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/

Reduced Mortality Associated With Vitiligo

The chances of mortality could be low for patients with vitiligo, according to a recent study published in the Journal of Investigative Dermatology.

In the population-based cohort study, researchers explored the mortality of vitiligo as there is limited information about the risks of mortality among these patients. The researchers investigated all-cause and cause-specific mortality of patients with vitiligo compared with controls without vitiligo using a nationwide database.

Exploring vitiligo mortality in a national cohort would allow a greater understanding of the burden of the autoimmune disease and lead to a deeper understanding of its nature, the authors of the study claim.

The study included a total of 107,424 patients in Korea with vitiligo and 537,120 matched controls without vitiligo who were observed between 2002 and 2019. The mean age of included patients was ~48 years, and 39.61% were male.

Patients’ medical records were thoroughly analyzed and revealed that individuals with vitiligo experienced significantly reduced risks of mortality across a spectrum of diseases.

Of these findings, the risks associated with infectious, oncologic, hematologic, endocrine, neurologic, cardiovascular, respiratory, and renal/urogenital diseases were markedly lower in patients with vitiligo, the study revealed.

Previous studies have highlighted the co-occurrence of vitiligo with various autoimmune diseases, pointing to shared genetic alterations involved in immune activation and regulation. Specific immune responses have been identified as contributors to melanocyte destruction, authors shared.

What sets this study apart is that vitiligo seems to present a protective effect against mortality, particularly when it comes to infections, inflammation, and cancers.

Researchers suggest that the role of autophagy in vitiligo, a self-degradation process that regulates cellular homeostasis, could also relate to their findings.

Previous studies suggest that increased expression of autophagy markers in vitiligo skin may play a protective role against metabolic stress and external degenerative processes. In addition, autophagy's regulation of the innate immune system could provide defenses against viral infections.

The study also aligns with prior research indicating a reduced risk of malignancies in patients with vitiligo. In fact, the risk of internal malignancies, including cancers of the colon, rectum, ovary, and lung, was significantly decreased in individuals with vitiligo. The findings suggest that vitiligo may provide a form of immunity against cancer development.

Additionally, the study considers the role of treatments for vitiligo in contributing to reduced mortality. While there is no drug specifically approved for vitiligo, treatments such as phototherapy could have broader health implications.

For example, studies have suggested that ultraviolet B radiation, a component of phototherapy, may influence internal organs beyond the skin, offering benefits such as reducing the risk of atherosclerosis and improving blood pressure, the study mentioned.

However, there are certain limitations to the study which include the absence of information on disease severity and subtypes of vitiligo, potential unmeasured factors, and not having different populations observed.

The authors of the study believe the findings contribute toward the mortality risks associated with vitiligo, challenging previous beliefs about the outcomes of autoimmune conditions.

They added the unexpected protective effects observed in vitiligo patients open avenues for further research to unravel the underlying mechanisms and potential implications for patient management.

Reference

1. Ju HJ, Kang H, Han JH, Lee JH, Lee S, Bae JM. All-cause and cause-specific mortality among patients with vitiligo: a nationwide population-based study in Korea. J Invest Dermatol. 2023;S0022-202X(23)02481-8. doi:10.1016/j.jid.2023.07.007

Vitiligolularda Ölüm Riski Daha Düşük!

Kore'de yayınlanan yakın tarihli bir araştırmaya göre, vitiligolu hastalarda ölüm şansı düşük olabilir.

Nüfusa dayalı kohort çalışmasında, bu hastalar arasındaki ölüm riskleri hakkında sınırlı bilgi olduğundan araştırmacılar vitiligonun ölüm oranını araştırdı. Araştırmacılar, ülke çapında bir veri tabanı kullanarak vitiligolu hastaların tüm nedenlere ve nedene özel ölümlerini, vitiligosuz kontrollerle karşılaştırarak araştırdılar.

Çalışmanın yazarları, ulusal bir kohortta vitiligo mortalitesinin araştırılmasının, otoimmün hastalığın yükünün daha iyi anlaşılmasına olanak sağlayacağını ve doğasının daha iyi anlaşılmasına yol açacağını iddia ediyor.

Çalışmaya Kore'de 2002 ile 2019 yılları arasında gözlemlenen vitiligolu toplam 107.424 hasta ve vitiligosuz 537.120 eşleştirilmiş kontrol dahil edildi. Dahil edilen hastaların ortalama yaşı ~48 idi ve %39,61'i erkekti.

Hastaların tıbbi kayıtları kapsamlı bir şekilde analiz edildi ve vitiligosu olan bireylerin çeşitli hastalıklarda ölüm risklerinin önemli ölçüde azaldığını ortaya çıkardı.

Çalışma, bu bulgulardan enfeksiyöz, onkolojik, hematolojik, endokrin, nörolojik, kardiyovasküler, solunum ve böbrek/ürogenital hastalıklarla ilişkili risklerin vitiligo hastalarında belirgin şekilde daha düşük olduğunu ortaya çıkardı.

Önceki çalışmalar, vitiligonun çeşitli otoimmün hastalıklarla birlikte ortaya çıktığını vurgulamış ve bağışıklık aktivasyonu ve düzenlenmesinde yer alan ortak genetik değişikliklere işaret etmiştir. Yazarlar, melanosit yıkımına katkıda bulunanlar olarak spesifik bağışıklık tepkilerinin tanımlandığını paylaştı.

Bu çalışmayı farklı kılan şey, vitiligo'nun özellikle enfeksiyonlar, iltihaplanma ve kanserler söz konusu olduğunda ölüm oranlarına karşı koruyucu bir etki göstermesidir.

Araştırmacılar, hücresel homeostazı düzenleyen bir kendi kendine bozulma süreci olan vitiligodaki otofajinin rolünün de bulgularıyla ilişkili olabileceğini öne sürüyorlar.

Önceki çalışmalar, vitiligo derisinde artan otofaji belirteçlerinin ekspresyonunun, metabolik strese ve dış dejeneratif süreçlere karşı koruyucu bir rol oynayabileceğini öne sürüyor. Ayrıca otofajinin doğuştan gelen bağışıklık sistemini düzenlemesi viral enfeksiyonlara karşı savunma sağlayabilir.

Çalışma aynı zamanda vitiligosu olan hastalarda malignite riskinin azaldığını gösteren önceki araştırmalarla da uyumludur. Aslında vitiligosu olan kişilerde kolon, rektum, yumurtalık ve akciğer kanserleri de dahil olmak üzere iç malignitelerin riski önemli ölçüde azalmıştır. Bulgular vitiligo'nun kanser gelişimine karşı bir tür bağışıklık sağlayabileceğini düşündürmektedir.

Ek olarak, çalışma vitiligo tedavilerinin mortalitenin azaltılmasına katkı sağlamadaki rolünü de değerlendirmektedir. Vitiligo için özel olarak onaylanmış bir ilaç bulunmamakla birlikte, fototerapi gibi tedavilerin sağlık üzerinde daha geniş etkileri olabilir.

Örneğin çalışmalar, fototerapinin bir bileşeni olan ultraviyole B radyasyonunun derinin ötesindeki iç organları etkileyebileceğini, ateroskleroz riskini azaltmak ve kan basıncını iyileştirmek gibi faydalar sağlayabileceğini ileri sürdü.

Ancak çalışmanın, hastalığın ciddiyeti ve vitiligo alt tipleri hakkında bilgi bulunmaması, potansiyel ölçülemeyen faktörler ve farklı popülasyonların gözlemlenmemesi gibi bazı sınırlamaları vardır.

Araştırmanın yazarları, bulguların vitiligo ile ilişkili ölüm risklerine katkıda bulunduğunu ve otoimmün durumların sonuçları hakkındaki önceki inançları çürüttüğüne inanıyor.

Vitiligo hastalarında gözlemlenen beklenmedik koruyucu etkilerin, altta yatan mekanizmaların ve hasta yönetimine yönelik potansiyel sonuçların ortaya çıkarılması için daha fazla araştırmaya açık yollar olduğunu eklediler.

Referans

1. Ju HJ, Kang H, Han JH, Lee JH, Lee S, Bae JM. All-cause and cause-specific mortality among patients with vitiligo: a nationwide population-based study in Korea. J Invest Dermatol. 2023;S0022-202X(23)02481-8. doi:10.1016/j.jid.2023.07.007

Newly Discovered Genes Could Change Vitiligo Treatment

 

A recent study has revealed 135 previously unknown genes that play important roles in regulating melanin production in humans—and that could lead to melanin-modifying drugs for vitiligo and other pigmentation diseases.

The research team was led by Vivek Bajpai, assistant professor in the School of Sustainable Chemical, Biological and Materials Engineering at the University of Oklahoma, with collaborators from Stanford University, where Bajpai did postdoctoral work.

Melanin synthesis is compartmentalized within the melanosome, in specialized pigment cells (melanocytes). The synthesis of melanin within the melanosomes varies, which is why human skin, hair, and eye color vary. Pigmentation-related diseases are associated with disruptions in melanogenesis.

Melanin’s particular physicochemical properties, such as high refractive index, determine its optical properties, the researchers wrote in their article, published in Science on Aug. 11. “We reasoned that an accumulation of melanin within melanosomes would change melanocytes’ light-scattering properties.”

Bajpai developed a novel method to detect and quantify the melanin-producing activity of melanocytes: Passing light through the melanocytes, he could record whether the light was absorbed or scattered by the melanin. “If there are a lot of melanin-producing melanosomes,” he said in a University of Oklahoma press release, “the light will scatter much more than in cells with little melanin.”

The team measured light scattering through flow cytometry, capturing “dynamic shifts” in melanin levels within melanosomes. They used CRISPR-Cas9 technology to genetically engineer cells, and conducted a genome-wide genetic screen, systematically removing more than 20,000 genes from hundreds of millions of melanocytes.

Their screen identified 169 genes, including some that were previously known and 135 new melanin-promoting genes whose deletion was associated with reduced light scattering—in other words, loss of melanin.

The melanin-promoting genes are involved in diverse biological pathways, such as transcription regulation, RNA processing, and endosomal transport, the researchers say. “Consistent with their melanin-promoting role, the expression of the majority of our screen hits is elevated in darkly pigmented, compared with lightly pigmented, human melanocytes. Our analyses revealed that select melanin-promoting genes are associated with skin color variation and show evidence of local adaptation in human populations.”

By focusing on specific previously unidentified candidates, the researchers say, “we implicated a new cargo recycling pathway in melanosome function and identified a transcription factor involved in melanosome maturation. Our work provides a rich resource for further studies of melanogenesis and its relationship with skin color variation and human diseases.”

Their findings are also meaningful to a broad swath of science beyond dermatology. Bajpai’s method of targeting melanin-producing genes could lead to prevention of fungi- and bacteria-related diseases in humans and crops.

Reference: https://www.managedhealthcareexecutive.com/view/newly-discovered-genes-could-change-vitiligo-treatment