turn induces follicle pigmentation. At 22 days after wounding, pigmented HF were observed in the excised skin after preparing the epidermal sheet (Figure 23 A-B). Control mice lacked pigmented HF (Figure 24).

[000224] In other experiments, continued expression of Dkkl after the 9-day period inhibited
formation of new HF.

[000225] The findings of this Example show that pigmented HF can be produced by suppressing expression of Wntl or by inducing expression of Dkkl during the period of re-epithelialization, then inducing expression of Wntl . In addition, the findings of this Example show that factors that inhibit neonatal hair follicle formation (e.g. Dkkl ) also inhibit EDIHN, thus further supporting the notion mat hair follicles formed by EDIHN are similar to normal hair follicles.

Also some human in vitro work demonstrating that it seems to work in us.

[000212] In additional experiments, adult human skin was grafted onto mice., abraded, and examined at 7 days post-abrasion. New HF were generated in the human skkx, which mimicked normal hair follicle formation during fetal development, as evidenced by staining for SlOO A6 or S100A4 (Figure 21B).

 

[harold]

Found the PGD2 patent

RESULTS

[ 00492] Haired and bald human scalp was procured from individuals undergoing hair transplantation, and representative tissue was examined histologically to confirm the presence of haired and bald scalp (Figure IA-B, respectively). Bald scalp exhibited a larger number of miniaturized, vellus-

20 like hair follicles (HF) that satisfied the formal definition of a reduction from the minimum normal hair diameter of 0.08 mm to < 0.06 mm. Generally there was a large variation in size of sectioned follicles in the bald scalp. Occasional follicles demonstrated fibroplasia in the inferior portion of the follicle below the hair shaft (called fibrous streamers). There was also a decrease in the normal percentage (>93%) of anagen follicles: In addition, many follicles were found to have inflammatory infiltrates, which were composed of

25 lymphocytes as well as mast cells, and were centered around the lower infundibulum of the HF. Hair follicle miniaturization was confirmed with scanning electron microscopy (SEM), which demonstrated dramatic miniaturization of follicles in the bald scalp (Figure ID-E).

[ 00493 ] None of the subjects showed histopathology consistent with other causes of inflammatory hair loss such as alopecia areata (lymphocytic infiltrates around bulbs of anagen follicles), or cicatricial' 30 alopecias (often lichenoid infiltrates associated with complete loss of follicular structures), confirming that the subjects had Androgenetic Alopecia.

A bit of statistical methodological mumbo-jumbo

13 common categories were found for the genes higher in the donor scalp, and 8

30 for the bald scalp (Figure 4D). The 4 most populated gene function categories were development, morphogenesis, organ development and organogenesis, with p values ranging from 1.99 x 10"'° to 4.72 x 10'12. In addition to multiple known genes, genes not known to be expressed in HF were discovered.

[00502] Thus, findings of the present invention reveal genes that participate in hair growth, healthy

HF maintenance and cycling, and hair loss.

[00506 ] To test the role of steroid metabolism in aging, the expression of genes involved in steroid metabolism was examined. The androgen receptor (AR) and the enzyme 3-beta-HSD were more abundant in the bald scalp (p < 0.05; Figure 5A), thus corroborating the findings of the present invention.

[00507 ] Immune-related gene expression in bald vs. haired scalp was also examined. Multiple MHC

20 genes, both class I and II, were enriched in the bald scalp (Figures 3 and 5A). In addition, transcripts specific for T cells, Langerhans cells and mast cells were enriched in a statistically significant manner in the bald scalp (CD4 [p=0.017], CdIa [p=0.0087], FCERlA [p=0.046] (Figure 5A). Several genes not known to be expressed in human HF are depicted in Figure 5B. These genes also exhibited a high degree of statistical significance (minimum p value=0.001 ) and minimum fold-enrichment in haired scalp of 4.5.

25 EXAMPLE 5: IN SITU AND IMMUNO-HISTOLOGICAL CHARACTERIZATION OF

NOVEL HF GENES

[00508] In situ hybridization and immuno-histochemistry was next used to determine tissue patterns of expression of significantly enriched transcripts in the haired scalp, using human haired scalp samples from different patients than those used to generate the array and flow cytometry data.

30 [ 00509 ] Microarray showed that LRRC 15 was upregulated 4.5 fold in the haired samples (Figure

5B). LRRCl 5 is a transmembrane glycoprotein with leucine-rich repeats. To determine whether LRRC 15

145

functions in cell migration, LRRC15 expression was measured in scalp samples by immuno- histochemistry. LRRCl 5 was present in Huxley's layer and the cuticle layer of the inner root sheath, especially at the lower follicle (Figure 6A), which is an area of rapid cell movement during hair growth. Thus, LRRCl 5 functions in cell migration necessary for hair growth.

5 [00510 ] Serpin A was up-regulated 5.7 fold in the haired samples. Serpin A is, in another embodiment, a clade A anti-protease in the same family as anti-trypsin and anti-chymotrypsin. Serpin A was expressed in the companion layer of the outer root sheath, as shown by immuno-histochemistry (Figure 6B).

[00511 ] GPR49 (LGF5, HG38), another leucine rich repeat-containing protein, was upregulated 6.8

10 fold in the haired samples, and was expressed in human outer root sheath cells, as shown by immuno- histochemistry (Figure 6C). GPR49 is known to be upregulated in the mouse bulge (outer root sheath), thus further confirming results of the present invention. Enrichment of this G-protein in anagen/terminal follicles show its utility as a drug target for stimulating hair growth.

[00512 ] The Angiopoietin-like gene CDT6 (upregulated 18 fold in the haired samples) is an anti-

15 vascular factor that is also expressed in the cornea (Corneal Derived Transcript 6), and thought to maintain the avascularity of the cornea. CDT6 was expressed in the outer root sheath, as shown by immuno- histochemistry (Figure 6D), which is also avascular.

[00513 ] GPRC5D (upregulated 19.5 fold in haired samples) is a homologue of RAIG-I

(retinoic acid inducible gene-1). GPRC5D was expressed in the inner root sheath and precorneal cells of 20 the hair, as shown by immuno-histochemistry (Figure 6E).

[ 00514 ] FGFl 8 (upregulated almost 6 fold in the haired samples; Figure 5B) was found to be expressed in the inner root sheath, the companion layer, and to a lesser extent in the suprabasal outer root sheath of the bulge area (Figure 6F-G).

[ 00515 ] The genes identified in this Example are all enriched in haired scalp, and are thus

25 therapeutic targets for stimulating hair growth.

And now the PGD2 stuff

RESULTS

[ 00517 ] In addition to the above genes, levels of the lipocalin (brain) isoform prostaglandin D2 synthase (PGD2S) were elevated in bald scalp relative to haired scalp (Figure 7A). To confirm this finding, PGD2 levels were tested in bald and haired tissue from 3 patients. PGD2 was elevated in all bald samples, 15 at an average fold increase of 11.6 (Figure 7B). This increase in PGD2 was verified in 1 individual by mass spectrometry. PGD2 was detected as 17 pg/mg of tissue in haired scalp and 75.5 pg/mg in bald scalp, representing a 4.4 fold increase in bald tissue. PGF2a also was slightly elevated in bald scalp with 6.7 pg/mg in haired scalp and 15.9 pg/mg in bald scalp. PGE2, however, exhibited the reverse trend with PGE2 present at 22.7 pg/mg in the haired scalp and 12.0 pg/mg in the bald scalp (Figure 7C).

20 [ 00518 ] The RT-PCR results were further confirmed in 2 individuals not measured in the original array study by quantitative RT PCR, demonstrating a 5.23 and 10.7 fold increase of L-PGDS in bald scalp over haired scalp (Figure 7D). Immunohistochemical staining of L-PGDS revealed an increase in bald scalp, with L-PGDS appearing in the cells along the fibrous root sheath populated by dermal fibroblasts, as well as in scattered locations intrafollicularly. Given the lack of expression of L-PGDS in hematopoietic

25 cells, increases in L-PGDS were not from the sparse inflammatory cell infiltrate occasionally present in Androgenetic Alopecia.

[ 00519 ] Thus, PGD2 synthase and PGD2 are targets for ameliorating common baldness, e.g. Androgenetic Alopecia

more

EXAMPLE 13: APPLICATION OF PGD2S INDUCES ALOPECIA

25 MATERIALS AND EXPERIMENTAL METHODS

[ 00528 ] 25 day-old (corresponding to end of the first telogen stage) wild-type c57/black mice were treated with 200 ng of PGD2 (Cayman Chemicals) diluted in 200?l of acetone applied to the central back after shaving. Subsequent treatments were performed every 3 days, ending on day 40 for a total of 5 applications. Photographs were taken on day 46 of life, after the end of the 2nd anagen. In the second

30 experiment, mice were shaved and treated with 10 ?g of PGD2 dissolved in 200 ?l of acetone on days 66

and 69 of life, and then photographed on day #121.

RESULTS

[ 00529 ] The effect of PGD2 on hair growth was directly determined by applying PGD2 to the backs of mice. Application of PGD2 induced alopecia following the second anagen phase (Figure 10A). In 5 another experiment, application of PGD2 was shown to prevent hair regrowth over 50 days after the last application (Figure 10B)

Finally Selenium seems to inhibit PGD2synthase

Prostaglandin D2 synthase induces apoptosis in PC12 neuronal cells.
Ragolia L, Palaia T, Frese L, Fishbane S, Maesaka JK.

1Department of Medicine, Division of Cell Biology, Winthrop-University Hospital, 222 Station Plaza North, Suite 505-B, Mineola, NY 11501, USA.

Apoptosis of neuronal cells is a proposed cause of certain neurological disorders. Here, we report on a 5- to 6-fold increase in apoptosis by exposure to prostaglandin D2 synthase (PGD2S) in PC12 neuronal cells. Apoptosis was detected by terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end-labeling (TUNEL) assay, and appears to be mediated via caspase-3 activation. Neutralization with anti-PGD2S antibody or pre-treatment with selenium, which inhibits PGD2S enzymatic activity, both significantly inhibited the PGD2S-induced apoptosis, however, neither had any effect on the apoptosis induced by the known neuronal apoptotic inducer, glutamate. In addition, prostaglandins E1, E2, and F2alpha all inhibited the PGD2S-induced apoptosis while prostaglandin H2 had no significant effect. Furthermore, PGD2S isolated from human serum was more effective at inducing apoptosis then recombinantly expressed protein, presumably due to glycosylation. This novel role of PGD2S, as an inducer of apoptosis, may have implications in PC12 differentiation and possibly some neurological disorders.

Misoprostol is a cheapish PGE1 analogue. Pharmaceutical PGE2 is available but expensive. I dont know how comparable the two are.
hh

 

[michael barry]

Harold, Bobs, guys............


I looked around last night for things that have been shown to inhibit PGD2 activity. I found some interesting things and some "contradictory" things. Here is what I found:


&Ginger has been shown to decrease PGD2. Ginger extract could be a possibility, but as a topical? Prostaglandin D2 helps you sleep..............Also, how many hours would the INGREDIENT IN GINGER be active in PGD2 suppression?


*An acid in cold water fish, eiposacenteioic acid (I probably mispelled and butchered that word), also inhbits prostaglandin D2. How much of this acid is in fish oil, how much do you have to take, and how many hours is it active (so do you need multiple doses per day, etc.?)



#* Green tea, although it inhibits prostaglandin D2, also inhibits wnt expression and we all know about its effect on angiogenesis. Those are things to consider. Is some wnt-expression at a minimum level desirable in scalp hair, or do you not need it at all after embryonic development of hair? Again, how long is green tea catechin ECGC active in human skin and how many times a day does one have to drink it or topically apply it?



Ibuprofen supposedly inhibits prostaglandin release, but I dont know if it effects the prostaglandin D-2 that we are concerned with.


Ketoconazole inhibited three or four prostaglandins, but not the one in question. In effect, it probably allows for more prostaglandin D2 to be metabolized form the more available aniachronidic (Im virtually certain I mispelled that) acid from which prostaglandin D2 is made.



Asprin is a "weak" prostaglandin inhibitor.


There are a couple of synthetic drugs that inhibit prostaglandin D2 exclusively.



Latanaprost DOES NOT inhibit prostaglandin D2, but does "get" three or so of the other prostaglandins.





Not all prostaglandins are apparently bad for hair, but they do control alot of functions. They can make smooth muscles contract or relax, and control alot of inflammatory processes apparently on whether or not an area is to be inflammed. I dont care what they do, I just want to f*** with what ever one suppresses hair growth.











Harold, that is fantastic info about the induction or blockage of DKK-1 during the wounding period (the first nine days I guess if Im interpreting it correctly), and then its blockage. If Im understanding this correctly, one would seemingly be better off being off finasteride for about a couple of days before the "wounding" and then staying off it for about nine more days afterwards to make sure MORE DKK1 was happening in the scalp so the new hairs were black and not white, all the while being on an internal (ginger a few times a day) prostaglandin D2 inhibitor? These are wild assumptions. I couldn't read the patent on my browser for whatever reason..........................without getting out magnifying glasses and literally reading page after page to get to the good stuff. The document wouldn't let me skip to where I wanted to read. I'd still be up reading the thing if I did that


Whatever happens Harold, I think Costarialis noting the severe uptick in D2 prostaglandin in bald scalp and how it suppresses hair growth in mice makes it a target in alopecia to be considered along with TGF-beta and DKK-1 (and PKC, TNF alpha) as the "main" inhibitories in head hair growth along with DHT.

 

[michael barry]

Arachidonic acid is the acid (told you guys I mispelled that word) that is necessary for prostaglandin formation. I wonder if there is a blocker of arachidonic acid available? Would inhibiting ALL prostaglandins be BAD for hair? Is there one that is necessary (likely my track record of looking into hair is to hold up).



On selenium...............................I had almost forgotten that (This is technical stuff, no?)
How many hours is it suppressive of prostaglandin D-2 release?
Could it be added to shampoo? How many hours would a topical application be suppressive of PGD2 assuming we could get the selenium through the skin and it stayed in the scalp?


Ive not done any searches for shampoos that contain selenium as an ingredient, but I had found shampoos with ginger in them. Some with both ginger and menthol. There are alot of shampoos with green tea extract.

 

[michael barry]

Bobs and Harold,

There are selenium sulfide shampoos and they have been experimented with for effects vs. Ketoconazole for other things than alopcia and were found to be about as effective as ketoconazole, http://www.ijdvl.com/article.asp?issn=0 ... t=Aggarwal

....................which means selenium in shampoo must have some "effect"

More: http://www.nlm.nih.gov/medlineplus/drug ... 82258.html





Look at the ingredients of this shampoo..........................
http://www.aubrey-organics.com/product1 ... &subcat=40
Interessant, ne pas?