Sensenbrenner Syndrome, or Cranioectodermal Dysplasia (CED), is a rare condition within the group of ciliopathies. Protheragen is applying their expertise on genetic kidney disorders to Sensenbrenner syndrome, resolving its multi-system complexity with targeted preclinical and therapeutic development work.
Introduction to Sensenbrenner Syndrome
Sensenbrenner Syndrome (SS) is one of the ultra-rare diseases with an autosomal recessive inheritance pattern, classified as a ciliopathy (with an incidence of fewer than one in a million). It is characterized by the occurrence of craniosynostosis, ectodermal dysplasia which presents as fine and sparse hair, skeletal anomalies, along with the progression of renal disease which includes tubulointerstitial fibrosis and cystic dysplasia. Renal disease often progresses to End-Stage Renal Disease (ESRD) by adolescence, with 40% also developing hepatic fibrosis. Recent work suggests IFT gene mutations resulting in disrupted Hedgehog signaling and abnormal collagen deposition.
Pathogenesis of Sensenbrenner Syndrome
The pathogenesis of Sensenbrenner Syndrome relates to mutations in genes that code for proteins within the intraflagellar transport (IFT) system, which is essential for the assembly and maintenance of primary cilia. Specifically, IFT122, IFT43, WDR19, WDR35, IFT140, and IFT52 mutations have been identified as causative. These genes are responsible for the proteins that form the IFT-A or IFT-B complexes, which carry macromolecular cargo in a bidirectional manner along ciliary microtubules.
Fig.1 Ciliary proteins mutated among the skeletal ciliopathies. (Zhang
et al., 2020)
Sensenbrenner Syndrome is associated with primary cilia defects due to impaired IFT machinery. Primary cilia serve as sensors for extracellular cues and are crucial for development and homeostasis. In the kidney, the disruption of cilia leads to abnormal renal tubule development and maintenance, resulting in the tubulointerstitial nephritis and cysts associated with nephronophthisis. Other organ ciliary defects contributing to skeletal, ectodermal, and hepatic manifestations emphasize the systemic nature of the ciliopathy. The mutation and gene associated with the disorder determines the elusive severity, specific phenotypic expression, and the particular features.
Therapeutic Development for Sensenbrenner Syndrome
| Drug/Technology |
Therapeutic Target |
Key Findings/Mechanism |
Development Stage |
| AAV-mediated gene replacement |
WDR19 gene |
Restores ciliary function in wdr19−/− zebrafish; Challenge: Multi-organ targeting |
Preclinical |
| CRISPRa activation |
WDR19 promoter |
Restores IFT-A complex in fibroblasts; Challenge: In vivo delivery unvalidated |
Preclinical |
| IFT43-ASO |
IFT43 pre-mRNA |
Leverages Alagille syndrome ASO success; Requirement: Renal-tropic delivery |
Preclinical |
| Purmorphamine |
Smoothened receptor (SMO) |
Effective in Joubert syndrome models; Need: Syndrome-specific data |
Preclinical |
| Pirfenidone |
TGF-β1 ligand |
Effective in hepatic fibrosis models |
Preclinical |
| Dimethyl Fumarate |
KEAP1 protein |
Reduces oxidative stress in patient fibroblasts |
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 specializes in developing advanced disease models for Sensenbrenner syndrome and offers comprehensive preclinical therapeutic development services. We focus on elucidating the diverse genetic and developmental impacts of IFT gene mutations that lead to the multi-systemic manifestations of Sensenbrenner syndrome.
Therapeutic Development Platform for Sensenbrenner Syndrome
Protheragen combines deep expertise in developmental biology, ciliopathies, and the genetics of rare multi-organ disorders with advanced molecular and cellular technologies to address the multifaceted mechanisms leading to Sensenbrenner Syndrome.
Disease Models Development for Sensenbrenner Syndrome
Protheragen offers innovative and comprehensive disease models to advance the preclinical research of Sensenbrenner Syndrome. Our platform integrates cell-based models, kidney organoids, and animal models to effectively capture the ciliary dysfunction and developmental defects that cause Sensenbrenner syndrome, supporting extensive drug discovery and mechanism-based investigations focused on multi-organ development and pathology.
Cell-based & Organoid Models
- IFT122R716Q mutant renal fibroblasts
- WDR35-KO osteochondral organoids
- 3D ciliated renal tubuloids with collagen deposition
- Hepatic-renal co-cultures with WDR19 mutations
Animal Models Development
- Ift122 knockout mouse models
- Wdr35 mutant animal models
- Zebrafish models with ift gene ortholog mutations
- Humanized WDR19p.Y103C knock-in rats
Drug Pharmacokinetics & Safety Evaluation Services
In Vitro ADME Services
- Renal Clearance Assay
- Drug-Transporter Interaction Screening
- Metabolic Stability Assay
- CYP Inhibition Screening
- Plasma Protein Binding
Protheragen provides integrated preclinical development solutions specifically designed for research in kidney disorders like Sensenbrenner syndrome. We specialize in disease model development, pharmacokinetics, and drug safety evaluation, enabling us to support your investigation from the initial stages to preclinical validation.
If you are interested in our services and advancing research for Sensenbrenner syndrome, please don't hesitate to contact us.
References
- Brndiarova, M., et al. "Sensenbrenner Syndrome Presenting with Severe Anorexia, Failure to Thrive, Chronic Kidney Disease and Angel-Shaped Middle Phalanges in Two Siblings." Mol Syndromol 12.4 (2021): 263-67.
- Zhang, W., et al. "Expanding the Genetic Architecture and Phenotypic Spectrum in the Skeletal Ciliopathies." Hum Mutat 39.1 (2018): 152-66.
All of our services and products are intended for preclinical research use
only and cannot be used to diagnose, treat or manage patients.
