Protheragen is focused on developing tailored preclinical therapies for Generalized Pustular Psoriasis (GPP), which is a complex inflammatory skin disease distinguished from chronic plaque psoriasis. GPP is rare and incurs severe health risks. This condition involves an intricate web of inflammation that currently lacks appropriate therapeutic interventions.
Introduction to Generalized Pustular Psoriasis
Generalized Pustular Psoriasis (GPP) falls under the category of rare autoinflammatory diseases and poses a significant threat to one's life. Episodic eruptions spring acute exacerbations comprising widespread, sterile pustules, erythema, febrile illness, leukocytosis and systemic symptoms. It gets triggered due to disrupted IL-36 signaling pathways as seen in mutations linked with IL36RN, CARD14 and AP1S3 genes. Patients experience severe dermal inflammation alongside neutrophilic infiltrates along with multi-organ complications. The estimated prevalence rate sits around 1 - 2 per million though there seems to be higher rates in East Asia, as well as greater incidence among females.
Pathogenesis of Generalized Pustular Psoriasis
GPP is characterized by hyperactivation of IL-36 pathways which triggers NF-kB and MAPK signal transduction pathways leading to chronic inflammation linked to skin lesions with organ system involvement, often resulting in life-threatening challenges for patients. S100A8/A9 proteins produced by keratinocytes are also thought to play a role in inducing IL-17/IL-23 loop processes, further intensifying the condition.
Fig.1 IL-36 autocrine and autoinflammatory circuits. Keratinocytes are the major source of IL-36 in the skin. (Young, Sarkar and Gudjonsson, 2021)
Therapeutics Development for Generalized Pustular Psoriasis
| Therapeutic Strategy |
Target / Intervention |
Key Findings / Rationale |
Development Stage |
| Spesolimab |
Anti-IL-36R monoclonal antibody |
Abrogates IL-36-driven neutrophil chemotaxis and keratinocyte hyperproliferation in 3D pustule models |
Approval |
| Imsidolimab |
Anti-IL-36R monoclonal antibody |
Suppresses IL-36α/γ-induced CXCL1/IL-8 secretion in skin organoids |
Phase III |
| HB0034 |
Anti-IL-36R bispecific antibody |
Dual blockade of IL-36R and TNF-α shows synergistic reduction in S100A9+ neutrophils |
Phase Ib |
| Infliximab |
Anti-TNF-α monoclonal antibody |
Modestly reduces IL-23/Th17 axis but fails to normalize IL-36 signatures in GPP biopsies |
Clinical use |
| Secukinumab |
Anti-IL-17A monoclonal antibody |
Paradoxically elevates IL-36γ in 30% of keratinocyte models; limited pustule prevention |
Approved |
| Guselkumab |
Anti-IL-23p19 monoclonal antibody |
Reduces Th17 cell infiltration but shows incomplete IL-36 pathway suppression |
Clinical trials |
Disclaimer: Protheragen focuses on providing preclinical research services. This table is for information exchange purposes only. This table is not a treatment plan recommendation. For guidance on treatment options, please visit a regular hospital.
Our Services
Protheragen offers a great range of capabilities to further the advancement of therapies for GPP. Expert scientists, dermatologists, and geneticists are on hand and leverage cutting-edge technologies in their focus on avenues for therapeutic development and disease model development services to support GPP-related projects.
Therapeutic Development Platforms for Generalized Pustular Psoriasis
Protheragen's GPP therapeutic development platforms leverage advanced biologics, small molecule discovery, and gene modulation technologies to target key inflammatory pathways, ultimately aiming to achieve rapid clinical response and sustained remission.
Disease Models Development for Generalized Pustular Psoriasis
Protheragen further offers a comprehensive suite of preclinical models to advance research associated with GPP, including cutting-edge 2D cell models, 3D skin models and animal models development, all tailored to replicate disease-specific pathologies and accelerate therapeutic development.
| 2D Cell Models& 3D Skin Models |
| Protheragen's preclinical research services for GPP are directed at having your studies yield solid foundations on which to develop therapies. With opportunities to run in vitro studies to engage in experimentation with either 2D cell models, 3D skin models, and other optional studies including organoids. |
| Optional Models |
- IL-36R Overexpressing Keratinocytes
- Patient-Derived Keratinocytes with IL36RN Mutations
|
- GPP Inflamed Skin Organoids
- Inflammatory Cytokine Response Chips
|
| Animal models |
| In vivo preclinical studies are also a key part of our services. We utilize genetically engineering models, to test the safety and efficacy of potential therapeutics. These animal models are carefully selected based on their ability to mimic the human condition of GPP. |
| Optional Models |
- Il36rn-/- (IL-36Ra deficient) Murine Models
- Imiquimod-Induced Psoriasis Models
|
- Transgenic Mice Overexpressing IL-36 Agonists
- Humanized GPP Skin Xenografts
|
| Optional Species |
Mice, Rats, Non-human primates, Others |
As a one-stop preclinical research services provider, Protheragen is dedicated to advancing therapeutics for rare skin diseases like generalized pustular psoriasis. Our end-to-end solutions seamlessly span from target discovery and disease modeling to drug safety evaluation and DMPK services. If you are interested in our services, please feel free to contact us.
References
- Bachelez, H., et al. "Trial of Spesolimab for Generalized Pustular Psoriasis." N Engl J Med 385.26 (2021): 2431-40.
- Young, K. Z., M. K. Sarkar, and J. E. Gudjonsson. "Pathophysiology of Generalized Pustular Psoriasis." Exp Dermatol 32.8 (2023): 1194-203.
All of our services and products are intended for preclinical research use
only and cannot be used to diagnose, treat or manage patients.
