JAK Inhibitors : a future association with RU58841 ?

Hair regrowth may finally be arriving for androgenic alopecia sufferers. Finasteride and other 5α-reductase inhibitors first allowed patients to stop balding, but those drugs are notorious for their side effects. More recently, RU58841 has offered a topical, side-effect-free solution to hair loss, but even it cannot make hair regrow. The combination of RU58841 and minoxidil to stop balding and promote hair regrowth, respectively, has been proposed as an option for restoring natural hair growth after balding begins, but minoxidil is hardly reliable for regrowing hair. JAK inhibitors, by contrast, seem to be extremely effective at making hair regrow and doing so without side effects. Like RU58841, JAK inhibitors work through non-steroidal pathways. Patients may soon combine RU58841 with JAK inhibitors to cure androgenic alopecia completely.

What Are JAK Inhibitors?

JAK inhibitors are a class of small-molecule immunosuppressant drugs commonly used to treat certain cancers and inflammatory conditions, such as rheumatoid arthritis. JAK inhibitors work on the Janus kinase, or Jak, family of tyrosine kinases. This family of kinases transduces signals mediated by cytokines, which are cell-signaling molecules that promote the body’s response to inflammation and infection (1). Researchers discovered that an inherited deficiency of Jak3, one member of the Janus kinase family, causes a severe type of immunodeficiency. The researchers realized that Jak3 inhibitors could be a new type of immunosuppressant treatment.

Early interest in making JAK inhibitors was complicated by the existence of 90 Janus kinase family members and the difficulty of specific, rather than general, kinase inhibition. General kinase inhibitors can inhibit ATP, which cells use for energy transfer. Of course, specific kinase inhibitors were ultimately developed, including tofacitinib, which is a potent inhibitor of Jak3 and Jak1 and a moderate inhibitor of Jak2 while barely affecting other kinases (2).

First JAK Inhibitor Applications for Hair Loss

Immunosuppressant drugs are often used to treat autoimmune conditions, in which the body attacks its own tissues. Two JAK inhibitors, ruxolitinib and tofacitinib, which are approved by the FDA for treating blood diseases and rheumatoid arthritis, respectively, are currently being tested for treating the autoimmune diseases plaque psoriasis and alopecia areata. In cases of alopecia areata, bald patches develop as the hair follicles are attacked by the immune system. From this research came interest in the possible use of JAK inhibitors to treat alopecia of several types (3).

Mechanism of JAK Inhibitors and Its Link to Hair Loss

The therapeutic effects of JAK inhibitors occur via blockade of the JAK-STAT signaling pathway (4). JAK-STAT, or Janus kinase/signal transducers and activators of transcription, is critical to the effects of cytokines on inflammation. Immune responses and cell growth can be stimulated by the binding and activation of cytokine type I and II receptors by cytokines. Inhibition of the JAK enzymes, which the cytokine receptors require in order to transduce signals, results in the blockade of cytokine signaling.

Evidence is mounting that among factors contributing to baldness, cytokine signaling is significant. For example, researchers found that levels of certain cytokines changed, and some went up, after an allergen was applied in a case of alopecia areata. However, there is evidence that the cytokines modulate the balding process rather than cause it outright (5).

The JAK-STAT pathway :

JAK inhibitor RU58841

How JAK Inhibitors Affect Hair Loss

Dr. Christiano, the lead researcher investigating the potential for treating hair loss with JAK inhibitors, discovered that these drugs do not only affect hair loss through their effect on immunity. This means that in addition to treating alopecia areata, an autoimmune disease that benefits from targeted immunosuppression, JAK inhibitors also hold promise for other forms of hair loss. In fact, researchers found in 2014 that macrophages play a part in activation of hair follicle stem cells in healthy skin (6). Macrophages, a type of white blood cell, have been shown to produce and release cytokines, whose signaling JAK inhibitors can block (7).

What Do Lab Tests Show About JAK Inhibition and Hair Loss?

Dr. Christiano and colleagues recognized that baldness often involves the switching of hair from anagen, its growth phase, to telogen, its resting phase, and that pharmacological approaches have generally failed to switch hair growth back on. After administering JAK inhibitors orally to mice and then applying the drugs topically to the skin, the researchers found that while both methods of administration triggered hair regrowth, topical application had the greatest effect. Mice that received JAK inhibitors for five days regrew hair in 10 days or less while the untreated mice remained bald.

The work of Dr. Christiano produced several important findings on how JAK inhibitors affect hair loss. Rather than preventing dormancy of the hair follicles when the resting phase first occurs, JAK inhibitors are effective later in the phase. The researchers also determined that JAK inhibition allows regrowth of hair directly as JAK-STAT signaling keeps the hair in the resting phase. Wnt and Shh signaling pathways, both essential to hair regrowth, are activated by JAK inhibitors so that regrowth occurs in a natural manner. Finally, tests showed that the positive effects of JAK inhibitors on hair growth did not depend on the action of the drugs on lymphocytes (8).

JAK inhibitors have not yet been tested on patients with androgenic alopecia, but research thus far makes success very likely. The thoroughness and speed with which JAK inhibitors stimulate hair regrowth is far more impressive than with other agents that have been explored. As researchers continue to investigate the usefulness of JAK inhibitors for restoring hair growth in different hair loss disorders, these new drugs may emerge as powerful complements to medications that stop hair loss, such as RU58841.

 

References:

(1) Genome Biol. 2004 Nov; 5(12): 253. The Janus kinases (Jaks)

(2) Current Opinion in Pharmacology. 2012 Aug; 12(4): 464-470. Jakinibs: A New Class of Kinase Inhibitors in Cancer and Autoimmune Disease

(3) Nature Medicine. 2014 Sep;20, 989–990. Inhibiting Janus kinases to treat alopecia areata

(4) Curr Opin Pharmacol. 2012 Aug; 12(4): 464-470. Jakinibs: A New Class of Kinase Inhibitors in Cancer and Autoimmune Disease

(5) Archives of Dermatological Research. 1996 Mar; 288(3): 153-156. Cytokines and growth factors influence hair growth in vitro. Possible implications for the pathogenesis and treatment of alopecia areata

(6) PLoS Biology. 2014 Dec; 12(12): e1002002. Macrophages Contribute to the Cyclic Activation of Adult Hair Follicle Stem Cells.

(7) Arthritis & Rheumatism. 2012 Nov; 64(12) 3856-3866. Regulation of inflammatory responses in tumor necrosis factor–activated and rheumatoid arthritis synovial macrophages by JAK inhibitors

(8) Science Advances. 2015 Oct; 1(9): e1500973. Pharmacologic inhibition of JAK-STAT signaling promotes hair growth

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