Advancing Next-Generation Gene Therapy to Improve Quality of Life in Creatine Transporter Deficiency

Creatine Transporter Deficiency (CTD) is a rare genetic disorder that primarily affects boys and causes serious problems with brain development. Children with CTD show intellectual disability, delayed speech, movement difficulties, behaviors similar to autism, and seizures. These symptoms result from a lack of creatine, a molecule that is essential for brain function. Unfortunately, there is currently no effective treatment for this condition. In a previous research project funded by Telethon, we showed that gene therapy, delivering a healthy version of the faulty gene to the brain, can improve many symptoms in a mouse model of CTD. However, we also found that overexpressing the gene may lead to side effects, limiting the safety of this approach for clinical use. This new project aims to develop a safer and more effective gene therapy. By using the gene’s own natural regulatory elements to control its expression in the brain, we hope to reduce potential side effects. We will first test the safety of the treatment in healthy mice. We will then treat CTD mice shortly after birth and examine whether the therapy restores brain creatine levels, improves brain function, and reduces cognitive problems, behavioral symptoms, and seizures. To ensure the reliability of our findings, the study will be conducted across two independent research centers. We will also test the effects of later treatment to better reflect real-world diagnosis timelines. This research aims to lay the groundwork for future clinical trials and a potential therapy for individuals with CTD.