Incontinentia Pigmenti (IP) is a rare X linked dominant genetic disorder that affects multisystem. Its causes stem from IKBKG NEMO gene mutations which results in improper NF-κB signaling and multi system manifestations. Protheragen focuses on preclinical IP development by employing complex molecular pathology and therapeutic innovation of this disorder.
Introduction to Incontinentia Pigmenti
Incontinentia pigmenti is caused by loss of function mutations in IKBKG which is an important gatekeeper in controlling NF-κB. Consequently, the signaling cascade of NF-κB gets disrupted which leads to impaired mobilization cellular responses to stress. This may lead to apoptosis inflammation and damage of tissue. Autopsy results in patients reveal hyperpigmentation of skin along with neuronal deformities. Most of the patient suffering from this disease are female with 1 in 40,000 incidence for this condition.
Pathogenesis of Incontinentia Pigmenti
- Genetic Disruption of NF-κB Signaling: Incontinentia Pigmenti is attributed to the mutation of the IKBKG gene which is known to code for NEMO. NEMO is known for its vital role in embarking NF K B. The loss of NEMO induced disruption leads to weakened cell stress alleviation enabling excess cell death from inflammation, leading to necrosis.
- Apoptosis and Multisystemic Inflammation: Dysregulated NF-κB signaling results in pathological apoptosis of epidermal and neural cells, which clinically presents as distinctive skin patches and marked neurological impairment. Worsened exacerbation tissue destruction in ectodermal systems is caused by concurrent hyperactivation of pro-inflammatory pathways.
Fig.1
IKBKG/NF-κB pathophysiology in incontinentia pigmenti. (How
et al., 2022)
Therapeutics Development for Incontinentia Pigmenti
| Therapeutic Strategy |
Target / Intervention |
Key Findings / Rationale |
Development Stage |
| Symptomatic Mgmt. |
Clinical Manifestations |
Manages diverse symptoms across multiple organs but doesn't address the root genetic cause; it's the current standard practice. |
Approved |
| Gene Therapy |
IKBKG gene (NEMO gene) |
Aims to fix the faulty IKBKG gene to restore NEMO function, potentially offering a cure. Faces delivery and safety challenges; currently tested preclinically. |
Preclinical |
| NF-κB Pathway Modulation |
NF-κB signaling pathway |
Seeks to normalize faulty NF-κB signaling downstream of NEMO using drugs. Targeting is difficult due to the pathway's complexity and risk of side effects. |
Preclinical |
| NEMO-Binding Domain (NBD) Peptides / Mimetics |
Interaction between NEMO and IKK kinases (IKKα/β) |
Uses peptides/mimetics to block NEMO/IKK interaction, reducing NF-κB activation. Relevance and delivery for IP are under investigation based on preclinical data. |
Preclinical |
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 complete service in developing therapies that focus on skin rare diseases such as incontinentia pigmenti. Our developed specialists, which include scientists, dermatologists, and geneticists, work on developing therapeutic and disease model to support research for all stages of the research project.
Therapeutic Development Platforms for Incontinentia Pigmenti
Disease Model Development for Incontinentia Pigmenti
Protheragen has custom 2D cell models and 3D skin models that replicate the molecular pathology of incontinentia pigmenti, including NF-κB signaling dysregulation and apoptosis-driven tissue damage. Our animal models exhibit key features of IP such as dental agenesis, neuronal apoptosis, and hyperpigmented skin, which make them suitable for testing therapies aimed at restoring NF-κB activity, anti-inflammatory, anti-apoptotic, and inflammation-suppressive strategies.
- Patient-Derived IP Keratinocytes
- HaCaT-ΔIKBKG
- Stratified Epidermal Equivalents
- Skin-Brain Organoids
- Conditional Ikkg Knockout Mice
- Humanized IKBKG Truncation Transgenic Mice
- Porcine IP Xenograft Model
- ikbkg−/− Zebrafish
As a preclinical research services provider, Protheragen aims to take the initiative in developing of therapeutics for rare skin conditions such as incontinentia pigmenti. Due to our proprietary model, there is a seamless transition from target discovery, disease modeling, and advanced drug safety evaluation to DMPK services. If you are interested in our services, please feel free to contact us.
References
- How, K. N., et al. "Uncovering Incontinentia Pigmenti: From DNA Sequence to Pathophysiology." Front Pediatr 10 (2022): 900606.
- Minic, S., et al. "Challenges in Rare Diseases Diagnostics: Incontinentia Pigmenti with Heterozygous Gba Mutation." Diagnostics (Basel) 12.7 (2022).
All of our services and products are intended for preclinical research use
only and cannot be used to diagnose, treat or manage patients.
