Townes-Brocks Syndrome (TBS) is a rare genetic disorder resulting from striking mutations in the SALL1 gene and features a disruptive triad of ear, thumb and anal anomalies alongside renal impediments like hypoplasia, dysplasia or even vesicoureteral reflux. Protheragen offers targeted preclinical and therapeutic development services for TBS while utilizing their knowledge on genetic kidney disorders to resolve its multisystem intricacy.
Introduction to Townes-Brocks syndrome
TBS stems from heterozygous mutation of the SALL1 gene, which is a potent zinc finger transcription factor responsible for organogenesis. It is marked with an estimated occurrence of 1 out of 250000, with its expression range being highly variable. Renal involvement is observed in approximately 40% of cases with associated features. It is often underreported because its features are overlapping with other syndromes. Centered on the range of CAKUT, renal involvement ranges from mild hypoplasia to severe dysplasia.
Pathogenesis of Townes-Brocks syndrome
TBS pathogenesis is based upon SALL1 haploinsufficiency, which leads to the alteration of transcription networks controlling embryonic patterning. Important mechanisms include:
- Loss of SALL1-mediated repression: Downward target regulatory TBX5 and FGF8 ureteric bud branching and metanephric mesenchyme differentiation suffers from underdevelopment Stalled SALL1 proteins are unable to execute appropriate control.
- WNT/β-catenin dysregulation: Mutations in SALL1 lead to dysregulation of WNT signaling important for nephron and renal hypoplasia formation.
- Epigenetic dysregulation: abnormal SALL1 activity changes chromatin structure and remodeling, thus changing the fate of renal progenitor cells.
Fig.1 Schematic representation of the SALL1 protein (1324 amino acids) and localization of our c.709C > T p.(Gln237*) SALL1 variant. (Lugli
et al., 2022)
Therapeutic Development for Townes-Brocks syndrome
| Drug/Technology |
Therapeutic Target |
Key Findings/Mechanism |
Development Stage |
| Bortezomib (TRIM21 Inhibitor) |
SALL1 protein stability |
Stabilizes SALL1 by inhibiting TRIM21-mediated degradation |
Phase II trial |
| CHIR99021 (Wnt Activator) |
Wnt/β-catenin signaling |
Compensates for SALL1 deficiency in limb development |
Preclinical |
| Vorinostat (HDAC Inhibitor) |
Epigenetic reprogramming |
Reactivates silenced SALL1 expression |
Preclinical |
| 3D-Printed Anorectal Scaffold |
Anorectal malformation repair |
Biodegradable scaffold with stem cells to reduce stenosis |
Clinically optimized |
| Cochlear Implant + Gene Therapy |
Inner ear defects |
AAV-SALL1 delivery combined with electrical stimulation |
Preclinical |
| Ramipril (ACE Inhibitor) |
RAS system modulation |
Slows SALL1-associated nephropathy progression |
Approved |
| SALL1 ASO Therapy |
Dominant-negative SALL1 mutants |
Degrades mutant mRNA while sparing wild-type alleles |
Preclinical |
| Recombinant GDNF (PAX2 Activator) |
Renal tubular development |
Enhances PAX2 expression to rescue nephrogenesis |
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 Townes-Brocks syndrome and offers comprehensive preclinical therapeutic development services. We focus on elucidating the diverse genetic and developmental impacts of SALL1 mutations that lead to the renal and systemic manifestations of TBS.
Therapeutic Development Platform for Townes-Brocks syndrome
Protheragen combines deep expertise in kidney developmental biology, the genetics of congenital anomalies of the kidney and urinary tract (CAKUT) like TBS, and advanced molecular and cellular technologies. Our team delivers tailored solutions for TBS research.
Disease Models Development for Townes-Brocks syndrome
Protheragen offers innovative and comprehensive disease models to advance the preclinical research of Townes-Brocks Syndrome. Our platform integrates cell-based models, kidney organoids, and animal models to effectively capture the genetic and developmental disruptions caused by SALL1 mutations, supporting extensive drug discovery and mechanism-based investigations.
- SALL1-mutant iPSC-derived nephron progenitors
- 3D kidney organoids with ureteric bud malformations
- Co-culture systems (metanephric mesenchyme + ureteric bud)
- SALL1 promoter-methylation models
- Sall1+/− heterozygous mice
- SALL1 c.824C>T knock-in rats (humanized mutation)
- Zebrafish sall1a/sall1b double mutants
- Patient-derived xenografts in renal capsule assays
Protheragen provides integrated preclinical development solutions specifically designed for research in rare genetic kidney diseases like Townes-Brocks syndrome. We specialize in disease model development, pharmacokinetics, and drug safety evaluation, enabling us to support your investigation from initial discovery through to preclinical validation.
If you are interested in our services and advancing research for Townes-Brocks syndrome, please don't hesitate to contact us.
References
- Lugli, L., et al. "Townes-Brocks Syndrome with Craniosynostosis in Two Siblings." Eur J Med Genet 65.12 (2022): 104642.
- Wang, Z., et al. "Identification of Two Novel Sall1 Mutations in Chinese Families with Townes-Brocks Syndrome and Literature Review." Orphanet J Rare Dis 18.1 (2023): 250.
All of our services and products are intended for preclinical research use
only and cannot be used to diagnose, treat or manage patients.
