Targeting Periplakin of Novel Benzenesulfonamides as Highly Selective Agonists for the Treatment of Vitiligo

 

Vitiligo is the most common cause of depigmentation worldwide, with immunosuppressive treatments often being inefficient and prone to recurrence, making it essential to identify new therapeutic targets. Periplakin (PPL) has been identified and confirmed as a key factor in vitiligo-related depigmentation. Based on this, a series of selective PPL agonists, specifically benzenesulfonamides, have been developed. Among these, compound I-3 exhibits superior efficacy compared to ruxolitinib, the only FDA-approved treatment for vitiligo. I-3 has been shown to increase cAMP levels by regulating PPL, which enhances MITF expression, a key transcription factor in melanin biosynthesis. Additionally, I-3 promotes melanin production by regulating tryptophan metabolism. In summary, PPL is a promising drug target, and I-3 has strong potential for future treatment of vitiligo due to its high selectivity and favorable druggability.

source: https://pubs.acs.org/doi/10.1021/acs.jmedchem.4c01717

Chicken models aid understanding of human immune diseases (Vitiligo)

The article on WATTPoultry.com highlights the use of Smyth line chickens, a breed prone to autoimmune diseases like vitiligo, as an important model for understanding human immune diseases. The research led by Professor Gisela Erf at the University of Arkansas explores immune responses by using a non-invasive feather sampling technique. This allows for a detailed study of immune cells in action without harming the animal, making the Smyth line an ethically favorable choice over traditional genetically modified models.

The article delves into the spontaneous development of vitiligo in these chickens, a condition that parallels the human form of the disease. Unlike genetically modified organisms (GMOs), these chickens naturally develop vitiligo, providing a more accurate and ethical model for studying autoimmunity and pigmentation diseases in humans.

Professor Erf's innovative feather sampling method leverages the chicken's feathers as a minimally invasive way to collect skin samples, which are then used to study various immune responses. This approach offers new insights into how immune cells behave in the context of autoimmune diseases and can be crucial for developing therapeutic strategies.

Moreover, the research underscores the need for collaboration between academic research and the poultry industry. The findings have implications not just for understanding human diseases but also for improving poultry health management. The study represents a fusion of animal science and immunology that could benefit both human medical research and agricultural practices.

For more details, visit the full article here.

A Major Breakthrough on the Path to Vitiligo Treatment

 Disorganisation of Basement Membrane Zone Architecture Impairs Melanocyte Residence in Vitiligo

This study investigates the causes of depigmentation in vitiligo patients by examining how disorganisation in the basement membrane zone (BMZ) architecture affects the residency and survival of melanocytes. The BMZ serves as the interface between the epidermis and dermis, maintaining the structural integrity of the skin. Vitiligo is a pigmentation disorder characterized by white patches on the skin, associated with the loss of melanocytes.

Key Findings:

1. Structural Disruptions in the BMZ: Using electron microscopy and immunofluorescence staining, the study observed abnormal BMZ architecture in vitiligo-affected skin samples. In healthy skin, the BMZ has a thin, continuous structure, while vitiliginous skin shows thickened, fragmented, and disorganized BMZ.

2. Role of MMP2: The study identified elevated expression of matrix metalloproteinase 2 (MMP2) in dermal fibroblasts of vitiligo-affected skin. MMP2 degrades key BM components such as collagen IV and laminin, leading to BM disruption and subsequent melanocyte loss.

3. Impaired Melanocyte Adhesion: In vitiligo, melanocyte adhesion to the BM is weakened due to reduced interactions between integrin β1-laminin and discoidin domain receptor 1 (DDR1)-collagen IV. This impaired adhesion results in melanocytes detaching from the BM and migrating to the upper layers of the epidermis.

4. Therapeutic Potential: MMP2 inhibitors were shown to reverse depigmentation in mouse models, indicating that targeting MMP2 could be a potential therapeutic strategy for vitiligo.

Conclusion: The study concludes that melanocyte loss in vitiligo is primarily linked to the disruption of BMZ integrity, largely due to overexpression of MMP2 in dermal fibroblasts. These findings open new avenues for therapeutic interventions to treat this challenging skin condition.

Reference: Yang, F., Yang, L., Kuroda, Y., Lai, S., Takahashi, Y., Sayo, T., Namiki, T., Nakajima, K., Sano, S., Inoue, S., Tsuruta, D., & Katayama, I. (2024). Disorganisation of basement membrane zone architecture impairs melanocyte residence in vitiligo. The Journal of Pathology, 264(1), 30-41. DOI: 10.1002/path.6321.

Antioxidant mechanisms of mesenchymal stem cells and their therapeutic potential in vitiligo

This review article discusses the therapeutic potential of mesenchymal stem cells (MSCs) in treating vitiligo, a skin disorder characterized by the loss of pigmentation due to melanocyte dysfunction. The authors explore the role of oxidative stress and reactive oxygen species (ROS) in the pathogenesis of vitiligo, highlighting how ROS can damage melanocytes and contribute to disease progression.

Traditional treatments for vitiligo, such as glucocorticoid therapy, UV light therapy, and topical calcium-modulated phosphatase inhibitors, have limitations like long treatment durations, side effects, and frequent relapses. In contrast, MSCs offer a promising alternative due to their paracrine effects, which can reduce oxidative stress, promote tissue repair, and suppress autoimmune responses.

The article reviews the mechanisms by which MSCs exert antioxidant effects, focusing on several signaling pathways, including the Nrf2/ARE and PI3K/AKT pathways. These pathways help regulate oxidative stress and support melanocyte survival. MSCs can also transfer healthy mitochondria to damaged cells, improving cellular function and reducing oxidative stress. While MSC-based therapies show potential, further research is needed to clarify their safety, effectiveness, and application in clinical settings.

This overview suggests that MSCs could provide a novel, effective treatment approach for vitiligo by addressing its underlying oxidative stress and immune dysfunction.

Keywords: Vitiligo, oxidative stress, mesenchymal stem cells, reactive oxygen species, antioxidant, melanocyte, paracrine effects.

*Reference: Yang, R.-l., Chen, S.-y., Fu, S.-p., Zhao, D.-z., Wan, W.-h., Yang, K., Lei, W., Yang, Y., Zhang, Q., & Zhang, T. (2023). Antioxidant mechanisms of mesenchymal stem cells and their therapeutic potential in vitiligo. Frontiers in Cell and Developmental Biology, 11, 1293101. doi: 10.3389/fcell.2023.1293101.

A NEW VITILIGO TREATMENT?

 

Ritlecitinib (under the commercial name LITFULO by Pfizer) is an anti-inflammatory and immunosuppressive drug that was recently approved for treatment of severe alopecia areata in the USA and Japan. The drug is being tested for treatment of vitiligo, ulcerative colitis, and Crohn’s disease, all of which are considered auto-immune disorders (Blair, 2023).

HOW DOES RITLECITINIB WORK?

Vitiligo is an auto-immune disorder, meaning that the body’s immune system mistakenly attacks and destroys its own cells – melanocytes (pigment cells), which results in formation of white patches. The immune system is incredibly complex and consists of various pathways and signalling molecules. Ritlecitinib is considered a kinase inhibitor, meaning it prevents kinases, which are certain proteins in the immune system, from working properly. This in turn blocks the immune pathways that are thoughts to contribute to development of auto-immune diseases, resulting in symptom improvements, such as repigmentation or stopping of disease progression in vitiligo (Xu et al., 2019; Pfizer Inc., 2023).

RITLECITINIB AND VITILIGO – A RECENT STUDY

A 48-week long phase 2b clinical trial on the effectiveness of ritlecitinib in vitiligo treatment has been published in February 2023 (Ezzedine et al., 2023). The trial compared patient groups taking various doses of ritlecitinib with a placebo group. The study assessed the changes in the proportion of vitiligo lesions on the face (Facial-Vitiligo Area Scoring Index, F- VASI) and found that a 50 mg tablet taken once daily resulted in significant improvements (up to 75% reduction in F-VASI compared to placebo at 24 weeks). Repigmentation began as early as 8 weeks after the start date, accelerated after 28 weeks, and was observed until 48 weeks when the trial ended. There was another important way to measure the effectiveness of ritlecitinib: the Patient Global Impression of Change-Vitiligo (PGIC-V) score, which is a 1-item questionnaire asking patients to report how much they feel their condition has changed. The responses range from ‘very much improved’ to ‘very much worse’. Patients across all treated groups reported meaningful changes, such as ‘much improved’ or ‘very much improved’ with the greatest proportion of patients reporting such changes at week 48 of the trial. The study also measured the safety of ritlecitinib and found it to be a safe drug with mild side effects, such as cough, sore throat, and headache. The side effects are likely because the drug lowers the immune defences of the body and makes it more prone to infections. Overall, the trial deemed ritlecitinib to be an effective and well-tolerated treatment for patients with active non-segmental vitiligo.

WHAT HAPPENS NOW?

The trial by Ezzedine et al. (2023) was a phase 2b trial, meaning that it tested the efficacy and safety of ritlecitinib in vitiligo in a relatively small patient group. Currently, there is a phase 3 trial underway (NCT05583526; Pfizer, 2023) with an estimated completion date in June 2025. Depending on the results of that trial, ritlecitinib may be approved for vitiligo treatment.

Reference: https://vitiligosociety.org/vitlife/ritlecitinib-a-new-vitiligo-treatment/

YENİ İLAÇ MI GELİYOR?

Ritlecitinib (Pfizer tarafından LITFULO ticari adıyla), yakın zamanda ABD ve Japonya'da şiddetli alopesi areata tedavisi için onaylanan anti-enflamatuar ve immünosupresif bir ilaçtır. İlaç, hepsi oto-immün bozukluklar olarak kabul edilen vitiligo, ülseratif kolit ve Crohn hastalığının tedavisi için test edilmektedir (Blair, 2023).

RITLECITINIB NASIL ÇALIŞIR?

Vitiligo bir oto-immün bozukluktur, yani vücudun bağışıklık sistemi yanlışlıkla kendi hücrelerine - melanositlere (pigment hücreleri) saldırır ve yok eder, bu da beyaz lekelerin oluşmasına neden olur. Bağışıklık sistemi inanılmaz derecede karmaşıktır ve çeşitli yollardan ve sinyal moleküllerinden oluşur. Ritlecitinib bir kinaz inhibitörü olarak kabul edilir, yani bağışıklık sistemindeki belirli proteinler olan kinazların düzgün çalışmasını engeller. Bu da oto-immün hastalıkların gelişimine katkıda bulunduğu düşünülen bağışıklık yollarını bloke ederek, vitiligoda yeniden pigmentasyon veya hastalığın ilerlemesinin durdurulması gibi semptomlarda iyileşme sağlar (Xu ve ark., 2019; Pfizer Inc., 2023).

RITLECITINIB VE VITILIGO - YENI BIR ÇALIŞMA

Vitiligo tedavisinde ritlecitinib'in etkinliğine ilişkin 48 hafta süren faz 2b klinik çalışması Şubat 2023'te yayınlanmıştır (Ezzedine ve ark., 2023). Çalışma, çeşitli dozlarda ritlecitinib alan hasta gruplarını bir plasebo grubu ile karşılaştırmıştır. Çalışma, yüzdeki vitiligo lezyonlarının oranındaki değişiklikleri (Facial-Vitiligo Area Scoring Index, F-VASI) değerlendirmiş ve günde bir kez alınan 50 mg'lık bir tabletin önemli iyileşmelerle sonuçlandığını (24 haftada plaseboya kıyasla F-VASI'de %75'e varan azalma) bulmuştur. Repigmentasyon başlangıç tarihinden 8 hafta sonra başlamış, 28 hafta sonra hızlanmış ve denemenin sona erdiği 48 haftaya kadar gözlenmiştir. Ritlecitinib'in etkinliğini ölçmenin bir başka önemli yolu daha vardı: Hastalardan durumlarının ne kadar değiştiğini hissettiklerini bildirmelerini isteyen 1 maddelik bir anket olan Patient Global Impression of Change-Vitiligo (PGIC-V) skoru. Yanıtlar 'çok iyileşti' ile 'çok kötüleşti' arasında değişmektedir. Tedavi edilen tüm gruplardaki hastalar 'çok iyileşti' veya 'çok iyileşti' gibi anlamlı değişiklikler bildirmişlerdir ve bu tür değişiklikleri bildiren hastaların en yüksek oranı çalışmanın 48. haftasında görülmüştür. Çalışma aynı zamanda ritlecitinib'in güvenliğini de ölçmüş ve öksürük, boğaz ağrısı ve baş ağrısı gibi hafif yan etkileri olan güvenli bir ilaç olduğunu ortaya koymuştur. Yan etkiler muhtemelen ilacın vücudun bağışıklık savunmasını düşürmesi ve enfeksiyonlara daha yatkın hale getirmesi nedeniyle ortaya çıkmıştır. Genel olarak, çalışma ritlecitinib'in aktif non-segmental vitiligo hastaları için etkili ve iyi tolere edilen bir tedavi olduğunu göstermiştir.

ŞİMDİ NE OLACAK?

Ezzedine ve arkadaşları (2023) tarafından yapılan çalışma bir faz 2b çalışmasıydı, yani vitiligoda ritlecitinib'in etkinliğini ve güvenliğini nispeten küçük bir hasta grubunda test etti. Şu anda devam etmekte olan ve tahmini tamamlanma tarihi Haziran 2025 olan bir faz 3 çalışması (NCT05583526; Pfizer, 2023) bulunmaktadır. Bu çalışmanın sonuçlarına bağlı olarak, ritlecitinib vitiligo tedavisi için onaylanabilir.

Reference: https://vitiligosociety.org/vitlife/ritlecitinib-a-new-vitiligo-treatment/