Lila Sciences

Psoriasis is an immune-mediated inflammatory disease (IMID) impacting more than 40 million people globally and characterized by skin plaques, elevated systemic levels of inflammatory cytokines, and psychosocial burden. Many patients remain undertreated. Available topical and oral treatments are typically less effective than biologic therapies and have safety considerations that may limit long-term use. Tyrosine kinase 2 (TYK2), a Janus kinase (JAK) enzyme, is a validated target in psoriasis and is also being investigated for other IMIDs. TYK2 mediates signaling of interleukin (IL)-23 and IL-17, central proinflammatory cytokines whose dysregulation contributes to chronic inflammation associated with psoriasis, and IL-12 and type I interferons (IFNs). Therefore, selective inhibition of TYK2 offers more targeted immunomodulation vs. broader immunosuppression associated with JAK 1/2/3 inhibition. Envudeucitinib (formerly ESK-001) is a next-generation, oral, allosteric TYK2 inhibitor under investigation for the treatment of psoriasis and systemic lupus erythematosus. Envudeucitinib selectively binds to the unique regulatory domain (JAK homology 2 [JH2]) of TYK2 to induce a conformational change that prevents ATP from binding the catalytic domain (JAK homology 1 [JH1]), thereby inactivating TYK2. This approach avoids adverse events associated with classic JAK inhibition. In preclinical and phase 1 studies, oral administration of envudeucitinib twice daily achieved maximal (90% inhibitory concentration [IC90]) TYK2 inhibition over 24 h, highlighting a level of sustained target engagement that distinguishes envudeucitinib from other oral immunomodulators. Envudeucitinib decreased type I IFN gene signatures in whole blood and pSTAT1 in T cells. These findings were corroborated in a phase 2 study in adults with moderate-to-severe plaque psoriasis; envudeucitinib showed maximal TYK2 inhibition at higher doses (40-80 mg daily), patients demonstrated significant and increasing efficacy responses through week 52, and the safety profile was favorable. The efficacy and safety of envudeucitinib are being further evaluated in the ongoing phase 3 ONWARD studies. Psoriasis, an inflammatory disease that develops when the immune system is overactive in the skin, impacts more than 40 million people globally. Patients with psoriasis have red, scaly, itchy skin plaques and high levels of inflammatory molecules in the blood. Many patients do not receive adequate treatment, highlighting the need for more effective and safer oral therapies. We describe how a new potential oral medicine for psoriasis, envudeucitinib, works. Envudeucitinib targets the tyrosine kinase 2 (TYK2) protein that is involved in the inflammation process associated with psoriasis. When taken twice daily, envudeucitinib achieved strong and sustained inhibition of TYK2 for a full 24 h, which is a distinguishing feature of this therapy. Selective reduction of TYK2 activity, while avoiding effects on other related proteins, may allow for more targeted adjustment of inflammatory signaling associated with psoriasis and may translate to clinical benefit. In early studies, envudeucitinib taken orally twice daily markedly reduced TYK2 activity and the levels of other inflammatory molecules over a 24-h period. These findings were confirmed in a phase 2 study in patients with psoriasis, where envudeucitinib again reduced TYK2 activity. Patients with psoriasis taking envudeucitinib had significant improvements in their skin after 12 weeks of treatment, and these improvements were sustained or continued to improve through 52 weeks of treatment without notable side effects. In summary, envudeucitinib is a new potential oral medication for psoriasis that reduces inflammation with an acceptable safety profile.

To analyze the association between the IRF5 gene variants rs3807135, rs3757385, and rs3778754 and mRNA expression levels in patients from western Mexico diagnosed with melanoma. An analytical cross-sectional study was conducted including 374 individuals (153 patients with newly diagnosed melanoma and no previous treatment, and 221 controls). The melanoma group was matched to the reference group. Genotyping of the rs3807135 (T>C), rs3757385 (T>G), and rs3778754 (C>G) variants was performed using the allelic discrimination method with TaqMan® probes. Relative mRNA expression was quantified by qPCR using the 2-ΔΔCT method, comparing IRF5 expression levels with those of the housekeeping gene GAPDH. Statistical analyses were performed in R, and allelic and genotypic frequencies were compared between patients and controls using the Chi-square test. No statistically significant associations were identified between IRF5 SNVs rs3807135, rs3757385, and rs3778754 and melanoma risk. The haplotypic pattern comprised TTC, CGG, and CGC, with CGG showing a non-significant protective tendency. The mean relative expression of IRF5 was lower in melanoma patients compared with controls (≈0.39 vs. 1.0; Δ = 0.61), although this difference did not reach statistical significance (U = 1725; p = 0.841). These findings suggest a modest modulatory effect of IRF5 at the haplotypic level, likely driven by combined variant effects. In conclusion, the present study did not identify statistically significant associations between the IRF5 single-nucleotide variants rs3807135, rs3757385, and rs3778754 and melanoma risk in the analyzed population from western Mexico. Likewise, no significant differences in allele or genotype distributions were observed between melanoma patients and control individuals. These findings suggest that the evaluated IRF5 genetic variants do not constitute major susceptibility factors for melanoma in this cohort.

Background: T-LAK cell-originated protein kinase (TOPK), a serine/threonine kinase, is aberrantly overexpressed in human tumors and promotes malignant proliferation. Melanoma is a highly immunogenic tumor in which CD8+ T cell-mediated cytotoxicity is usually less effective in tumor control and responsive to immune checkpoint blockade. It is unclear whether the expression and functional characterization of TOPK within the immune cells affect the tumor microenvironment (TME) in patients with melanoma. This study aims to elucidate the expression pattern and immunoregulatory function of TOPK in CD8+ T lymphocytes during antitumor responses. Methods: Public single-cell RNA-sequencing (scRNA-seq) dataset analysis and flow cytometry assessed TOPK in tumor-infiltrating CD8+ T cells from patients with melanoma. Genetic deletion and pharmacological inhibition of TOPK using HI-TOPK-032 tested T cell-mediated melanoma control. Flow cytometry and tumor cell coculture killing assays measured effector release and target-cell apoptosis. Mechanistic analyses included assessment of interferon regulatory factor 5 (IRF5) expression, together with combination therapy using a programmed cell death protein 1 (PD-1)-blocking antibody in vivo. scRNA-seq of tumor-infiltrating lymphocytes (TILs) from Topk fl/fl and Cd8 Cre Topk fl/fl mice was also performed to define TOPK-dependent immune programs within the melanoma TME. Results: Single-cell transcriptomes identified a TOPK+ subset of tumor-infiltrating CD8+ T cells in melanoma, which was higher than that in normal lymph nodes (LNs), and exhibited suppressed cytotoxic and cytokine programs. CD8+ T cell-specific Topk deletion increased granzyme B (GzmB), tumor necrosis factor-α (TNF-α), and interferon-γ (IFN-γ) secretion and improved tumor control. TOPK-deficient CD8+ T cells showed elevated activation-associated signaling pathways and immune effector gene expression. In murine TIL scRNA-seq, Cd8 Cre Topk fl/fl tumors exhibited increased effector and activation programs, reduced exhaustion and dysfunction programs, and enhanced immune crosstalk in the TME. Mechanistically, TOPK suppressed IRF5 expression and HI-TOPK-032 restored CD8+ T cell cytotoxicity in vitro and, with anti-PD-1, further inhibited tumor growth and increased intratumoral cytokine production. In human CD8+ T cells, enforced TOPK expression impaired cytotoxicity and cytokine secretion, reversed by IRF5 coexpression. Conclusions: These findings establish TOPK as the immune checkpoint limiting CD8+ T cell functionality in tumors and indicate the potential of TOPK inhibition as a strategy to augment T cell-based immunotherapies.

To define and systematically characterize the human E3 ubiquitin ligase (E3) landscape, we generated the E3-ome, a compendium of E3s encoded by the human genome. The E3-ome integrates experimental data, bioinformatics, and published research, revealing 672 high-confidence E3s. We standardized E3 classifications to create a unified framework for annotation and comparative analysis. The E3-ome identified several previously unrecognized domains, motifs, E3 candidates, and relationships, expanding the diversity of E3s. Furthermore, the E3-ome mapped the spatial and physiological organization of E3s across human tissues and cell types, revealing context-dependent E3s. Genetic analyses identified disease-associated variants across the E3-ome, linking E3s to diverse human pathologies. Together, these analyses define the human E3 landscape at high resolution and deliver a foundational resource to drive mechanistic and therapeutic discovery.

Previous bibliometric analyses focus on primary specialty, potentially overlooking authors whose contributions span multiple disciplines. Given the increasing recognition of dysregulated immunological processes in dermatological conditions and the targeting of immune pathways in therapeutics, this study aims to evaluate the h-index of authors in both dermatology and immunology, capturing the multifaceted research landscape of dermatology and providing a comprehensive assessment of scholarly impact. A search of the Web of Science (WOS) schema from 1980 to 2024 was conducted using the InCites dataset, limited to original articles, editorial materials, and meeting abstracts, and authors were ranked by InCites h-index. Over the past 5 years, the top 20 authors by InCites h-index in dermatology and immunology research were 65% males and 35% females, with USA (30%), Germany (20%), and France (15%) representing the highest proportions of authors. The trends across decades showed increased representation of female authors, presence of institutions outside the United States, and cross-disciplinary productivity in dermatology and immunology. The cross-disciplinary associations in dermatology underscore the utility of the h-index in assessing scholarly impact across multiple fields. The observed growth in interdisciplinary productivity and global representation among leading authors reflects translational research exploring immune pathways and molecular profiles that have driven the advancement and translational revolution of immunology-based therapies in dermatology.

The concept of a therapeutic window of opportunity, defined as the period from symptom onset during which treatment initiation yields the most favorable patient outcomes, is applied in routine clinical practice across a range of inflammatory conditions. It has become an increasingly important area of interest in hidradenitis suppurativa (HS), a disease in which recurrent inflammation and accumulating damage can lead to irreversible destruction of skin architecture. Biologic therapies, aiming to suppress the inflammatory burden and prevent disease progression, are currently only permitted in moderate to severe HS. However, as there is no consensus definition of moderate disease, physicians may face uncertainty about when to consider or switch biologic therapy. To identify the boundaries of the window of opportunity within HS, global HS experts have developed frameworks for defining moderate HS and disease progression. It is proposed that prompt medical treatment should be administered to patients with moderate HS, defined as patients with inadequate control of HS symptoms on conventional therapies, or one inflamed skin tunnel (draining/non-draining), or four or more inflammatory lesions (including inflammatory nodules and abscesses) involving two or more anatomic areas. Furthermore, the proposed definition for disease progression is the development of one or more new tunnel(s) and/or the extension of existing tunnels, or development of one or more persistent HS lesions in an anatomical region not previously affected, or any increase in the number of persistent HS lesions in an affected anatomical region. The proposed frameworks aim to provide practical advice to physicians and support targeting the window of opportunity during routine clinical practice.