Andersen-Tawil Syndrome (ATS) is a rare genetic disorder characterized by a triad of symptoms: periodic paralysis, cardiac arrhythmias (specifically prolonged QT interval), and distinctive dysmorphic features. Protheragen offers comprehensive preclinical services focusing on novel therapies for refractory Andersen-Tawil syndrome, with particular emphasis on rare tubular transport disorders.
Introduction to Andersen-Tawil Syndrome
Andersen-Tawil Syndrome (ATS), also known as Long QT Syndrome Type 7 (LQT7), is an extremely rare, autosomal dominant genetic disorder. It is primarily caused by mutations in the KCNJ2 gene, which encodes the Kir2.1 subunit of inwardly rectifying potassium channels. These channels are crucial for maintaining the resting membrane potential in various excitable cells, including skeletal and cardiac muscle cells. The syndrome is defined by periodic paralysis, cardiac arrhythmias (prolonged QT interval), and dysmorphic features (e.g., low-set ears, widely spaced eyes). ATS's rarity and complex presentation necessitate a deep understanding of ion channel biology for effective therapeutic development.
Fig.1 The Kir2.1 channel structure. (Moreno-Manuel
et al., 2023)
Pathogenesis of Andersen-Tawil Syndrome
The pathogenesis of Andersen-Tawil Syndrome (ATS) is directly linked to pathogenic variants in the KCNJ2 gene, which encodes the Kir2.1 protein, a subunit of inwardly rectifying potassium channels. In ATS, KCNJ2 mutations typically lead to a loss-of-function of the Kir2.1 channel. This disruption causes impaired Kir2.1 channel function in skeletal muscle fibers, leading to periodic paralysis. In cardiac myocytes, reduced Kir2.1 function manifests as a prolonged QT interval and increased susceptibility to ventricular arrhythmias. The ubiquitous expression of Kir2.1 channels during development also contributes to the characteristic dysmorphic features. Understanding this direct link between a single gene mutation and a multi-systemic disorder with a clear ion channel defect is key to developing targeted therapies.
Fig.2 Possible Kir2.1 trafficking pathways. (Moreno-Manuel
et al., 2023)
Therapeutics Development for Andersen-Tawil Syndrome
| Therapeutic Strategy |
Therapeutic Target |
Key Mechanisms/Advances |
Development Stage |
| AAV9-KCNJ2 Therapy |
Kir2.1 channel |
Delivers functional Kir2.1 channels; normalizes QT interval and suppresses bidirectional ventricular tachycardia (BVT) in mouse models; limited by immunogenicity and skeletal muscle targeting |
Preclinical |
| CRISPR-Cas9 Repair |
PIP2 domain |
Corrects KCNJ2 mutations; in vivo off-target risks require mitigation |
Preclinical |
| Flec-ATS1 |
BVT |
Selective INa-L blocker; suppresses BVT without worsening muscle weakness |
Phase II |
| RyR2 Stabilizer S107 |
Calcium leak (RyR2) |
Reduces sarcoplasmic reticulum Ca2+ leakage; suppresses triggered activity in ATS-CPVT overlap phenotypes |
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 specialized services in developing advanced disease models for Andersen-Tawil syndrome, complemented by comprehensive preclinical therapeutic development. Our efforts are dedicated to deciphering the complex genetic and physiological factors that underpin this ion channelopathy and its impact on excitable tissues.
Therapeutic Development Platforms for Andersen-Tawil Syndrome
Disease Models Development for Andersen-Tawil Syndrome
Protheragen offers innovative and comprehensive disease models to advance the preclinical research of Andersen-Tawil syndrome. Our platform integrates cell-based models, kidney organoids, and animal models to effectively capture the ciliary dysfunction and developmental defects that cause Andersen-Tawil syndrome.
- ATS patient-derived iPSC line
- KCNJ2-mutant cardiomyocyte
- KCNJ2-deficient skeletal myocyte
- ATS patient-derived cardiac organoid
- Neuromuscular junction co-culture organoid
- Cardiomyocyte-specific KCNJ2 KO mouse
- KCNJ2 point mutation rabbit
- kcnj2a/kcnj2b morpholino knockdown zebrafish
- kcnj2 mutant zebrafish
- Humanized KCNJ2 mutation rat
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 is committed to accelerating the development of novel therapies for challenging rare diseases like ATS. Our comprehensive preclinical services, including disease model development, pharmacokinetics, and drug safety evaluation are designed to address the unique complexities of multi-systemic genetic disorders, guiding your research from discovery to preclinical validation.
Contact us today to accelerate your Andersen-Tawil syndrome research with end-to-end solutions.
References
- Maffe, S., et al. "Therapeutic Management of Ventricular Arrhythmias in Andersen-Tawil Syndrome." J Electrocardiol 58 (2020): 37-42.
- Vivekanandam, V., et al. "Andersen-Tawil Syndrome: Deep Phenotyping Reveals Significant Cardiac and Neuromuscular Morbidity." Brain 145.6 (2022): 2108-20.
All of our services and products are intended for preclinical research use
only and cannot be used to diagnose, treat or manage patients.
