Rothmund-Thomson Syndrome (RTS) is associated with consuming mutations in the RECQL4 helicase gene along with increased cancer risk, skeletal abnormalities, and poikiloderma. Protheragen is leading the initiative in preclinical development of novel therapies for genetic disorders, including Rothmund-Thomson syndrome.
Introduction to Rothmund-Thomson Syndrome
Rothmund-Thomson syndrome is a rare disorder with autosomal recessive inheritance and an unusual combination of clinical features that involve the skin, skeleton, and eyes, and an increased susceptibility to malignancy. Typically, RTS patients (Type II) have mutations in the RECQL4 gene which is responsible for a helicase enzyme within a DNA structure. The DNA helicase is crucial in the maintenance of genomic equilibrium due the involvement in DNA replication and DNA repair mechanisms. The lack of proper RECQL4 function causes inefficient responses to DNA damage which leads to unstable chromosomes, and this explains the syndrome's several pathologies.
Fig.1 Biochemical pathway for fatty aldehydes and fatty alcohols in SLS. (Martins
et al., 2023)
Biomarkers Development for Rothmund-Thomson Syndrome
- DNA Damage and Genomic Instability Markers
RTS is caused by unresolved oxidative damage and replication stress due to the lack of a RECQL4 helicase. Systemic genomic instability is noted by plasma 8-OHdG (oxidized guanine) and urinary γH2AX (marker of double-strand breaks) elevation. Biomarkers of renal tubular injury also correlate with disease severity. These markers console effortless cellular repair deficit monitoring as well as the responsiveness to therapy in preclinical models.
- Senescence-Associated Secretory Phenotype (SASP) Profiling
Chronic DNA damage in RTS drives cellular senescence and is marked with elevated plasma IL-6 concentration alongside p16INK4a in biopsy samples from kidneys. Moreover, urinary β2-microglobulin and NAG (N-acetyl-β-D-glucosaminidase) define the underlying and previously undiagnosed clinical dysfunction of the proximal renal tubules that connects senescence and the progression of nephropathy.
Therapeutics Development for Rothmund-Thomson Syndrome
| Therapeutic Strategy |
Therapeutic Target |
Specific Drug/Candidate |
Key Findings/Mechanism |
Development Stage |
| PARP Inhibitors |
PARP1 signaling |
Olaparib / Niraparib |
Synthetic lethality in RECQL4-deficient cells; enhances tumor cell apoptosis in RTS-associated cancers. |
Preclinical |
| ATR/CHK1 Kinase Inhibition |
ATR/CHK1 pathway |
Ceralasertib (ATRi) / Prexasertib (CHK1i) |
ATR/CHK1 inhibitors selectively kill RECQL4-deficient cells by exacerbating replication stress. |
Preclinical |
| BMP Supplementation |
Bone morphogenetic proteins |
Recombinant BMP-2 |
Promotes osteogenesis in RTS skeletal defects (e.g., radial hypoplasia). |
Preclinical |
| WEE1 Kinase Inhibition |
WEE1 kinase |
Adavosertib (AZD1775) |
Induces synthetic lethality in RECQL4-deficient osteosarcoma cells. |
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 has advanced thought of Rothmund-Thomson syndrome therapeutic development by providing integrated preclinical solutions, making us unique in the industry. Our specialists employ sophisticated tools for fast tracked drug and diagnostic development, working in synergy with robust therapeutic and advanced disease models.
Therapeutics Development Platforms for Rothmund-Thomson Syndrome
Disease Model Development for Rothmund-Thomson Syndrome
Protheragen customizes RTS pathology-relevant 2D cell models, 3D skin models as well as animal models that recapitulate DNA repair defects, genomic instability, and senescence-associated renal tubular dysfunction. Our models integrate RECQL4 mutation-driven oxidative stress, impaired stem cell differentiation, and chronic inflammation pathways to advance nephrology-focused therapeutic discovery.
2D Cell Models & 3D Skin Models
- RECQL4-Mutant Renal Tubular Epithelial Cells
- RECQL4-KO HEK293 Cells
- RECQL4-Deficient Podocytes
- 3D Renal Organoids
Animal Models Development
- Conditional Recql4 Knockout Mice
- Humanized RECQL4 p.Arg377Ter Transgenic Rats
- Recql4-Mutant Zebrafish
- Xenograft Models with RTS Patient-Derived Tumor Cells
Drug Safety Evaluation and DMPK Services
Protheragen offers comprehensive drug safety evaluation and DMPK services, designed to accelerate the preclinical development of novel therapies for Rothmund-Thomson Syndrome. We are dedicated to providing robust data to support the efficacy and safety of your innovative drug candidates.
- Metabolic Stability
- Reaction Phenotyping
- CYP450 Inhibition/Induction
- Blood/Plasma Partitioning
- Single-Dose PK Studies
- Multiple-Dose PK Studies
- Bioavailability and Bioequivalence Studies
- Tissue Distribution Studies
As a preclinical research service provider focused on nephrology and multi-organ genetic disorders, Protheragen accelerates therapies for systemic conditions like Rothmund-Thomson syndrome. We deliver RECQL4 gene target validation, RTS-specific disease modeling, drug safety evaluation and DMPK services.
Contact us to explore how our end-to-end solutions can advance your Rothmund-Thomson syndrome research.
References
- Ahn, J. W., et al. "Histopathologic Features of Rothmund-Thomson Syndrome." JAAD Case Rep 5.8 (2019): 726-28.
- Martins, D. J., et al. "Rothmund-Thomson Syndrome, a Disorder Far from Solved." Front Aging 4 (2023): 1296409.
All of our services and products are intended for preclinical research use
only and cannot be used to diagnose, treat or manage patients.
