Drug discovery for alopecia: gone today, hair tomorrow

Abstract

Introduction: Hair loss or alopecia affects the majority of the population at some time in their life, and increasingly, sufferers are demanding treatment. Three main types of alopecia (androgenic [AGA], areata [AA] and chemotherapy-induced [CIA]) are very different, and have their own laboratory models and separate drug-discovery efforts.

Areas covered: In this article, the authors review the biology of hair, hair follicle (HF) cycling, stem cells and signaling pathways. AGA, due to dihydrotesterone, is treated by 5-α reductase inhibitors, androgen receptor blockers and ATP-sensitive potassium channel-openers. AA, which involves attack by CD8(+)NK group 2D-positive (NKG2D(+)) T cells, is treated with immunosuppressives, biologics and JAK inhibitors. Meanwhile, CIA is treated by apoptosis inhibitors, cytokines and topical immunotherapy.

Expert opinion: The desire to treat alopecia with an easy topical preparation is expected to grow with time, particularly with an increasing aging population. The discovery of epidermal stem cells in the HF has given new life to the search for a cure for baldness. Drug discovery efforts are being increasingly centered on these stem cells, boosting the hair cycle and reversing miniaturization of HF. Better understanding of the molecular mechanisms underlying the immune attack in AA will yield new drugs. New discoveries in HF neogenesis and low-level light therapy will undoubtedly have a role to play.

Keywords: 5-α-reductase inhibitor; alopecia areata; androgenic alopecia; anti-androgen; baldness; chemotherapy-induced alopecia; hair follicle; low-level laser (light) therapy; stem cells; topical immunotherapy.

Figure 1

Cross-section of a normal hair showing central medulla, intermediate cortex, and outer cuticle.

Figure 2

Schematic organization of the telogen-phase adult HF showing location of the stem cells. The stem cell populations are represented by their well-marked gene/protein-expression or promoter-activity: Lgr5 (hair germ and bulge), CD34 (bulge), LRC (bulge), Lgr6 (lower isthmus), Lrig1/MTS24 (isthmus), Blimp1 (sebaceous gland) and K15* (K15 promoter, bulge area). HF: Hair follicle.

Figure 3

Hair follicle IRS structure. This features three distinct layers of epithelial cells, which are known as Henle’s layer, Huxley’s layer, and the IRS cuticle. IRS: Inner root sheath.

Figure 4

Hair cycle and its transitions. There are three main phases of the hair growth cycle; anagen, catagen and telogen with anagen further subdivided into proanagen, mesanagen and metanagen.

Figure 5

Interactions between stem cells, progenitor cells, and cells in and related to the skin. IFESCs: Interfollicle epidermal stem cells; HFSCs: Hair follicle stem cells; SGSCs: Sebaceous gland stem cells; fPSCs: follicle nestin + pluripotent stem cells; Lgr6 + fPSCs, could be identical to fPSCs.