Category Archives: Angela Christiano

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.

JAK-STAT Signaling Jump Starts the Hair Cycle

Over the past few years, I have discussed the janus kinase signal transducer and activator of transcription (JAK-STAT) signaling pathway a number of times.  It has become of increasing importance in the hair loss world ever since JAK inhibitors were first shown to cure alopecia areata (AA) in 2014.  Even prior to that development, there had always been some interest in the JAK-STAT signaling pathway and its relationship to the hair follicle cycle.

However, since 2014, research in this area seems to have multiplied significantly.  In 2015, I discussed Dr. Angela Christiano, Dr. Claire Higgins et al’s groundbreaking paper titled “Pharmacologic inhibition of JAK-STAT signaling promotes hair growth“.

Now, in the latest (November 2016) issue of Journal of Investigative Dermatology, Columbia University’s Dr. Angela Christiano, Dr. Etienne Wang and Dr. Sivan Harel have published a new paper titled “JAK-STAT signaling jump starts the hair cycle“.  Thanks to the commentator in the last post who notified us about this.

However, it should be noted that this paper does not pertain to any new study or research by Dr. Christiano!  Instead, it is largely an analysis by the Columbia University team of a study/paper that was published earlier this year by Dr. Julien Legrand and his team at The University of Queensland.  This study from Australia was titled “STAT5 activation in the dermal papilla Is important for hair follicle growth phase Induction“.  The conclusion of that paper was that “STAT5 activation acts as a mesenchymal switch to trigger natural anagen entry in postdevelopmental hair follicle cycling“.  STAT5 is an acronym for signal transducer and activator of transcription 5.

Dr. Christiano’s team raises some interesting points in their analysis, especially the fact that while Dr. Legrand’s research has shown that JAK/STAT5 signaling in the dermal papilla is required for anagen onset in the murine (mice) hair cycle, other researchers have shown that JAK inhibition is able to induce the transition of telogen to anagen in wild-type mice.  This contradiction highlights the complexity  and still yet to be fully understood nature of JAK-STAT signaling in the various stem cell niches of the hair follicle.

Dr. Christiano continues to believe that topical JAK inhibitors could work to treat regular male pattern hair loss via the following quotes:

“Targeting the JAK-STAT pathway might be a potential treatment for nonimmune alopecias”.

“Further work in this exciting area may uncover novel pathways that control hair follicle stem cell quiescence and activation.  Targeting
these pathways pharmacologically may facilitate the discovery of new therapies to treat various forms of alopecia”.

“In our recent study (Note: its the one I mentioned earlier from 2015) we found that in wild-type mice, topical application (rather than systemic treatment) with JAK inhibitors was required to trigger the telogen-to-anagen transition, possibly due to a requirement for high threshold local concentrations of the drug in the hair follicle.  Further, we found that the timing of topical treatment was crucial: treatment induced hair growth only if administered after 8.5 weeks, during late telogen“.

Nothing groundbreaking in this development, but it seems like the University of Queensland based Australian team of researchers is important enough to warrant inclusion in my global map of hair loss research centers.  One of the co-authors (Dr. Kiarash Khosrotehrani) of their paper specifically mentions research interest in “hair follicle biology, cycling and regeneration” in his biography page.

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