Category Archives: JAK-STAT

Aclaris Therapeutics and Mechanism of Action

March 2019

In March of 2019, Dr. Angela Christiano’s Columbia University based lab’s Twitter account posted the following:

Etienne Wang's Thesis

In recent years, the Christiano-led Columbia team have published a number of important papers related to JAK inhibitors, JAK-STAT signaling and hair growth. Since I have covered their work many times on this blog, I did not pay much attention to this latest paper. I was also not too keen to yet again research dry subjects such as TREM2+ dermal macrophages, oncostatin and JAK-STAT5 activation.

I am also a bit wary of covering JAK inhibitors too often. Largely due to the slow pace of progress in JAK inhibitor trials for androgenetic alopecia, led by US-based Aclaris Therapeutics. Moreover, technical posts on scientific research papers are not well received by most readers except for the most scientifically minded ones.

May 2019

Aclaris JAK Inhibitor Mechanism of Action

In May of 2019, I outreached to Aclaris Therapeutics to ask them about the progress in their JAK inhibitor trials for male pattern hair loss. In the past, they never replied. However, this time, one of their vice presidents got back to me immediately with the following response:

“Stay tuned. Data in May/June. New MOA postulated In attached paper.”

MOA means “Mechanism of Action”.

Lo and behold, the Aclaris VP had attached the previously discussed Ettiene Wang et. al’s full thesis paper titled:

“A Subset of TREM2+ Dermal Macrophages Secretes Oncostatin M to Maintain Hair Follicle Stem Cell Quiescence and Inhibit Hair Growth.”

June 2019

Last week, Aclaris Therapeutics’s CEO Dr. Neal Walker presented at the annual Jefferies 2019 Healthcare Conference in New York. I used to cover these presentations regularly. The full presentation can be found here.

On page 28, they discuss a new mechanism of action in understanding how JAK inhibitors could help patients with androgenetic alopecia (AGA). In brief, the administration of a JAK inhibitor will turn STAT5 to the OFF position. This in turn promotes hair follicle stem cell activation, and subsequent hair growth.

For some reason, the Aclaris PowerPoint slide’s reference is to Dalessandri, T and Kasper, M., who in turn refer to the Wang paper I discussed earlier.

“TREMendous Macrophages Inhibit Hair Growth”.

Aclaris Topical ATI-50002 JAK Inhibitor Trials

According to the Aclaris vice president who emailed me in May:

The 6-month results from the Phase 2 open-label 31-patient ATI-50002 clinical trial will be finalized during the second quarter of 2019. 12-month data are expected in the fourth quarter of 2019. If the results from this trial are positive, Aclaris expects to initiate an additional Phase 2 trial in the first half of 2020. Note that they sometimes refer to ATI-50002 as ATI-502.

The above information was essentially confirmed in the latest June Aclaris Investor Presentation audio. Best case scenario is that Phase 3 trials will start in 2020.

UCLA vs USC in the Hair Loss World

University of California Los Angeles (UCLA) and University of Southern California (USC) are both based in Los Angeles, California in the USA. They have one of the most intense and historic rivalries in American college sports, especially in American football. The two campuses are separated by just 12 miles. In an amazing coincidence, the two most important hair loss research related discoveries in the world this month came out of these very two universities.

UCLA scientists find two new ways to activate hair follicle stem cells

For our purposes, the UCLA findings (published just today) seem to have the greatest significance. Scientists (led by Heather Christofk and William Lowry) have found two drugs that activate hair follicle stem cells in mice. Interestingly, both drugs are topical, and one (RCGD423) involves activating the JAK-STAT signaling pathway. No idea if this drug is connected to JAK inhibitors in any way, but that acronym keeps coming up regularly these days.

Both drugs involve increasing lactate production. Apparently, lactate production is strongly connected to hair follicle stem cell activation and hair cycling. In their initial research, the UCLA scientists blocked lactate production genetically in mice and found that this prevented hair follicle stem cell activation. Thereafter, they found that increasing lactate production genetically in mice accelerated hair follicle stem cell activation and increased the hair cycle.


The first drug, RCGD423, activates the JAK-STAT signaling pathway, which in turn leads to an increase in the production of lactate. This then activates hair follicle stem cells and also leads to quicker hair growth. UCLA holds the original patent for RCGD423, related to its ability to rejuvenate cartilage, and has filed a provisional patent for its use for hair growth purposes.


The second drug, UK5099, blocks pyruvate (a glucose metabolite) from entering cell mitochondria. Interestingly, this forces an increase in the production of lactate in the hair follicle stem cells and therefore accelerates hair growth. UCLA has filed a provisional patent for using UK5099 for hair growth purposes.

Perhaps the most interesting quote from the earlier linked article summarizing these findings is: “I think we’ve only just begun to understand the critical role metabolism plays in hair growth and stem cells in general“. On this blog, I have covered the connection between fat cells (adipose tissue) and hair growth numerous times due to significant recent research in that area. So I am not surprised at all that metabolism is also important when it comes to hair growth.

It is, however, surprising that hair loss research has uncovered so many new distinct pathways and mechanisms in the past few years. All of these are unrelated to the tried and tested method of targeting dihydrotestosterone (DHT) reduction. This is great news, since we already know that even close to 100 percent reduction in DHT will not bring back long-lost hair for most people, plus often comes with side effects.

USC scientists restore hair generation in defunct adult cells

A team of scientists from USC (led by Dr. Mingxing Lei, with collaboration from others in China and the UK) have managed to restore hair regeneration properties in adult mice cells that had stopped growing hair. A non-scientist friendlier summary of this work can be found here. One of the co-authors of this paper is Dr. Cheng-Ming Chuong, who I covered on this blog before.

Using intensive video analysis and documentation, bioinformatics, and molecular screenings, the scientists figured out a:

Molecular “how to” guide for driving individual skin cells to self-organize into organoids that can produce hair.


In the future, this work can inspire a strategy for stimulating hair growth in patients with conditions ranging from alopecia to baldness.

Very unlikely to come to fruition anytime soon of course, but considering that some of the research collaborators are from China… perhaps things may move faster than I am guessing if they could shift their research and potential clinical trials to that country?