Timothy Syndrome
Timothy syndrome, which includes multiple system malfunctions (especially the prolonged corrected QT interval), along with simultaneous hand/foot syndactyly, is a life-threatening arrhythmia that affects infants. Protheragen is an example of a premier provider offering drug research and development services and pays special attention to advancing novel discoveries related to rare cardiovascular diseases, including Timothy syndrome.
Overview of Timothy Syndrome
Timothy syndrome, known as long QT syndrome type 8 (LQT8), is a rare autosomal dominant disorder that results from one or more pathogenic variants in the CACNA1C gene which is responsible for encoding the α1C subunit of voltage-gated calcium channel CaV1.2.
Timothy syndrome has traditionally been associated with only a small number of genetic alterations leading to prolonged QT interval of the heart's electrical cycle, syndactyly, and neurodevelopmental delay. Its prevalence is estimated to be less than 1 in 1 million individuals. More importantly, cases of Timothy syndrome show extremely early onset ages for developing neonates.
Fig.1 Timothy syndrome is a rare pediatric multi-organ disease. (Jiang, C., and Zhang, Y. 2023)Pathogenesis of Timothy Syndrome
The initiating event for the development of Timothy syndrome has been linked with an abnormality in the CACNA1C gene which encodes the CaV1.2 subunit of the cardiac L-type voltage-gated calcium channel (LTCC). Most classical mutations are in exon 8 or 8a (alternative splicing isoform) of the CACNA1C transcript, leading to de novo substitution of missense p.Gly406Arg (G406R mutation). Nevertheless, the total number of identified variants causing Timothy syndrome is increasing, along with their symptom profiles, which are strikingly intricate and diverse.
Fig.2 Signaling dysregulation in Timothy syndrome. (Jiang, C., and Zhang, Y. 2023)Therapeutics Development for Timothy Syndrome
| Drug Names | Mechanism of Action | Targets | Research Phase |
|---|---|---|---|
| Mexiletine | Eliminates T-wave alternans by reducing QTc and peak-to-end of the T wave. | SCNA | Approved |
| Ranolazine | A multi-functional ion channel blocker reduces episodes of atrial and ventricular fibrillation. | NaV1.5 | Approved |
| Roscovitine | A cyclin-dependent kinase (CDK) inhibitor restores phenotypes in induced pluripotent stem cell-derived cardiomyocytes from individuals with Timothy syndrome. | CDK5 | Preclinical |
| Antisense oligonucleotide | Reduce inclusion of exon 8A in human cells and functionally corrects CaV1.2 channel. | CACNA1C exon 8A | Preclinical |
Disclaimer: Protheragen focuses on providing preclinical research services. This table is for information exchange purposes only. This table is not a therapy plan recommendation. For guidance on therapy options, please visit a regular hospital.
Our Services
With every step of our process, we guarantee quality and efficacy by working alongside industry partners and academic specialists through collaboration. These broad disciplines enable us to achieve seamless researching Timothy syndrome, which allows us to provide an integrated solution for drug discovery and development, ranging from diagnostics, therapeutics, complex disease model development services, and more.
Therapeutic Development Services
Animal Model Development for Timothy Syndrome
Animal models serve as an efficient platform for testing the potential effectiveness, safety, and side effects of new prospective drugs. Our company specializes in animal model creation services tailored for Timothy syndrome research aimed at accelerating your research and translating discovery into applications.
Genetically Engineering Animal Model
Genetically engineering animal models for Timothy syndrome primarily involve modifications to the CACNA1C gene.
Optional models:
- TS2-neo model
- Other models
- CaV1.2 G406R knock-in model
Protheragen's integrated approach ensures that proper vetting for efficacy and safety has been completed on each candidate compound prior to trial advancement by incorporating pharmacokinetics and drug safety evaluations. We aim to reshape the paradigms of drug development with our services that comprehensively validate efficacy and safety while discovering drug candidates. Should you wish to learn more about our services, please do not hesitate to contact us.
Reference
- Jiang, Congshan, and Yanmin Zhang. "Current updates on arrhythmia within Timothy syndrome: genetics, mechanisms and therapeutics." Expert reviews in molecular medicine 25 (2023): e17.
For research use only, not for clinical use.