Hair Cuts 5

HAI RCUTS Vol ume5 Se pt e mbe r1-De c e mbe r31 ,2023

FI RSTPATENTI NDESCI•T3/ 4PRODUCTI ON •DELI VERYVEHI CLEPARTNERSHI P •UNLI MI TEDTRANSPLANTS? VERTEPORFI NMADNESS•TWI ST1COLLABORATI ON•TRHSTUDY•HAI RYREWARDS

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HAIR CUTS 5: September 1st, 2023 - December 31st, 2023 Intro Metrics Governance

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ONGOING PROJECTS

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First Patent in Desci: Thyroid Hormone Formulation Twist-1/2 Study Dutasteride Delivery Vehicle Study Topical Thyrotropin-Releasing Hormone (TRH) Study Verteporfin Funding Top Rated Comments HAIR CUTS Leaderboard

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Score Board

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Intro In HAIR CUTS 5, the HairForce filed the first patent in Decentralized Science (DeSci), grew over 30% across social media channels, and voted on a record number of governance proposals. Our pre-clinical research took significant steps forward: our Twist-1 study design is complete, thanks to collaboration with Dr. Claire Higgins of Imperial College London; our Dutasteride Delivery Vehicle study has begun with Dr. Tais Gratieri at the University of Brasilia; and our Thyrotropin-Releasing Hormone (TRH) study has been initiated at the University of Miami. We also took our first step to support the promising research by Dr. Bloxham and Dr. Bargouthi on Verteporfin, in search of unlimited donor regions for our hair transplants. Jumpman, Endana, and Herbert continued to lead us, while Jdesantos, Kabab, Catbellyrubs, and the rest of the HairForce followed suit. Grab your combs, folks, because HAIR CUTS 5 is about to blow your minds—but hopefully not your hairlines.

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Metrics

Community Metrics Our community metrics showed strong growth this epoch. Discord server members increased by over 30%, with members sending over 56k messages to each other; our most viewed Tweet to date went semi-viral (someone petition Elon for better analytics on follower growth); and the #HAIRDAO hashtag now has over 500k views on TikTok.

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Governance

The past epoch was our most active in governance thus far. Since the beginning of September, HairDAO has voted on 12 HairDAO Improvement Proposals (HIP’s). Our community voted on:

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ONGOING PROJECTS

First Patent in Desci: Thyroid Hormone Formulation We have filed the first patent in DeSci! This breakthrough is the product of our collaboration with the renowned hair loss scientist, Dr. Ralf Paus, of the University of Miami. As mentioned in HAIR CUTS 4, our study with Dr. Paus tested Liothyronine (T3) and Levothyroxine (T4), synthetic forms of hormones naturally produced in the body.

These compounds have demonstrated hair growth promoting potential by extending the growth phase (anagen) of in vitro hair follicles. Their mechanism and role in hair loss due to thyroid disease is well-documented, with FDA approval for treating hypothyroidism and a long-standing safety profile from their use by millions annually.

Our preclinical research on human scalp skin ex vivo exhibited encouraging signs of hair growth.

Thyroid Hormone Formulation in Production

We have now initiated the pivotal phase of transitioning our treatment from the research laboratory to patients. To ensure everything we do is compliant with the appropriate regulatory bodies, we engaged an FDA regulatory consultant to guide us through the necessary steps. Based on the consultant’s input, we’ve decided to partner with 503a compounding pharmacies and prescribing physicians, offering access to our formulation through a compliant telehealth platform. This transition included @AJT123 scraping the web to identify all compounding libraries in Florida. The subsequent outreach campaign was managed by a stellar team comprised of @Royalty, @Damilolaeth, @Kabab, @Shekelberg, and @Kenichi. Their concerted efforts

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facilitated reach-out to over 500 compounding pharmacies and has already culminated in several partnerships.

Building on this initial success, we extended our efforts to include compounding facilities in other locations that we anticipate will have high demand for our treatment, such as New York and California. @Damilolaeth and @Royalty have again played instrumental roles in this expanded campaign. @BenTD has also enriched the team for this next phase, having “formerly worked as a compounding pharmacy rep here in CA,” he has “3 pharmacies onboard and ready to go here in LA with licenses to ship anywhere in CA, NV, and AZ.” We still have hurdles to pass before launching the telehealth, such as HIPAA-compliant data management, but our follicles are tingling with excitement. @Jdesantos was particularly excited to see results from ”people with at least some vertex balding to improve data quality, so NW3V minimum.” However, HairDAO, along with any claims made in its public application and Discord server, does not replace medical advice. HairDAO encourages consumers to seek confirmation of any results external to HairDAO. Next Steps/How You Can Help: While we’re excited to see what happens next, HairDAO can make no claims regarding the efficacy or safety of its Thyroid Hormone formulation! HairDAO is not a medical provider and cannot prescribe or recommend any medicines. HairDAO encourages consumers to consult their medical practitioner prior to using any product. If you’re interested in learning more about HairDAO’s proprietary products, you can reach out in the #T3 channel in the HairDAO public Discord server.

Twist-1/2 Study @Jumpman has been the driving force behind our pioneering research to downregulate Twist-1 and Twist-2 proteins in our hair cells. The existing literature, predicated on animal studies and human dermal papilla cell cultures, suggests that complete Twist-1 suppression is not only beneficial for hair growth, but may also suppress cancer metastasis. The level of Twist-2 suppression that we would like to target is less clear, as Twist-2 suppression exhibits biphasic effects. Accordingly, we will initially target 50% Twist-2 suppression and adjust accordingly during the study.

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The amount of research poured into this project has been mindblowing, a multi-year brainchild of the internet’s most prolific hair loss researcher. As @Jayy wrote on Jumpman, “Dude is on a mission…mission to find (the) cure.” We also share @potential_Dingo’s excitement about Jumpman’s pioneering research and are all “looking forward to the trial. This is one of our most important projects, thanks for all that you do, Jumpman. (I’m) still in awe of your first post about TWIST.” In order to develop a Twist-1/2 inhibiting treatment, we first need to validate the target. @Averbs123 informed us, ”we're almost ready to start our hair follicle organ culture model”. Promising data means much less before it is tested in a complete human hair follicle. Our first step was to design the study, deciding which small molecules, PROTACs, and siRNA’s to test (or not test) for Twist-1/2 silencing of human hair follicles. As @Jumpman highlighted, there are different ways to suppress Twist, “There's the chance a more selective and potent harmine derivative will actually be as good if not better than full inhibition. The move is to test validated siRNAs against the best harmine derivative that we can get right now.” In turn, we discovered five novel Harmine derivatives via in-silico analysis, and have received several manufacturing quotes at @Endorstoi’s direction. After completing our study design,we received quotes from two labs, before ultimately choosing to run the study with Dr. Claire Higgins from Imperial College London.

Next Steps/How You Can Help: Now that we have designed the study and identified the initial Twist inhibitors that we would like to test, we are finalizing our contract with the Imperial College of London.

All indicators suggest that we should begin the study within the month. The best way for HairDAO members to assist with this study would be to search the patent registries and get us in touch with anybody who holds a patent on a Twist suppressor. Check out @AJT123’s tutorial for guidance on how to navigate the patent database. We’d love to include more suppressors in our follow up work. Other than that, stay tuned! Wen Dr. Claire Higgins on Hairy Matters?!

Dutasteride Delivery Vehicle Study As discussed in HAIR CUTS 4, we are collaborating with Professor Gratieri and Professor Gelfuso from the University of Brasília to develop a variety of new topical Dutasteride formulations. While Dutasteride is currently only approved for benign prostatic hyperplasia (BPH), its off-label use has been shown to be the most effective

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treatment for hair loss today. Dutasteride's efficacy is unfortunately overshadowed by a series of significant side effects, including depression, anxiety, erectile dysfunction, and infertility. To mitigate these adverse effects while ensuring hair regrowth, our team at the University of Brasilia has proposed three innovative delivery vehicle formulations. These vehicles are designed to maximize Dutasteride’s hair follicle specificity, thereby reducing systemic absorption and its associated side effects while preserving the drug’s efficacy in the follicle.

We selected Professors Gratieri and Gelfuso after interviewing over 25 delivery vehicle researchers, with HUGE help from @Herbert and @Endana. We all shared BenTD’s gratitude and enthusiasm when he said, “Awesome stuff, Herbert! Never been more pumped to see that everyone is working on topical 5ari formulas.” For those who missed it, we filmed Hairy Matters Episode 5 with Professor Gratieri to discuss the study. The entire community wanted the answer to @Aube_Remix's question "If she [Dr. Gratieri] had to pick her top 3 formulations that she thinks are most likely to turn out well, which would she pick?" If you watch Hairy Matters 5, you might find out ;).

Professor Tais Gratieri on the Hairy Matters Podcast

When the community had questions about dosage, @Herbert90 came to the rescue and highlighted that "Dutasteride’s nonlinear half-life means that, at low dosages, the drug can actually clear from the blood very quickly." Additionally, @Herbert90 noted, "peak concentration will be low because it's a slow release formulation," which aligns with our goal of minimizing side effects. Further discussing the benefits of collaboration, @Averbs123 added, "Realistically we (HairDAO) know more about dutasteride. Her area of expertise is delivery. Yeah, dut(asteride) blocks both isoforms of 5AR, which yields more efficacy but probably worse side effects.

However, we’re counting on a low dose and the drug’s lipophilicity to reduce systemic absorption". In addition to our three proprietary delivery vehicle formulations, we will

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also include delivery vehicles designed by third-party companies, so that patients can see an apples-to-apples comparison of the broadest range of formulations possible.

Next Steps/How You Can Help: We had been engaged in discussions with the University of Brasília’s Tech Transfer Office (TTO) to secure advantageous terms for HairDAO concerning the intellectual property of our funded research, and are glad to announce that we have come to an agreement and started working together! In parallel, we continue to look for additional third-party delivery vehicle companies to participate in our study. We currently have two companies on board but have room for five more. Any and all suggestions or connections would be greatly appreciated!!

Topical Thyrotropin-Releasing Hormone (TRH) Study We voted unanimously to approve HIP-17, our second study with Dr. Ralf Paus, testing the impacts of Thyrotropin-Releasing Hormone (TRH) on the human scalp skin organ culture model. Based on previous work by Ralf, we expect that TRH will exhibit complementary hair growth effects with our Thyroid Hormone formulation. TRH and Thyroid Hormones both operate within the hypothalamus-pituitary-thyroid axis, but via completely different mechanisms of action. Additionally, TRH is listed as a cosmetic agent in Europe, which may make regulatory approvals easier to navigate. For more information on the TRH thesis, check out what Ralf had to say on Hairy Matters 3 and/or @andy1’s write up!

Next Steps/How You Can Help: We have already signed the Joint Development Agreement with Cutaneon (Ralf’s Lab) with a start date of January 1st, 2024. We can expect milestone reports on TRH’s efficacy as a hair growth promoter after 6 months and 12 months, while we should understand our path to market after 9 months. Initially, the most challenging step will be to optimize the vehicle to ensure TRH is adequately delivered to the base of the human hair follicle. While there is not much work to be done in relation to this study now, keep your eyes peeled for opportunities to contribute!

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Verteporfin Funding

Verteporfin, an FDA-approved drug for macular degeneration, has shown promising potential as an anti-scarring solution when used during hair transplants. Hair transplants are generally effective, however, they come with a significant limitation: the hair extracted from the donor area doesn't regrow, limiting the number of transplantable hairs. Early trials suggest that Verteporfin could change this via enabling the regeneration of hair follicles in the donor region, potentially providing a limitless supply of donor hair.

The key to Verteporfin's effectiveness lies in its role as a YAP inhibitor, which promotes slower healing without scarring, and, as a result, appears to encourage hair regrowth post wound healing. @Jumpman further analyzed the treatment approach, suggesting that "Vert is the best there is if TEAD inhibition doesn't work. The problem with TEAD is that it has YAP1-independent effects too, and there's no telling if those will be beneficial." Preliminary research, including trials by Dr. Bargouthi and Dr. Bloxham, suggests a higher number of hairs regrowing (double in one case!) in areas treated with Verteporfin compared to control areas. @MarthaHalli encouraged our community’s involvement by suggesting, "Dr. Barghouti posted on the hair restoration site about the FUE he did. I think we should post on other groups we are in, to encourage more people to ask Dr. Bargouthi for their HT. Dr. B needs to be rewarded with more patients for his effort." @AJT123’s Verteporfin tweet thread on HairDAO’s account spread the word further, earning over 3,000 views.

Dr. Bargouthi Study: Control Area vs. Verteporfin Area

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Unfortunately, Verteporfin is currently extremely difficult to source, as the ophthalmic industry has moved on from Visudyne (FDA-approved brand of Verteporfin). @Jumpman highlighted the ethical implications, asking, “How can you deprive a patient of an FDA-approved 30-year-old drug that prevents disfigurement?" Our effort to make Verteporfin broadly accessible takes a village, the HairDAO village. @Aspect__x revealed an exciting update he got from Melvin: “I'm trying to get a bottle [of Visudyne] sent to Dr. Mohebi; he is interested in doing a trial now. I will also contact AmerisourceBergen to try and get this sourced to Dr. Pittella." @andy1 proposed, "we could also start making the protocol/info materials for other doctors," to broaden the reach of this research.

Over the past 18 months, nobody in our community has played a more pivotal role in facilitating our Verteporfin work with Dr. Bargouthi and Dr. Bloxham than @Endana. To support this research, HairDAO has purchased state-of-the-art TrichoLAB machines, valued at ~$15,000 each, for Dr. Bargouthi and Dr. Bloxham. These tools will enable more detailed analysis of Verteporfin's effectiveness, along with other novel treatments tested by two of the world’s most forward-thinking hair doctors. @Jdesantos emphasized the importance of these devices, as "repeat trichoscans over time may be even more convincing, as the number of visible hairs isn't a static value. Compare these to baseline and/or any same-head control area, and we should have a clear picture of efficacy."

While our optimism is high based on early findings, it is still important to note that the results so far come from a limited number of patients. Over the next year, we anticipate the collection of more extensive data. @Endana, a pivotal figure in our hairy community, shared his cautious optimism: "Boys we might be cured. Let's pray that there was actual regeneration -- remember this was just the first trial and there's so much more to improve on."

Given the current challenges in sourcing Visudyne for hair transplant applications, we are also considering developing our own improved formulation that could be more easily accessible to hair transplant specialists. As @Endana noted, "Dr. Bloxham already did three patients but now cannot do more, as he’s having trouble sourcing the med," highlighting the current sourcing challenges. Provided the research continues to yield positive outcomes, we hope to help. For a deeper dive into Verteporfin for hair transplants, listen to our interview with Dr. Bargouthi in Hairy Matters Episode 7 here.

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Top Rated Comments

HairDAO at Paus Lab by @Averbs123: ”HairDAO is officially in the Paus Lab

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On T3/T4 research by Averbs123: “i’ll be immunostaining our t3/t4 scalp skin organ cultures today , will be extra careful” @Hcjen on our collaboration with Dr. Claire Higgins: “What an incredibly knowledgeable person Dr Higgins is! Her, Gill Westgate and Paul Kemp together in a room was so much nerdy fun! Anyway, there was some good discussion about the potential longevity of what we’re aiming to do…

Dermal papilla (DP) cells appear to possess quorum sensing that allows them to rebuild a DP niche to a certain number. If this works as hypothesized, then the DHT insensitive cells could signal to produce a full DP and, over time as the DHT sensitive cells are lost, the DP could become completely populated with DHT insensitive DP cells!”

Micro needling guide by @Jumpman: Jumpman has created a guide for micro needling, accessible via Discord link: https://discord.com/channels/1102313145575419996/1102313146514944082/11608531 15722006619

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Strategic focus suggestions by @Jdesantos: “I've harped on each of these quite a bit so will just paste them one last time: 1. **larger community** (where's the next endana going to come from otherwise?)

2. **lower barriers to entry** (lots of people want to help, but there's nothing obvious for them to do or what's there is too big/hard) 3. **increase overall engagement** (larger community will help, engagement-bait research could go viral, prediction market could be fun, etc.)

4. **increase relative incentive value** by targeting countries where $HAIR exchange rate is more favorable (I'm in the US and in financial terms nothing here could possibly motivate me alone).”

TikTok strategy by @Kranz: Kranz is prioritizing follower growth and views on TikTok for HairDAO, having achieved 500k views on the HairDAO hashtag: “Right now I’m trying to prioritize follower growth and views and after that I will start making videos only about hair.” @Jumpman shouts out @Leferty& @MonoSpoon: Many thanks to @Leferty and @MonoSpoon for documenting their experience, and sharing their pictures. “These first sets are monospoon's pics from using ADQ, and then a few months after adding TM5441” : https://discord.com/channels/1102313145575419996/1102313146154225693/11599856 24061837362 @Jumpman comes up with standardized picture methodology, crucial for at-home efficacy measurements:”Trying to come up with a way to standardize pictures, but that is also not too hard to follow, and can be done without people having to buy new equipment. First draft here. Would appreciate any suggestions.

Pictures should be taken overhead in the same exact location and the same exact lighting, with the same camera. Hair should be the same length, and combed the exact same way. Hair should be dry, and the camera flash should be on. Your head should be tilted at the same angle. Just moving one step can change the lighting enough to make your hair appear a full norwood different on camera. Tilting your head 10 degrees differently can do the same. Sit in the same chair each time you take your before and after pictures. Note where it sits on the floor so that you can sit in the exact same spot next time. This is very important. Sit straight back in the chair. While looking straight ahead, at the exact same spot each time, take your camera and extend your arms all

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the way out above your head. This is to make sure you take your pictures from the same distance each time. Take a picture with the flash on. Repeat until you have a clear picture of your entire scalp.

Next take an empty toilet paper roll. Brush your hair aside and place one end on the center of your scalp towards the crown. Pick a spot that it will be easy for you to recreate, such as if you have a ridge or birthmark. Place the camera over the toilet paper roll, and take a picture with the flash on. You should have a clear picture showing microscopic detail.” @Moemanthe2nd sharing his exciting hair growth journey : First pic before and then halfway in, the current pic is 6 months post the last dose: https://discord.com/channels/1102313145575419996/1102313146154225693/11813852 88556236841

HAIR CUTS Leaderboard **Unless stated otherwise, all tokens awarded in this edition of HAIR CUTS will be vested over a three-year period and will also be locked for one year. If you do not claim your HAIR within 3 months of this publication by posting your wallet address in the #hair-drop channel of our Discord server, your right to HAIR will be forfeited.

1. xjumpmanx (2,113.95): Jumpman continued his reign as the HairForce’s lead researcher. Our General spearheaded our Twist-1 pre-clinical research to its next checkpoint, elucidating the science, selecting molecules to test, and co-designing our study with Dr. Claire Higgins. A renowned insomniac, he also provided immeasurable leadership on our Thyroid Hormone, Dutasteride, Thyrotropin-Releasing Hormone, and Verteporfin studies. As Aspect stated, “Nothing is more powerful than our father Jumpman.”

2. Endana (1,413.53): In second, we’re blessed to anoint King Endana. The tradesman led our Thyroid Hormone go-to-market strategy, Verteporfin research, Delivery Vehicle reach-out, and numerous business development ventures. He served as our primary point of contact with Dr. Taleb Barghouthi and Dr. Blake Bloxham, enabling the purchase of our TrichoLAB equipment, to allow for future in vivo research at their clinics.

He frequently played the role of admin, navigating decision-trees, orchestrating members of the HairForce on strategies to maximize their contributions, and bookkeeping results. We’re grateful to have him lead us.

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3. Herbert (1,017.34): The bronze medal is awarded to our delivery vehicle and newly appointed cloning expert. Herbert ensured that the HairForce remained at the forefront of both fields, through industry-leading basic research and business development efforts with relevant experts. As every drug requires a vehicle and cloning remains a potential cure, Herbert’s expertise remains invaluable. He also contributed significantly to our research strategy and gene target analysis, a full-stack weapon for the HairForce.

4. Rob English (575.00): 'The Rob English?' Rob has played a mission critical role in bringing our Thyroid Hormone formulation to market, selecting an FDA regulatory consultant and ideating novel pathways to optimize both spend and data collection. Rob has communicated with the HairForce weekly through text, email, and calls, consistently delivering exceptional results for our treatment’s next steps.

5. Jdesantos (135.75): Always difficult to identify thanks to several “sock puppet” accounts, Jdesantos provided a plethora of useful insights on gene targets, treatments, governance issues, product direction, and more. He also provided invaluable analysis to our Thyroid Hormone study protocol, including takeaways to apply to all in vivo research.

6. Kabab (101.92): Kabab was instrumental in expanding our network of compounding pharmacies, winning our bounty to onboard a hairful of pharmacies in Florida. He also led the launch of HairDAO India with Catbellyrubs and Potential Dingo, reaching out to several contract research organizations (CROs) and pharmacies in the region, and shared research and go-to-market strategies for various treatments.

7. Catbellyrubs (99.49): Catbellyrubs contributed valuable business development and research to the HairForce, with a focus on our Verteporfin and Thyroid Hormone studies. He also co-developed numerous pieces of content and helped launch HairDAO India, alongside Kabab and Potential Dingo.

8. Kranz6080 (96.26): Kranz single-handedly led the #HairDAO movement on TikTok, earning over 500k views. He has a deep understanding of content generation, from technical know-how to cultural trends, which has resulted in a number of very popular videos. His work is crucial for onboarding the next generation of HairForce members.

9. Casual Participant (91.21): Casual Participant, an anon with connections throughout the hair loss industry, led valuable research and business development efforts for the HairForce. He connected us with several leading cloning companies this epoch, providing analysis of their solutions in the process. He also shared numerous updates on leading companies bringing pharmaceuticals to market.

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10. Pevjo (88.72): Pevjo provided in-depth analysis on a range of targets and treatments, from hair to reproductive health to longevity to more. His research has guided direction for the HairForce’s present and future research in terms of treatments to test, genes to measure, and additional indications whose underlying causes may overlap with hair loss.

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Score Board

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