OniX OnPoint - Issue 31, Week 8, 2025: Advancing Scleroderma Research
Novel Targets and Therapeutic Approaches
This week's OniX OnPoint highlights significant advances in scleroderma research and therapeutics, spanning from molecular mechanisms to clinical applications and emerging therapeutic strategies.
Sponsored Projects showcase six key research initiatives exploring diverse mechanisms underlying scleroderma. The University of Michigan's Johann Eli Gudjonsson is investigating the Hippo pathway in scleroderma pathogenesis, focusing on how this signaling pathway affects fibroblast and endothelial cell transitions. At Showa University in Japan, Komine Rai is analyzing Hic-5 and other TGF-β-inducible molecules through single-cell analysis, which may reveal new targets for anti-fibrotic therapies. Rebecca Wells at the University of Leeds is studying the primary cilium's role in morphogen signaling and TGF-beta modulation, potentially uncovering new insights into fibroblast activation. Miriam Nacagami Sotto from the Federal University of Minas Gerais is conducting comparative immunohistochemical studies of fibrogenesis across multiple conditions, while Thomas Krieg at University Hospital Cologne is exploring TANGO1 modulation in collagen production for fibrosing skin diseases. Rounding out these initiatives, Jimmy Stalin at the University of Fribourg is investigating endothelial MAGI1's protective role against inflammation and fibrosis, particularly in lung fibrosis and scleroderma.
Technology Transfer presents innovative therapeutic strategies from leading research institutions that could transform scleroderma treatment. Thomas Wynn at NIAID has developed methods for treating fibrosis by inhibiting the IL-21/IL-21R interaction, which has shown promise in reducing Th2 immune responses and subsequent fibrosis in preclinical studies. UC Davis researcher Ameer Taha is pioneering the use of anti-inflammatory lipids derived from milk fat, offering a naturally derived treatment option for managing inflammatory diseases including scleroderma. At Stanford University, He You has created synthetic bi-functional degraders of αV integrins that target these key receptors implicated in fibrotic diseases through lysosomal degradation rather than simply blocking their activity. Joseph Shin from Johns Hopkins University is developing targeted epigenetic therapy against TGFβ2 expression, providing a novel disease-modifying approach for scleroderma and other fibrotic disorders. From Emory University, Stylianos Bournazos presents novel endoglycosidase derivatives that remove sugars from IgG antibodies, potentially offering a targeted approach to treating IgG-mediated autoimmune diseases with fewer side effects.
Biotechnology Sector shows significant activity in scleroderma therapeutics, with several companies developing innovative approaches to address this challenging condition. MDI Therapeutics in Michigan is advancing a first-in-class orally available inhibitor of plasminogen activator inhibitor (PAI-1) based on technologies developed at the University of Michigan. Ohio-based BioMendics is committed to developing its small molecule liquid crystal MTORX™ Technology for rare dermatologic disorders including scleroderma. Accutis from Georgia has discovered that a deficit in the mitochondrial deacetylase Sirtuin 3 (SIRT3) is a pathogenic mechanism underlying fibrosis in systemic scleroderma, and is working to leverage SIRT3's anti-fibrotic properties. Netherlands-based Philikos aims to change the treatment landscape by using its innovative T-Guard compound to reset the patient's immune system, while Swiss company TOPADUR is designing drugs targeting the cGMP-Enzyme Regulation System to improve blood circulation and correct insufficient cell-cell communication.
Recent News and Developments highlight three significant advances that could impact scleroderma treatment. A new study has revealed the critical role of transglutaminase 2 (TGM2) in scleroderma skin fibrosis, showing that TGM2 is overexpressed in scleroderma fibroblasts and contributes to fibrosis markers like collagen type 1 and αSMA. Research into exosomes derived from adipose mesenchymal stem cells (AMSCs) shows promise for treating scleroderma skin fibrosis by inhibiting the TGF-β1/Smad3 pathway, reducing collagen synthesis in fibroblasts and improving skin fibrosis in mouse models. A preliminary study suggests that Selexipag may be effective for treating scleroderma-related digital ulcers and Raynaud's Phenomenon, showing improved healing and reduced attacks compared to standard care, potentially offering a safe and effective option for scleroderma vasculopathy.
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SPONSORED PROJECTS
1. Role of the Hippo pathway in scleroderma pathogenesis, Johann Eli Gudjonsson, University of Michigan, USA
The research on Systemic Sclerosis (SSc) involves Asset(s) and Technology such as siRNA targeting and novel therapeutic targets like Hippo signaling and VGLL3. The Target includes the Hippo signaling pathway and interactions between LAMP3+ dendritic cells and stromal cells. The Mechanism of Action (MoA) involves modulating the Hippo signaling pathway to inhibit fibroblast-to-myofibroblast and endothelial-to-endo-MT transitions. This research is in the Stage of Development of preclinical or early research phases. The primary Indication is Systemic Sclerosis (SSc), with potential applications in other autoimmune diseases. Additionally, Other Indications could include fibrotic diseases if successful. The Drug Development Potential and Implication of these novel targets and therapies offer significant potential for improving SSc treatment by addressing underlying pathogenic mechanisms, which could lead to more effective treatments for fibrotic diseases and autoimmune conditions, enhancing patient outcomes and quality of life.
2. Analysis of novel target molecules for systemic scleroderma using single cell analysis, Komine Rai, Showa University, Japan
The Asset(s) and Technology in this research involve TGF-β-inducible molecules, particularly Hic-5, which is implicated in fibrosis across various organs. The Target is Hic-5, a molecule involved in fibroblast activation and potentially in the pathogenesis of systemic sclerosis. The Mechanism of Action (MoA) involves understanding how Hic-5 contributes to fibrosis, likely through pathways similar to those of TGF-β, which promotes myofibroblast differentiation and excessive matrix deposition. This research is in the Stage of Development of early-stage research, with plans for in vivo experiments using mouse models and cell-based studies. The primary Indication is systemic sclerosis, with potential applications in other fibrotic diseases such as liver, pancreatic, and pulmonary fibrosis. Additionally, Other Indications could include conditions where TGF-β plays a significant role in fibrosis. The Drug Development Potential and Implication of targeting Hic-5 or similar TGF-β-inducible molecules is promising, as it could provide novel therapeutic strategies for treating fibrotic diseases by addressing the molecular basis of fibrosis and potentially offering more effective treatments for systemic sclerosis.
3. Role of primary cilium in morphogen signalling modulation by Transforming Growth Factor-beta (TGF-beta) and its involvement in tissue fibrosis and abe, Rebecca Wells, University of Leeds, UK
The Asset(s) and Technology in this project involve advanced molecular biology techniques, high-resolution imaging, and biochemical assays to study fibroblast activation and primary cilium morphology. The Target includes the signaling pathways of morphogens like Shh, Wnt, and TGF-β, as well as the primary cilium, which acts as a cellular antenna for key receptors. The Mechanism of Action (MoA) involves understanding how changes in primary cilium morphology and signaling pathways contribute to fibroblast activation and fibrosis. This research is in the Stage of Development of early-stage research, focusing on molecular and cellular mechanisms. The primary Indication is fibrotic diseases, using scleroderma as a model, with potential applications in other fibrotic conditions affecting various organs. Additionally, Other Indications could include conditions where fibrosis plays a significant role, such as liver or lung fibrosis. The Drug Development Potential and Implication of this research is promising, as it could lead to novel therapeutic strategies targeting fibroblast activation and primary cilium morphology, offering new avenues for treating fibrotic diseases by addressing underlying molecular and cellular mechanisms.
4. Comparative immunohistochemical study of fibrogenesis in keloids, lobomycosis and scleroderma, Miriam Nacagami Sotto, Federal University of Minas Gerais (UFMG), Brazil
The Asset(s) and Technology in this research involve advanced immunohistochemistry techniques to analyze fibrogenesis markers such as alpha-actin, collagen type 1, vimentin, fibroblast-specific protein 1, and cytokeratins. The Target includes understanding the cellular sources of fibrosis, such as resident fibroblasts, epithelial-mesenchymal transition, and the Hedgehog signaling pathway. The Mechanism of Action (MoA) involves elucidating how chronic inflammation and growth factors lead to excessive extracellular matrix deposition, causing tissue remodeling and destruction. This research is in the Stage of Development of early-stage research, focusing on qualitative and quantitative analyses of collagen deposition in keloid, lobomycosis, and scleroderma. The primary Indication is fibrotic skin diseases, with potential applications in other fibrotic conditions such as pulmonary or liver fibrosis. Additionally, Other Indications could include conditions where fibrosis plays a significant role, such as cardiac fibrosis. The Drug Development Potential and Implication of this research is promising, as it could provide novel insights into fibrogenesis, potentially leading to targeted therapies that address the underlying mechanisms of fibrotic diseases, offering new avenues for treatment.
5. Regulation of collagen production in fibrosing skin diseases by modulation of TANGO1, Thomas Krieg, University Hospital Cologne, Germany
The Asset(s) and Technology in this context involve TANGO1, a protein critical for collagen secretion, and specific inhibitors targeting TANGO1. The Target is the TANGO1 protein, which plays a crucial role in facilitating collagen secretion from the endoplasmic reticulum. The Mechanism of Action (MoA) involves inhibiting TANGO1 to reduce collagen secretion, thereby limiting tissue scarring and fibrosis. This research is in the Stage of Development of preclinical studies, with both in vitro and in vivo experiments being conducted. The primary Indication is fibrosing diseases, such as scleroderma, with potential applications in other conditions characterized by excessive collagen deposition. Additionally, Other Indications could include liver fibrosis and other fibrotic diseases where collagen deposition is a major issue. The Drug Development Potential and Implication of TANGO1 inhibitors is significant, as they could provide a novel therapeutic approach to preventing excessive collagen deposition and thereby reducing fibrosis, offering new hope for treating fibrosing diseases.
6. Unraveling the protective role of endothelial cell MAGI1 in vascular-dependent inflammation and fibrosis, Jimmy Stalin, University of Fribourg, Switzerland
The Asset(s) and Technology in this research involve endothelial MAGI1, an intracellular adaptor protein, and advanced experimental models such as in vivo mice models of fibrosis and in vitro cellular models. The Target is endothelial MAGI1, which is believed to play a protective role against fibrosis by regulating cell-cell adhesion and modulating immune/inflammatory responses. The Mechanism of Action (MoA) involves endothelial MAGI1's ability to suppress angiogenesis, macrophage and myofibroblast infiltration, and fibrotic tissue deposition, potentially by influencing the expression of genes involved in inflammation and fibrosis. This research is in the Stage of Development of early-stage research, with ongoing experiments using established models. The primary Indication is lung fibrosis, including idiopathic pulmonary fibrosis and scleroderma, with potential applications in other fibrotic diseases. Additionally, Other Indications could include conditions where fibrosis plays a significant role, such as liver or cardiac fibrosis. The Drug Development Potential and Implication of targeting endothelial MAGI1 is promising, as it could provide novel therapeutic strategies for treating fibrotic diseases by addressing underlying molecular mechanisms, potentially leading to more effective treatments for lung fibrosis and related conditions.
TECHNOLOGY TRANSFER
1. Methods for Treating or Ameliorating Fibrosis by Inhibiting the Interaction between IL-21 Receptor (IL-21R) and IL-21, Thomas Wynn, NIAID, USA
The Asset(s) and Technology in this approach involve anti-IL-21R monoclonal antibodies, anti-IL-21 monoclonal antibodies, and soluble IL-21R, which are used to inhibit the interaction between IL-21 and its receptor. The Target is the IL-21/IL-21R interaction, which plays a critical role in promoting fibrosis through the induction of Th2 immune responses and the activation of CD8+ T cells. The Mechanism of Action (MoA) involves blocking IL-21 signaling, thereby reducing the Th2 immune response and subsequent fibrosis. This research is in the Stage of Development of preclinical studies, with evidence from animal models demonstrating reduced fibrosis upon IL-21R antagonism. The primary Indication is fibrotic diseases, including pulmonary fibrosis, scleroderma, and asbestosis, with potential applications in other fibrotic conditions such as liver fibrosis and idiopathic pulmonary fibrosis. Additionally, Other Indications could include conditions where fibrosis is a significant component, such as cystic fibrosis and schistosomiasis. The Drug Development Potential and Implication of targeting IL-21/IL-21R is promising, as it could provide novel therapeutic strategies for treating fibrosis by addressing the underlying immune mechanisms, offering new hope for patients with fibrotic diseases.
2. In-situ Production of Anti-inflammatory Lipids for Treating Inflammation, Ameer Taha, UC Davis, USA
The Asset(s) and Technology in this approach involve a novel method for isolating anti-inflammatory lipids from milk fat, utilizing enzymatic oxidation to produce therapeutic compounds. The Target is inflammation associated with autoimmune and inflammatory diseases, such as rheumatoid arthritis, lupus, and scleroderma. The Mechanism of Action (MoA) involves the anti-inflammatory effects of these lipids, which can modulate immune responses and reduce inflammation. This research is in the Stage of Development of early-stage research, with laboratory prototyping completed. The primary Indication is autoimmune and inflammatory diseases, with potential applications in conditions like type 1 diabetes, multiple sclerosis, and Crohn's disease. Additionally, Other Indications could include fibrotic diseases where inflammation plays a significant role. The Drug Development Potential and Implication of these anti-inflammatory lipids is promising, as they offer a naturally derived, scalable, and potentially effective treatment option for managing autoimmune and inflammatory diseases, providing new avenues for therapy that could complement existing treatments.
3. Synthetic bi-functional degraders of aV integrins, He You, Stanford University, USA
The Asset(s) and Technology in this approach involve synthetic bi-functional protein degraders that induce lysosomal degradation of αV integrins, which are key receptors implicated in fibrotic diseases. The Target is αV integrins, which play a crucial role in fibrosis by mediating cell-extracellular matrix interactions and activating TGF-β signaling. The Mechanism of Action (MoA) involves promoting the degradation of αV integrins via lysosomal targeting, rather than simply blocking their activity, which can enhance tissue specificity and reduce undesired effects. This research is in the Stage of Development of proof-of-concept, with potential applications in treating various fibrotic diseases. The primary Indication is fibrotic diseases, including renal, cardiac, hepatic, pulmonary, cystic fibrosis, and scleroderma fibrosis. Additionally, Other Indications could include conditions where integrins play a significant role in disease progression. The Drug Development Potential and Implication of these protein degraders is promising, as they could provide a novel therapeutic strategy for treating fibrosis by addressing the limitations of traditional integrin inhibitors, offering improved efficacy and specificity in targeting fibrotic diseases.
4. Targeted Epigenetic Therapy against Distal Regulatory Element of TGFB2 Expression for Scleroderma and Fibrotic Disease, Joseph Shin, Johns Hopkins University, USA
The Asset(s) and Technology in this approach involve targeted epigenetic editing techniques to modulate the expression of TGFβ2, a cytokine implicated in fibrosis. The Target is a specific epigenetic enhancer responsible for the upregulation of TGFβ2 in systemic sclerosis (SSc). The Mechanism of Action (MoA) involves normalizing TGFβ2 expression by targeting this enhancer, thereby reducing fibrosis. This research is in the Stage of Development of in vitro proof-of-concept, with pharmacological compositions showing disease-modifying effects. The primary Indication is systemic sclerosis and other fibrotic diseases where TGFβ2 plays a significant role. Additionally, Other Indications could include conditions where TGFβ2-mediated fibrosis is a major component, such as idiopathic pulmonary fibrosis and cardiac fibrosis. The Drug Development Potential and Implication of this targeted epigenetic therapy is promising, as it offers a novel disease-modifying approach that could improve outcomes for patients with scleroderma and other fibrotic disorders by addressing the underlying molecular mechanisms driving fibrosis.
5. Novel Endoglycosidase Derivatives Treating Diseases of the Adaptive Immune System, Stylianos Bournazos, Emory University, USA
The Asset(s) and Technology in this approach involve a new class of endoglycosidase enzymes that remove sugars from the surface of IgG antibodies, thereby modulating their immune signaling functions. The Target is IgG-mediated autoimmune diseases, where these enzymes can reduce the pathogenic effects of IgG antibodies. The Mechanism of Action (MoA) involves deglycosylation of IgG antibodies, which abolishes their effector functions mediated by the Fc region, such as binding to Fcγ receptors and complement activation. This research is in the Stage of Development of preclinical studies, with robust in vitro activity demonstrated for four novel compounds. The primary Indication is autoimmune diseases, including conditions like rheumatoid arthritis, lupus, and scleroderma. Additionally, Other Indications could include other IgG-mediated pathologies such as myasthenia gravis and autoimmune hemolytic anemia. The Drug Development Potential and Implication of these endoglycosidase derivatives is promising, as they offer a targeted approach to treating autoimmune diseases by specifically addressing the role of IgG antibodies, potentially leading to more effective treatments with fewer side effects.
STARTUPS/BIOTECHS
· MDI Therapeutics (Michigan, USA) is a pharmaceutical company developing novel therapies for the treatment of fibrosis and fibroproliferative diseases. The Company was founded on key enabling technologies developed at the University of Michigan. MDI’s lead program is a first-in-class orally available inhibitor of plasminogen activator inhibitor (PAI-1).
· BioMendics (Ohio, USA) is committed to advancing its small molecule liquid crystal MTORX™ Technology to develop life-enhancing medicines for people suffering from epidermolysis bullosa, epidermolytic ichthyosis, pachyonychia congenita, and other rare dermatologic disorders including Scleroderma.
· Accutis (Georgia, USA) has discovered and validated that a deficit in the mitochondrial deacetylase Sirtuin 3 (SIRT3) is a pathogenic mechanism underlying fibrosis in Systemic Scleroderma in humans and that SIRT3 has cell-intrinsic potent anti-fibrotic properties.
· Philikos (Nijmegen, Netherlands) aims to change the treatment landscape of scleroderma and other severe immune disorders by using its innovative T-Guard compound to rapidly and safely reset the patient’s immune system thereby restoring normal immune function and providing patients with a healthier long-term outlook.
· TOPADUR (Schlieren, Switzerland) designed new drugs that target the cGMP-Enzyme Regulation System. TOPADUR’s compounds regulate the activity of sGC and PDE5 enzymes to increase the level of cGMP. This ultimately enables blood circulation and corrects the insufficient cell-cell communication.
News
· Unraveling Fibrosis: The Role of Transglutaminase 2
A Key Player in Scleroderma Skin Fibrosis
This study highlights the critical role of transglutaminase 2 (TGM2) in scleroderma skin fibrosis. TGM2 is overexpressed in scleroderma fibroblasts, contributing to fibrosis markers like collagen type 1 and αSMA. Inhibiting TGM2 reduces fibrosis markers, suggesting a potential therapeutic target by modulating TGFβ signaling.
References:
Tam, A. Y. Y. et al. (2025). Critical role for Transglutaminase 2 in scleroderma skin fibrosis and in the development of dermal sclerosis in a mouse model of scleroderma. Arthritis & Rheumatology, https://doi.org/10.1002/art.43104
Hashtags:
#Scleroderma #Fibrosis #Transglutaminase2 #TGFβ #SkinFibrosis #ConnectiveTissueDisease
· Stem Cells to the Rescue?
Exosomes Show Promise for Scleroderma Skin Fibrosis
This study suggests that exosomes derived from adipose mesenchymal stem cells (AMSCs) alleviate scleroderma skin fibrosis by inhibiting the TGF-β1/Smad3 pathway. Exosomes mimic the effects of AMSCs, reducing collagen synthesis in fibroblasts and improving skin fibrosis in a mouse model.
References:
Xiao, Y., et al. (2025). Mesenchymal stem cells function alleviate scleroderma skin fibrosis by inhibiting the TGF-β1/Smad3 axis. Scientific Reports, 15, 7162. https://doi.org/10.1038/s41598-024-72630-6
Hashtags:
#Scleroderma #SkinFibrosis #Exosomes #MesenchymalStemCells #TGFβ #CellTherapy
· Selexipag: A Ray of Hope for Scleroderma Vasculopathy?
New Insights into Treating Digital Ulcers and Raynaud's Phenomenon
This preliminary study suggests Selexipag is promising for treating scleroderma-related digital ulcers (DUs) and Raynaud's Phenomenon (RP). Selexipag improved DU healing and reduced RP attacks compared to standard care. Selexipag may be safe and effective for treating SSc vasculopathy.
References:
Giuggioli, D. et al. (2025). A New Promising Role for Selexipag in the Treatment of Scleroderma Vasculopathy: Preliminary Results From a Third Level Italian Scleroderma Center. International Journal of Rheumatic Diseases, 28, e70037. https://doi.org/10.1111/1756-185X.70037
Hashtags:
#Scleroderma #DigitalUlcers #RaynaudsPhenomenon #Selexipag #Vasculopathy #Rheumatology