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Fringe benefits: Side effects of an immunosuppressant lead to treatment for hair loss

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IMAGE: This is the immunofluorescence of β-catenin protein (red) and cell nuclei (blue) in the human hair follicle bulb, the command center for maintaining hair growth. view more 

Credit: Nathan John Hawkshaw

Hair loss can cause major psychological distress in patients, but a new drug could ease the distress of men and women who suffer from baldness, according to researchers from the University of Manchester's Centre for Dermatology Research. The study from the laboratory of Prof Ralf Paus, publishing 8 May in the open access journal PLOS Biology shows that a drug originally designed as a treatment for osteoporosis has a dramatic effect on human hair follicles donated by patients undergoing hair transplantation surgery.

Currently only two drugs - minoxidil and finasteride - are available for treatment of male-pattern balding (androgenetic alopecia). However, both agents have moderate side effects and often produce disappointing hair regrowth results. The only other option available to patients is hair transplantation surgery.

In this PhD project, Nathan Hawkshaw and colleagues sought to develop new strategies to promote human hair growth with the hope of finding novel, well-tolerated agents for treating androgenetic alopecia. The approach was to first identify the molecular mechanisms of an old immunosuppressive drug, Cyclosporine A (CsA), which has been commonly used since the 1980s as a crucial drug that suppresses transplant rejection and autoimmune diseases. CsA often has severe side-effects, the least serious - but most interesting - of which is that it enhances cosmetically unwanted hair growth.

Dr Hawkshaw and colleagues carried out a full gene expression analysis of isolated human scalp hair follicles treated with CsA. This revealed that CsA reduces the expression of SFRP1, a key protein that negatively regulates Wnt signalling, a master pathway that is crucial for the development and growth of many tissues, including hair follicles. This identifies a completely novel mechanism of action of this old and widely used immunosuppressant.

Simultaneously it provides a convincing explanation for why CsA so often induces undesired hair growth in patients treated with it: this drug removes an inbuilt and potent molecular brake on human hair growth. Importantly, this inhibitory mechanism is completely unrelated to CsA's immunosuppressive activities, making SFRP1 a new and highly promising therapeutic target for anti-hair loss strategies.

After some detective work, Dr Hawkshaw noted that a compound that was originally developed to treat osteoporosis, called WAY-316606, targets the same mechanism as CsA by specifically antagonising SFRP1. When he then treated hair follicles with WAY-316606, things got exciting: this non-immunosppressive, chemically unrelated agent also effectively enhanced human hair growth ex vivo in the same manner as CsA. Therefore the external application of WAY-316606 or similar compounds to balding human scalp may promote hair growth to the same magnitude as CsA (if not better), yet without its side effects.

"Thanks to our collaboration with a local hair transplant surgeon, Dr Asim Shahmalak, we were able to conduct our experiments with scalp hair follicles that had generously been donated by over 40 patients and were then tested in organ cultures. This makes our research clinically very relevant, as many hair research studies only use cell culture", said Dr Hawkshaw, adding that "Interestingly, when the hair growth-promoting effects of CsA were previously studied in mice, a very different molecular mechanism of action was suggested; had we relied on these mouse research concepts, we would have been barking up the wrong tree."

He concluded: "The fact that this new agent, which had never even been considered in a hair loss context, promotes human hair growth is exciting because of its translational potential: it could one day make a real difference to people who suffer from hair loss. Clearly though, a clinical trial is required next to tell us whether this drug or similar compounds are both effective and safe in hair loss patients."

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In your coverage please use this URL to provide access to the freely available article in PLOS Biology: http://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.2003705

Citation: Hawkshaw NJ, Hardman JA, Haslam IS, Shahmalak A, Gilhar A, Lim X, et al. (2018) Identifying novel strategies for treating human hair loss disorders: Cyclosporine A suppresses the Wnt inhibitor, SFRP1, in the dermal papilla of human scalp hair follicles. PLoS Biol 16(5): e2003705. https://doi.org/10.1371/journal.pbio.2003705

Image Caption: Immunofluorescence of β-catenin protein (red) and cell nuclei (blue) in the human hair follicle bulb, the command center for maintaining hair growth.

Image Credit: Dr Nathan John Hawkshaw

Funding: Giuliani S.p.A. https://giulianipharma.com/en/. supported a PhD student fellowship to NJH. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing Interests: This study was financed by Giuliani S.p.A for which Professor Ralf Paus consults.

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