Promising Advances in Hair Loss Research: From UCLA Discoveries to Novel Therapies

Hair loss disorders represent a significant global health concern, impacting millions worldwide and substantially affecting their quality of life. While approved treatments like minoxidil and finasteride exist, their effectiveness remains limited, highlighting the urgent need for more targeted and effective solutions. Recent research efforts, including those at UCLA, are exploring innovative approaches to hair loss drug discovery, focusing on small-molecule inhibitors, biologics, and stem cell-based therapies. By integrating insights from molecular mechanisms and leveraging advancements in research methods, next-generation therapeutics hold the potential to transform the clinical management of hair loss disorders.

Understanding the Roots of Hair Loss

Hair loss can stem from a multitude of factors, including aging, stress, hormonal imbalances, and genetic predisposition. Hair loss disorders, including androgenetic alopecia (AGA) and alopecia areata (AA), are among the most prevalent dermatological conditions affecting millions of individuals worldwide. Existing pharmacological treatments, such as minoxidil (a potassium channel opener) and finasteride (a 5α-reductase inhibitor), have demonstrated partial success in slowing hair loss and promoting regrowth. However, their effects are often temporary, and many patients experience inadequate responses or undesirable side effects.

Current Pharmacological Treatments

Several pharmacological treatments are currently available for hair loss disorders, with minoxidil, finasteride/dutasteride, and JAK inhibitors being among the most widely used.

Minoxidil

Minoxidil is a potassium channel opener that promotes vasodilation, improving blood flow to hair follicles. It extends the anagen phase of the hair cycle and stimulates dermal papilla cell (DPC) activity. Approved by the FDA in 1988 for both male and female AGA, minoxidil is available as a topical solution or foam. However, its exact molecular mechanism remains only partially understood. Hair regrowth usually becomes visible after 3-6 months of continuous use, with peak efficacy at around 12 months. Affected areas can become smaller in 62% of subjects, remain unchanged in 35.1%, and become larger in 2.9%. Hair density increases by approximately 10-30%, while hair thickness improves by 10-25% with Minoxidil treatment. A 5% minoxidil solution is more effective than the 2% formulation, but women are generally advised to use the 2% solution due to potential side effects. Additionally, discontinuation leads to resumed hair loss. Common side effects include scalp irritation, itching, and unwanted facial or body hair growth (hypertrichosis). Low-dose oral minoxidil (0.25-5 mg/day) is emerging as an alternative to topical application, and studies suggest that it offers better patient adherence than the topical form. However, side effects such as low blood pressure, swelling, and excessive hair growth in unwanted areas have been reported.

Finasteride and Dutasteride

Hair follicles in the scalp (especially the front and crown areas) exhibit high levels of AR expression. Testosterone and DHT bind to these receptors, triggering molecular signals that shorten the hair growth cycle. DHT shortens the anagen phase, meaning that hair stops growing sooner and falls out more quickly. Over time, hair follicles produce only vellus hairs, leading to baldness. Finasteride and dutasteride inhibit 5α-reductase enzymes, blocking the conversion of testosterone to dihydrotestosterone (DHT)-a crucial mediator in hair follicle miniaturization. By reducing scalp DHT levels, these drugs can slow hair loss progression and, in some cases, promote regrowth. Finasteride was FDA-approved for male AGA in 1997 (although not approved for women due to potential side effects) and is administered orally. Male AGA patients experience significant hair regrowth, but finasteride is ineffective for autoimmune-related hair loss. Finasteride increased hair density by 10-20% in cases of AGA after one year, and thicker hair shafts were observed in most patients. Over 80% of men maintained their existing hair over a five-year period. Finasteride is more effective than minoxidil for preventing hair loss. Some studies suggest that combining finasteride and minoxidil provides better results than using either treatment alone. Side effects such as erectile dysfunction, reduced libido, and gynecomastia occur in some men and may persist even after stopping therapy. A systematic review suggested that dutasteride (0.5 mg) was more effective than finasteride (1 mg) in increasing hair counts (up to 1.5-fold), but approved in Asian countries. Finasteride inhibits only Type II 5α-reductase, while dutasteride inhibits both Type I and Type II 5α-reductase, making it more potent in reducing DHT levels. Due to its longer half-life, dutasteride provides sustained benefits but also carries a higher risk of side effects.

JAK Inhibitors

Alopecia areata is an autoimmune disorder in which the immune system mistakenly attacks hair follicles, leading to sudden hair loss. JAK inhibitors work by blocking the activity of Janus kinase enzymes, thereby interrupting the inflammatory signaling pathways that contribute to hair follicle miniaturization and loss. Early studies demonstrated that these JAK inhibitors could effectively reverse hair loss in patients with moderate to severe AA. This oral JAK inhibitor has been approved by the FDA for treating severe AA in adults and adolescents. Ruxolitinib and tofacitinib significantly increased hair shaft length, indicating their potential in promoting hair growth. Clinical trials have also shown that baricitinib can lead to substantial hair regrowth, with some patients achieving at least 50% improvement compared to placebo. Deuruxolitinib, a selective JAK1/JAK2 inhibitor, was recently FDA-approved for treating severe AA in adults. Significant scalp hair regrowth was observed in approximately 65-70% of patients treated with deuruxolitinib, with improvements in hair thickness, coverage, and density. Unlike JAK1, which is broadly expressed in many tissues, JAK3 expression is largely restricted to hematopoietic cells. Of interest, selective inhibiting JAK3 signaling by ritlecitinib is sufficient to prevent and reverse AA. 65-70% of patients in clinical trials achieved 50% or more scalp hair regrowth, and improvements in eyebrows and eyelashes were also noted. Although JAK inhibitors have proven beneficial in AA, they are not FDA-approved for AGA and can be costly. Known risks include heightened susceptibility to infections, thrombosis, and cardiovascular events, especially with prolonged use. For example, JAK inhibitors have been associated with an increased risk of deep vein thrombosis and pulmonary embolism, particularly in high-risk patients. Long-term use may slightly elevate the risk of heart attacks and strokes, especially in older patients with pre-existing cardiovascular conditions. Moreover, once patients discontinue therapy, previously regrown hair may be lost again.

Emerging Molecular Targets and Therapies

Recent progress in understanding inflammatory processes, hormonal imbalances, stem cell dysfunction, and immune dysregulation has driven the discovery of novel molecular targets for treating various types of alopecia.

Androgen Receptor Inhibitors (ARIs)

AR inhibitors (ARIs) are pivotal in treating androgen-dependent conditions, notably prostate cancer and AGA. Both systemic and topical ARIs are in development to enhance efficacy and mitigate resistance. Spironolactone, a potassium-sparing diuretic with anti-androgenic properties, is commonly used off-label for AGA and hirsutism. Clascoterone (Breezula®) is a topical AR inhibitor developed by Cassiopea, (San Diego, CA, USA) originally approved as Winlevi® for acne and currently in trials for AGA. Kintor Pharmaceuticals’ pyrilutamide, a nonsteroidal topical ARI, has shown promising preliminary results, including significant increases in hair count. OliX Pharmaceuticals is investigating OLX72021, an RNA interference-based therapy targeting AR for AGA. This approach aims to reduce AR expression, potentially mitigating hair loss. These developments underscore the growing potential of ARIs in hair loss treatment.

Wnt/β-catenin Pathway Modulators

The Wnt/β-catenin pathway is integral to hair follicle development and regeneration, making it a prime target for AGA therapies. Biosplice Therapeutics (formerly Samumed) has developed SM04554, a small-molecule Wnt modulator. JW Pharmaceutical has developed JW0061 (GFRA1 agonist), a first-in-class drug candidate that promotes hair follicle proliferation and hair regeneration by activating the Wnt signaling pathway in skin and hair follicle stem cells. KY19382, a novel CXXC5-Dvl interaction inhibitor, fosters Wnt/β-catenin signaling, thereby enhancing hair regrowth and wound-induced hair neogenesis.

Thyroid Hormone-Based Therapies

Thyroid hormones play a crucial role in regulating metabolism, development, and tissue homeostasis, including hair follicle function. Mice lacking TRα1 and TRβ (the main thyroid hormone binding isoforms) display impaired hair cycling associated to a decrease in follicular hair cell proliferation. In addition, TRα1/TRβ-deficient mice developed alopecia after serial depilation. Thyroid hormone signaling is an important determinant of the mobilization of stem cells out of their niche in the hair bulge. TDM-105795 is a topical small molecule drug candidate developed by Technoderma Medicines for the treatment of AGA. As a potent thyromimetic, it offers potential advantages in efficacy and safety over existing treatments. A Phase 2a clinical trial involving mild to moderate AGA proved efficacy of TDM-105795.

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Prostaglandin Analogs

Prostaglandin (PG) derivatives have been found to influence hair growth in different ways. Specifically, prostaglandin F2α (PGF2α) derivatives promote hair growth, whereas prostaglandin D2 (PGD2) has been shown to inhibit it. For example, PGD2 levels were approximately three times higher in balding scalp areas compared to non-balding regions in men with AGA. Latanoprost and Bimatoprost, originally developed to reduce intraocular pressure in glaucoma treatment, were observed to induce hair growth as a side effect. These compounds stimulate follicular cell proliferation and extend the anagen phase of the hair cycle, leading to increased hair density and length. DLQ01 is a topical prostaglandin F2α analog developed by Dermaliq Therapeutics for the treatment of AGA, and Dermaliq announced positive results from a Phase 1b/2a clinical trial. DLQ01 treatment resulted in a 12.3% increase in hair counts from baseline, and 83% of subjects treated with DLQ01 experienced positive hair growth.

Lactate Dehydrogenase (LDH) Modulators

Recent research has highlighted the role of lactate dehydrogenase (LDH) in hair follicle stem cell (HFSC) activation, offering promising avenues for developing novel hair loss treatments. HFSCs utilize glycolytic metabolism, producing significant amounts of lactate. This lactate production is crucial for HFSC activation, as deleting the enzyme LDH in these cells prevented their activation. Pelage Pharmaceuticals is developing a topical small molecule drug that targets this metabolic pathway. Their approach aims to activate dormant HFSCs by modulating lactate production, thereby stimulating hair growth. Pelage’s treatment is designed to be non-invasive and suitable for all genders, and hair types. They have initiated a Phase 2a clinical trial to evaluate the safety and efficacy of their lead compound, PP405, in individuals with AGA.

Phosphodiesterase 4 (PDE4) Inhibitors

Phosphodiesterase 4 (PDE4) inhibitors are being explored as potential treatments for AA. PDE4 is an enzyme that modulates inflammatory pathways, and its inhibition can reduce inflammation. Apremilast is a well-known PDE4 inhibitor (CC-10004), and recent studies have investigated its efficacy in promoting hair regrowth in patients with AA. For instance, a Japanese patient with AA showed significant hair regrowth after 14 weeks of treatment with apremilast. Apremilast leads to the downregulation of inflammatory cytokines such as TNF-α, IL-17, and IFN-γ, which play a significant role in autoimmune diseases.

Necroptosis Inhibitors

Necroptosis, a programmed form of inflammatory cell death, has been increasingly recognized as a contributing factor to hair follicle dysfunction and hair loss. By inhibiting RIPK1, RIPK3, or MLKL, necroptosis-related damage may be reduced. Necrostatin-1s (Nec1-s) has shown protective effects on human outer root sheath cells and improved hair regrowth in mouse models by limiting follicular inflammation.

Biologics and Stem Cell-Based Therapies

Beyond small-molecule inhibitors, novel therapeutic modalities such as biologics and stem cell-based therapies aim to address hair loss more precisely, potentially improving upon traditional interventions. Beyond efficacy, future efforts must emphasize long-term safety and personalized approaches.

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Antibody Therapies

Antibody-based treatments have emerged as a targeted approach for AA, a condition in which existing immunosuppressants often yield variable results. Antibodies are rarely developed for AGA therapy due to the requirement to be responsive to androgens and their receptors surrounding the hair follicle. However, direct injection into the areas of hair loss is also feasible, potentially enhancing treatment efficacy while minimizing systemic side effects. Dupilumab, initially approved for atopic dermatitis, is under Phase 2 evaluation for AA. Dupilumab is a humanized monoclonal antibody against IL-4Rα that downregulates TH2 response.

The UCLA Connection: Astressin-B and PP405

Astressin-B: An Accidental Discovery

A team led by researchers from UCLA and the Veterans Administration, while investigating how stress affects gastrointestinal function, may have found a chemical compound that induces hair growth by blocking a stress-related hormone associated with hair loss - entirely by accident. The serendipitous discovery is described in an article published in the online journal PLoS One. The research team, which was originally studying brain-gut interactions, included Million Mulugeta, Lixin Wang, Noah Craft and Yvette Taché from UCLA; Jean Rivier and Catherine Rivier from the Salk Institute for Biological Studies in La Jolla, Calif.; and Mary Stenzel-Poore from the Oregon Health and Sciences University.

For their experiments, the researchers had been using mice that were genetically altered to overproduce a stress hormone called corticotrophin-releasing factor, or CRF. As these mice age, they lose hair and eventually become bald on their backs, making them visually distinct from their unaltered counterparts. The Salk Institute researchers had developed the chemical compound, a peptide called astressin-B, and described its ability to block the action of CRF. Stenzel-Poore had created an animal model of chronic stress by altering the mice to overproduce CRF. UCLA and VA researchers injected the astressin-B into the bald mice to observe how its CRF-blocking ability affected gastrointestinal tract function. About three months later, the investigators returned to these mice to conduct further gastrointestinal studies and found they couldn't distinguish them from their unaltered brethren. They had regrown hair on their previously bald backs.

Of particular interest was the short duration of the treatments: Just one shot per day for five consecutive days maintained the effects for up to four months. Whether it also happens in humans remains to be seen, said the researchers, who also treated the bald mice with minoxidil alone, which resulted in mild hair growth, as it does in humans. This suggests that astressin-B could also translate for use in human hair growth. In fact, it is known that the stress-hormone CRF, its receptors and other peptides that modulate these receptors are found in human skin. UCLA and the Salk Institute have applied for a patent on the use of the astressin-B peptide for hair growth.

PP405: Waking Up Dormant Follicles

UCLA scientists have identified a small molecule, PP405, that can awaken long-slumbering but undamaged follicles. In scientific terms, the PP405 molecule is isolated and applied to a protein in the follicle stem cells that keeps the cells dormant. This inhibits the protein, and the stem cells are moved to awaken. Lab work on the molecule has been going on for almost a decade. In the first human trials, researchers found that application of PP405 as a topical medicine onto the scalp at bedtime for a week produced promising results.

The three UCLA scientists behind the breakthrough - William Lowry, professor of molecular, cell and developmental biology; Heather Christofk ’01, professor of biological chemistry; and Michael Jung, distinguished professor of chemistry - are optimistic about the potential of the treatment to reverse pattern hair loss, which affects more than half of all men and one-fourth of all women by the age of 50. Through UCLA’s Technology Transfer Group, which transforms brilliant research into global market products, the scientists have co-founded a medical development company called Pelage Pharmaceuticals. Pelage Pharmaceuticals is developing a topical small molecule drug that targets this metabolic pathway. Their approach aims to activate dormant HFSCs by modulating lactate production, thereby stimulating hair growth. Pelage’s treatment is designed to be non-invasive and suitable for all genders, and hair types. They have initiated a Phase 2a clinical trial to evaluate the safety and efficacy of their lead compound, PP405, in individuals with AGA

Typically, hair toggles through phases of activity and rest, governed by the hair-follicle stem cells. In periods of activity, these cells awaken and regenerate the hair follicle, developing into the different components that make up hair. But when they’re resting, the hair stops growing and eventually falls out. With illness, stress, or an unlucky roll of the genetic dice, these stem cells can become permanently dormant. But Christofk and her collaborator, William Lowry, Ph.D., a stem cell biologist at UCLA, discovered a way to wake them back up.

Lowry and Christofk soon recruited fellow UCLA professor and medicinal chemist, Michael Jung, Ph.D., who helped them design an analog of UK-5099-dubbed PP405, after a major thoroughfare in Southern California. Not only was PP405 better at inhibiting the protein that moved pyruvate into mitochondria, its action was confined to the scalp. This means it’s unlikely to cause side effects, a problem that plagues other drugs that treat hair loss. To date, the drug, applied topically to the scalp, has gone through two clinical trials to test safety. The next target: a trial to test its effectiveness, set to begin next year.

The Future of Hair Loss Treatment

Future drug development for hair loss disorders should prioritize antibody therapy and cell-based treatments, as these approaches offer unprecedented opportunities to address the limitations of existing options. Antibody therapies enable precise targeting of key molecular pathways involved in hair follicle regulation, providing highly specific and effective interventions.

While hair transplantation remains the gold standard-especially for moderate to advanced hair loss, PP405 would likely be most useful in the earliest stages of hair thinning, where follicles are dormant but still salvageable. Dormant follicles are still alive but inactive. Treatments like PP405, minoxidil, or PRP may help stimulate these. Dead follicles are permanently miniaturized or scarred. No medication or topical solution can bring them back. If you already have visible thinning or bald areas, there’s likely a mix of both.

With ongoing research and development efforts, the future of hair loss treatment holds great promise. From accidental discoveries to targeted therapies, scientists are continually working to unlock the secrets of hair growth and develop effective solutions for the millions affected by hair loss worldwide.

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