LEF1

A research team embarked on a quest to understand the diversity and cellular mechanisms of human Th2 cells. By conducting gene expression analyses of inflamed tissues, they pinpointed a subset of Th2 cells called Th2-MPP cells. Their findings suggested that these cells might serve as precursors to several crucial Th2 cell populations responsible for disease symptoms. These discoveries lay the groundwork for therapeutic interventions targeting these cells, potentially offering relief to patients living with allergic diseases. Currently, most therapies for allergic diseases require lifelong treatment. Allergic reactions, characterized by ongoing (type 2) inflammation in response to chronic antigen exposure, underlie many chronic diseases in humans, including asthma, atopic dermatitis, ulcerative colitis and more. T helper 2 (Th2) cells play an important role in the body's immune response, particularly in allergic reactions. Despite their central role, the sustained activity of Th2 cells during allergic reactions, even in the face of constant antigen exposure, has long puzzled researchers. A research team that included authors from Mass General Brigham, including members Brigham and Women's Hospital, Massachusetts General Hospital, and Mass Eye and Ear, embarked on a quest to understand the diversity and cellular mechanisms of human Th2 cells. By conducting gene expression analyses of inflamed tissues, they pinpointed a subset of Th2 cells called Th2-MPP cells. Their findings suggested that these cells might serve as precursors to several crucial Th2 cell populations responsible for disease symptoms. These discoveries lay the groundwork for therapeutic interventions targeting these cells, potentially offering relief to patients living with allergic diseases. Results are published in Nature Immunology. The research team created a single cell transcriptomic atlas, a comprehensive database of genes that are turned "on" and "off" in individual cells in the body, using inflamed tissues from patients with nine different chronic allergic diseases. They used this atlas to identify Th2-multipotent progenitor (Th2-MPP) cells, which chronically expressed two transcription factors, TCF7 and LEF1. These transcription factors allowed Th2-MPP cells to exhibit characteristics similar to stem cells in cancer and chronic infection, acting as progenitor cells that can give rise to other kinds of cells. The team also performed detailed studies on Th2 cells from nasal tissue in patients with chronic rhinosinusitis. They found that Th2-MPP cells could be the precursor for multiple types of Th2 cells that cause disease symptoms. "We still have much to learn about the contribution of progenitor cells to chronic human inflammation, but we are hopeful that the study of this area of immunity could provide opportunities for future disease-modifying therapeutic approaches," said senior author Patrick Brennan, MD, PhD, a physician-researcher in the Brigham Division of Allergy and Clinical Immunology. "Our work suggests that Th2-MPP cells have the potential to sustain type 2 inflammation in the face of chronic antigen exposure and lays the foundation for further investigation to better understand their contribution to disease," said lead author Radomir Kratchmarov, MD, a research fellow in the Brigham Division of Allergy and Clinical Immunology.

VYN201 demonstrated positive effect on key biomarkers relevant to vitiligo Data supports VYN201’s rapid onset of action and previously announced positive clinical results Program is on track for Phase 2b initiation in Q2 Jan. 10, 2024 (GLOBE NEWSWIRE) -- VYNE Therapeutics Inc. (Nasdaq: VYNE) (“VYNE” or the “Company”), a clinical-stage biopharmaceutical company developing proprietary, innovative and differentiated therapies for the treatment of immuno-inflammatory conditions, today announced new biomarker data from the previously completed Phase 1b trial in patients with nonsegmental vitiligo. The data show that BET inhibitor, VYN201, had a positive effect on multiple disease-associated biomarkers. Positive clinical data from the Phase 1b trial were announced in October 2023. The trial was a 16-week open-label study assessing the safety, tolerability, pharmacokinetics, and exploratory efficacy of once-daily topical VYN201 in 29 patients with a clinical diagnosis of active nonsegmental vitiligo, in three dose cohorts (0.5%, 1.0% and 2.0% strengths). Enrolled subjects had two, non-facial active vitiligo lesions. One lesion, selected for treatment with VYN201, had skin tissue biopsies taken prior to first application of VYN201 and after 8 weeks of treatment. Biopsies were analyzed to quantify the effect of VYN201 on specific biomarkers related to inflammation associated with vitiligo, melanocyte proliferation, and melanogenesis. Exploratory data from the 1.0% and 2.0% cohorts showed that VYN201 treatment demonstrated biological activity and a positive effect on certain key biomarkers relevant to vitiligo disease severity and progression. The magnitude of biomarker modulation was more pronounced in the 2.0% dose cohort than in the 1.0% dose cohort, indicative of an emerging dose-response. Results from the biomarker analyses include the following: Downregulation of Matrix metalloproteinase-9 (MMP-9) levels: VYN201 induced the downregulation of MMP-9 in biopsied lesional skin after 8 weeks of treatment compared to baseline. MMP-9 is an inflammatory biomarker associated with the detachment and subsequent loss of melanocytes from skin in vitiligo and is elevated in patients with vitiligo. At Week 8, there was a median reduction in MMP-9 of 40.8% in lesional skin compared to baseline for subjects in the 2.0% cohort. Upregulation of melanocyte-related transcription factors (MRTFs): VYN201 induced the upregulation of multiple MRTFs, including SRY-box transcription factor 10 (SOX10), Lymphoid-enhancing factor-1 (LEF1), β-Catenin and Microphthalmia associated transcription factor (MITF), after 8 weeks of treatment compared to baseline. Each of these markers are linked to the proliferation of melanocytes, recovery in melanogenesis, and subsequent re-pigmentation of skin. In the 2.0% cohort, SOX10, LEF1, β-Catenin and MITF transcription factors had median increases of 36.1%, 90.2%, 16.5% and 15.2% in their respective expression levels in lesional skin compared to baseline. “VYN201’s potential to reduce melanocyte detachment by downregulating MMP-9 and by upregulating the expression of proteins relevant to melanocyte proliferation and melanogenesis is promising, and I look forward to the continued advancement of VYN201 as a potential differentiated therapy for vitiligo,” said Amit Pandya, M.D., former President of the Global Vitiligo Foundation and Dermatologist, Department of Dermatology, Palo Alto Foundation Medical Group. “We are encouraged by these new biomarker data from the Phase 1b trial for VYN201, building on our recently announced positive clinical results,” said David Domzalski, President and CEO of VYNE. “We’ve made considerable progress in advancing this program, and we look forward to initiating a Phase 2b trial evaluating VYN201 in patients with both active and stable nonsegmental vitiligo in the second quarter of this year.” The loss of functional melanocytes in vitiligo is associated with the generation of inflammatory mediators that facilitate melanocyte detachment in skin.1 This cellular detachment occurs due to the disrupted surface distribution of adhesion molecule E-cadherin and the release of soluble E-cadherin.2 E-cadherin cleavage may be induced by several metalloproteinases including MMP-9. MMP-9 is secreted by the keratinocytes in response to various proinflammatory cytokines such as IFN-γ and TNF-α.3 The Wnt/β-catenin pathway plays an essential role in pigmentation by regulating both melanocyte differentiation and melanogenesis through the action of MITF.4 β-catenin is increased by the binding of Wnt proteins to their receptors, leading to transport of β-catenin into the nucleus, where it regulates transcription of MITF through interactions with several transcription factors that include LEF1 and SOX10. MITF also regulates transcription of downstream genes key for melanin synthesis and melanocyte cell development. Vitiligo is a chronic autoimmune depigmenting disorder of the skin, characterized by the loss of pigment producing cells known as melanocytes. Vitiligo is the most common depigmenting skin condition, with a prevalence estimated at 0.5-2.0% of the world population.5 There is currently only one FDA-approved product for the treatment of vitiligo. Nonsegmental vitiligo is the most common type of vitiligo. VYN201 is a pan-bromodomain BET inhibitor designed to be locally-administered as a “soft” drug to address diseases involving multiple, diverse inflammatory cell signaling pathways while providing low systemic exposure. To date, VYN201 has produced consistent reductions in pro-inflammatory and disease-related biomarkers and improvements in disease severity, and demonstrated local activity in several preclinical models (using several different routes of administration). BET proteins play a key role in regulating gene transcription via epigenetic interactions (“reading”), and recent research has determined a key role for these proteins in regulating B cell and T cell activation and subsequent inflammatory processes. As epigenetic readers, BET proteins regulate the recruitment of transcriptional factors that are key to the production of several pro-inflammatory cytokines. BET inhibitors have the potential to treat a range of immuno-inflammatory and fibrotic diseases by blocking pro-inflammatory cytokine transcription with additional potential in myeloproliferative neoplastic disorders. 1. Picardo, M. et al. Nat. Rev. Dis. Primer 1, 15011 (2015). 2. Delmas, V. & Larue, L. Exp. Dermatol. 28, 662–666 (2019). 3. Boukhedouni, N. et al. JCI Insight 5, 133772 (2020). 4. Zhao SJ et al, Clin Cosmet Investig Dermatol. Sep 1;14:1089-11031 (2021). 5. Rosmarin et al, Lancet (2020);396:110-120. VYNE’s mission is to improve the lives of patients by developing proprietary, innovative and differentiated therapies for the treatment of immuno-inflammatory conditions. The Company’s unique and proprietary bromodomain & extra-terminal (BET) domain inhibitors, which comprise its InhiBET™ platform, include a locally administered pan-BD BET inhibitor (VYN201) and an orally available BD2-selective BET inhibitor (VYN202) that were licensed from Tay Therapeutics Limited. 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Researchers have discovered key insights into the molecular basis of skin color variations among African populations. Their findings broaden the understanding of human evolution and the genetics underpinning contemporary human skin color diversity. Researchers from the University of Pennsylvania have discovered key insights into the molecular basis of skin color variations among African populations. Their findings, published in Nature Genetics, broaden the understanding of human evolution and the genetics underpinning contemporary human skin color diversity. "Despite the abundant genetic diversity within African populations, they have been historically underrepresented in genetic studies," says senior author Sarah Tishkoff, a Penn Integrates Knowledge University Professor with appointments in the Perelman School of Medicine and School of Arts & Sciences. "Our findings offer novel information about the genetic basis and evolutionary history of skin color diversity, contributing to a clearer depiction of human evolution." The story of human evolution is as rich and diverse as the adaptations found across the world's populations, Tishkoff says. She notes that, among many adaptive traits, skin color stands out as one of the most well-known. Darker skin tones, prevalent in equatorial regions, serve as nature's very own sunblock, evolving over millennia to shield these populations from the sun's intense ultraviolet radiation. Conversely, lighter pigmentation, as seen in populations closer to the poles, is an adaptation to mitigate the risks of insufficient sun exposure by maximizing vitamin D production, which is triggered by UV exposure. "Our approach involved genome-wide association studies of skin color from more than 1,500 eastern and southern African individuals as well as scanning the genome to identify genetic variants that are highly differentiated between lightly-pigmented Khoesan-speaking San population and other darkly pigmented Africans and may play a role in local adaptation in that population," says Yuanqing Feng, first author of the paper and a postdoctoral researcher in the Tishkoff Lab. The researchers note that pigmentation is a complex trait influenced by hundreds of variants scattered across the genome, with the majority situated in noncoding regions. These noncoding variants may affect the expression of genes located up to one million bases away. The vast number of mutations associated with skin color and the uncertainty surrounding the target genes regulated by these mutations make it particularly arduous for researchers to find the precise genetic mechanisms governing this trait. Feng and collaborators used massively parallel reporter assays to discern the regulatory activities of thousands of variants. This high-throughput technique narrowed down the thousands of candidates to 165 functional variants. To identify the target genes of these functional variants, Feng further constructed high-resolution chromatin interaction maps in melanocytic cells using chromatin conformation capture assays. "This is a high-resolution 3D genome map in melanoma cells that will be valuable for gene regulation studies in pigmentation and melanoma biology," Feng says. Using CRISPR/Cas9-based genome editing, the researchers discovered that mutations in an enhancer of OCA2, a gene associated with albinism, could lead to a 75% reduction in melanin levels when compared to control cells. Within the same OCA2 enhancer, the researchers identified two closely located regulatory variants, estimated to be 1.2 million years old and 57 thousand years old, with the latter coinciding with the period of human migration from Africa. "This case illustrates the continuous evolution of human skin color, and it's remarkable to observe the significant effects on skin pigmentation attributed to a single enhancer," Feng says. San people have relatively lighter pigmentation compared to other African populations and possess the oldest genetic lineages in humans. While it is hypothesized that the light skin color of the San may result from adaptation to a southern African environment, the genetic underpinnings of this adaptation remain elusive. The researchers pinpointed several crucial regulatory variants near MITF, LEF1, and TRPS1 that contribute to the skin color adaptation observed in the San. "MITF, LEF1, and TRPS1 are involved in signaling pathways regulating both melanocyte differentiation and hair development," Tishkoff says. "This suggests that the variants influencing the lighter skin pigmentation observed in the San people may also contribute to their distinctive hair morphology." Notably, the variant near TRPS1 associated with lighter skin color is at nearly 100% frequency in the San and in most non-Africans, whereas the variant associated with darker skin color is common in most other African populations and in the darkly pigmented Melanesian population, a striking example of global adaptations to UV exposure." Additionally, the researchers found a novel gene impacting human skin pigmentation, CYB561A3, which regulates iron homeostasis and influences melanin levels in melanocytic cells. "To our knowledge, the role of CYB561A3 in skin pigmentation has not been reported before. Intriguingly, there have been reports linking intravenous iron infusion to skin hyperpigmentation. Given that CYB561A3 encodes an iron reductase, I am curious about the role of this protein in this process," Tishkoff says. "Our findings underscore the complexity of genetic factors influencing skin color and the benefits of including ethnically diverse and underrepresented populations in genetic studies," she says. "Conducting functional studies on the impact of noncoding variants will enhance our comprehension of the genetics underlying complex human traits and disease risk." "The populations included in this study are from remote regions of Africa and required the use of a mobile lab set up in the field sites," Tishkoff says. "The collaboration with our partners in Africa was key to the success of this research project." In future research, the Tishkoff lab would like to use its innovative functional genomics approach to identify more genetic variants contributing to human pigmentation and other adaptive traits in a larger sample of ethnically diverse Africans. Sarah Tishkoff is the David and Lyn Silfen University Professor in Genetics and Biology and a Penn Integrates Knowledge University Professor with appointments in the Perelman School of Medicine's Department of Genetics and Department of Medicine and in the School of Arts & Sciences' Department of Biology at the University of Pennsylvania. Yuanqing Feng is a postdoctoral fellow in the Tishkoff lab at Penn. Other authors include Ning Xie, Chao Zhang, Fang Zhang, and Matthew E.B. Hansen of Penn; Fumitaka Inoue of Kyoto University; Shaohua Fan of Fudan University; Thomas Nyambo of Hubert Kairuki Memorial University; Sununguko Wata Mpoloka and Gaonyadiwe George Mokone of the University of Botswana; Charles Fokunang and Alfred K. Njamnshi of the University of Yaoundé; Gurja Belay of Addis Ababa University; Michael S. Marks of the Children's Hospital of Philadelphia Research Institute; Elena Oancea of Brown University; and Nadav Ahituv of the University of California, San Francisco. This research was supported by the National Institutes of Health (grants R35GM134957-01, 3UM1HG009408-02S1, 1R01GM113657-01, 5R01AR076241-02, and 1S10OD010786-01) and the Penn Skin Biology and Disease Resource-based Center (Grant NIH P30-AR069589).