This paper (Harshuk-Shabso, S., Dressler, H., Niehrs, C. et al.) is a major breakthrough in understanding the onset of catagen, and how to delay it. We may even be able to put this information to practical use right now. The key revelation is that a drop in R-spondins is responsible for the transition from anagen to catagen, and that this reduction in R-spondins is mediated primarily by FGFR1 and FGFR2. When you silence FGFR1/2 then R-spondin levels remain elevated longer, and the anagen phase is extended for as long as R-spondins remain elevated. Eventually R-spondins still drop, and catagen is induced, but it's substantially delayed.
Rspo2/3 is a major factor in Androgenetic Alopecia pathology. They are mostly redundant, one or the other is all you need. See this excellent thread for a detailed explanation of the role of R-spondins in HF physiology. I will share a graph from that thread toward the end of this post.
From this new study:
Wnt signaling in the DP induces Rspo in the matrix, which creates a positive feedback loop allowing for b-catenin accumulation. Fgf signaling through FGFR1/2 increases throughout anagen, reducing Rspo levels, which interrupts the positive feedback loop and initiates catagen. If we silence FGFR1/2 we can use Wnt agonists to upregulate Rspo2/3 and keep hair in anagen.
Here is what happens in mice when you keep Wnt signaling high in the DP and silence FGFR1/2, delaying the reduction of R-spondins and the onset of catagen.
There have been studies over the last few years showing the importance of Rspo in treating Androgenetic Alopecia, and I believe a couple companies have been working on developing some Rspo2 agonists, but there's been no word on them. Perhaps you could pretty much cure Androgenetic Alopecia if you silence the AR(dutasteride/RU/CB), upregulate Wnts(GSK3b,SFRP1/2,DKK1/2 inhibition), and upregulate Rspo2/3.
The new cancer drug Infigratinib antagonizes FGFR. It is highly selective for FGFR1, FGFR2, and FGFR3, with a 40-60 fold affinity over FGFR4, and >128 fold over VEGFR2. It is not easily absorbed, so microneedling or DMSO will probably be required. It is an oral medication, but it is metabolized by CYP3A4 so it should be active topically. Due to CYP3A4 metabolism, ketoconazole and spironolactone are among the contraindicated drugs. Day 1 half-life is 3-7 hours, but plasma clearance is high, so oral dosing is 4x/day at 75-125mg, with 3 weeks on and 1 week off. Twice daily dosing should be sufficient for topical application, with the high plasma clearance reducing the potential for systemic side effects. The dose will be much lower topically than orally. As for the safety, there's no telling. It's currently undergoing clinical trials, but this link has some safety data from a phase II trial. I wouldn't want to use it orally.
Given this, hopefully less than 20mg/day topically will not cause side effects. I would think that dose would be more than sufficient with light skin disruption.
Infigratinib increased the length of hair/fur in rats and dogs over 13 weeks. That is great because it shows the murine study's findings are likely consistent with at least one larger animal model, increasing the possibility that it extends to humans.
This is the concerning part:
However, that is an oral dose that is probably 20-100x higher than what would be applied to the scalp.
Hair loss is actually a reported side effect of this drug(38%), but the patients in the clinical trials are not realizing the anagen promoting effect of silencing FGFR, because this only works in conjunction with Wnt signaling. Cancer patients would not be taking a Wnt agonist, they would be taking Wnt antagonists if anything. Hair loss would be expected in that case. However, when combined with a Wnt agonist hair growth would be expected. In my opinion the benefit of Rspo2/3 expression would substantially outweigh any downside to blocking fgf signaling in the DP as far as hair growth is concerned. I don't recommend using this drug, but it would certainly be interesting to see what it could do for Androgenetic Alopecia when combined with something like SM04554 or CHIR99021, or even minoxidil.
Here you can clearly see why hair growth would not be expected in the cancer trials with this drug. At least in kidney cells Rspo2 alone does little to induce beta-catenin. However, when combined with Wnt agonists, you can see the activation of beta-catenin is remarkable to say the least. The same appears to apply in the HF. Also, notice how the combination of Rspo2+Wnt agonists trounces Wnt agonists alone in terms of beta-catenin activation. Imagine the far left of the graph representing the hair growth potential of SM04554, while the right represents the potential of SM04554+Rspo2.
The only questions in my mind are: Are the available Wnt agonists sufficient for inducing beta-catenin and Rspo, or do we also need something like KY19382? Considering Samumed got decent results with their Wnt agonist in an Androgenetic Alopecia trial, I'd say that what we have is sufficient. So really the only question is, does silencing FGFR1/2 in a bald scalp prevent a drop in Rspo like it does in mice, and apparently dogs? I don't see why it wouldn't. If it does then this has a lot of potential. It's a shame we can't get our hands on Rspo2 recombinant protein. We could keep hair in anagen forever.
Rspo2/3 is a major factor in Androgenetic Alopecia pathology. They are mostly redundant, one or the other is all you need. See this excellent thread for a detailed explanation of the role of R-spondins in HF physiology. I will share a graph from that thread toward the end of this post.
From this new study:
Wnt signaling in the DP induces Rspo in the matrix, which creates a positive feedback loop allowing for b-catenin accumulation. Fgf signaling through FGFR1/2 increases throughout anagen, reducing Rspo levels, which interrupts the positive feedback loop and initiates catagen. If we silence FGFR1/2 we can use Wnt agonists to upregulate Rspo2/3 and keep hair in anagen.
Here is what happens in mice when you keep Wnt signaling high in the DP and silence FGFR1/2, delaying the reduction of R-spondins and the onset of catagen.
There have been studies over the last few years showing the importance of Rspo in treating Androgenetic Alopecia, and I believe a couple companies have been working on developing some Rspo2 agonists, but there's been no word on them. Perhaps you could pretty much cure Androgenetic Alopecia if you silence the AR(dutasteride/RU/CB), upregulate Wnts(GSK3b,SFRP1/2,DKK1/2 inhibition), and upregulate Rspo2/3.
The new cancer drug Infigratinib antagonizes FGFR. It is highly selective for FGFR1, FGFR2, and FGFR3, with a 40-60 fold affinity over FGFR4, and >128 fold over VEGFR2. It is not easily absorbed, so microneedling or DMSO will probably be required. It is an oral medication, but it is metabolized by CYP3A4 so it should be active topically. Due to CYP3A4 metabolism, ketoconazole and spironolactone are among the contraindicated drugs. Day 1 half-life is 3-7 hours, but plasma clearance is high, so oral dosing is 4x/day at 75-125mg, with 3 weeks on and 1 week off. Twice daily dosing should be sufficient for topical application, with the high plasma clearance reducing the potential for systemic side effects. The dose will be much lower topically than orally. As for the safety, there's no telling. It's currently undergoing clinical trials, but this link has some safety data from a phase II trial. I wouldn't want to use it orally.
Given this, hopefully less than 20mg/day topically will not cause side effects. I would think that dose would be more than sufficient with light skin disruption.
Infigratinib increased the length of hair/fur in rats and dogs over 13 weeks. That is great because it shows the murine study's findings are likely consistent with at least one larger animal model, increasing the possibility that it extends to humans.
This is the concerning part:
However, that is an oral dose that is probably 20-100x higher than what would be applied to the scalp.
Hair loss is actually a reported side effect of this drug(38%), but the patients in the clinical trials are not realizing the anagen promoting effect of silencing FGFR, because this only works in conjunction with Wnt signaling. Cancer patients would not be taking a Wnt agonist, they would be taking Wnt antagonists if anything. Hair loss would be expected in that case. However, when combined with a Wnt agonist hair growth would be expected. In my opinion the benefit of Rspo2/3 expression would substantially outweigh any downside to blocking fgf signaling in the DP as far as hair growth is concerned. I don't recommend using this drug, but it would certainly be interesting to see what it could do for Androgenetic Alopecia when combined with something like SM04554 or CHIR99021, or even minoxidil.
Here you can clearly see why hair growth would not be expected in the cancer trials with this drug. At least in kidney cells Rspo2 alone does little to induce beta-catenin. However, when combined with Wnt agonists, you can see the activation of beta-catenin is remarkable to say the least. The same appears to apply in the HF. Also, notice how the combination of Rspo2+Wnt agonists trounces Wnt agonists alone in terms of beta-catenin activation. Imagine the far left of the graph representing the hair growth potential of SM04554, while the right represents the potential of SM04554+Rspo2.
The only questions in my mind are: Are the available Wnt agonists sufficient for inducing beta-catenin and Rspo, or do we also need something like KY19382? Considering Samumed got decent results with their Wnt agonist in an Androgenetic Alopecia trial, I'd say that what we have is sufficient. So really the only question is, does silencing FGFR1/2 in a bald scalp prevent a drop in Rspo like it does in mice, and apparently dogs? I don't see why it wouldn't. If it does then this has a lot of potential. It's a shame we can't get our hands on Rspo2 recombinant protein. We could keep hair in anagen forever.
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