The Live Mouse Tracker (LMT) as a versatile drug screening platform for rare neurological diseases. 01/01/2025 - 31/12/2025

Abstract

Establishing effective therapies for rare neurodevelopmental diseases remains one of the greatest challenges in molecular medicine. Although advances in next-generation sequencing technologies have led to the discovery of hundreds of novel genetic syndromes over the past decade, the development of individualized therapies continues to lag behind. Each rare disorder, while affecting a small group, contributes to a global burden estimated to impact over 300 million individuals. The complexity arises from the fact that these disorders, often caused by mutations in different genes, affect multiple cellular pathways, generating an overwhelming volume of data that must be analyzed to inform therapeutic strategies. Current drug interventions have seen limited success in translating promising preclinical findings into patient-ready treatments. The rapid rise of AI technologies, however, has the potential to transform this landscape. AI-driven algorithms are increasingly capable of navigating vast biomedical datasets, revealing drug candidates for rare diseases at an unprecedented pace. Many start-ups are already capitalizing on this potential, generating a flood of drug candidates for preclinical evaluation. However, this surge in candidate therapies has shifted the bottleneck from drug discovery to preclinical testing. Traditional murine test batteries are labor-intensive, expensive, and time-consuming, necessitating a standardized, scalable, and efficient platform to meet the growing demand for drug screening. We propose the development and commercialization of our Live Mouse Tracker (LMT) platform, a cutting-edge tool designed to address this critical need. The LMT system automates behavioral analysis, capable of tracking up to 39 different behaviors in groups of mice over 24-hour periods. This high-throughput capability provides a rapid and comprehensive assessment of drug efficacy in preclinical models. Our initial validation will focus on the fragile X syndrome, a widely studied neurodevelopmental disorder for which no effective treatment currently exists. By evaluating drugs that target multiple affected pathways simultaneously, we aim to pioneer a new approach to rare disease therapy development. During this project, we will validate the robustness of the LMT platform and extend it into a fully integrated service, as well as explore collaboration with other university partners to offer comprehensive preclinical drug testing solutions. This service platform has the potential to revolutionize the drug development pipeline, ensuring that AI-generated candidate drugs can be rapidly and reliably assessed, accelerating the path from bench to bedside. Through this initiative, we aim to bridge the gap between drug discovery and therapeutic application, bringing hope to millions of patients with rare neurological diseases.

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Project type(s)

  • Research Project

Dynamic CGG Short Tandem Repeat Mutations as a Cause of Neurodevelopmental Disorders. 01/10/2024 - 30/09/2027

Abstract

CGG short tandem repeats (STRs) are stretches of low-complexity, CG-rich, repetitive DNA that inherit unstably in pedigrees and play a role in neurodevelopmental disorders (NDDs). While CGG STRs are causative for several disorders, here, I hypothesise that the amount of NDDs, resulting from dynamic mutations in CGG STRs, is grossly underestimated. I focus on CGG STRs due to their role in NDDs and because of the epigenetic silencing of the repeat-containing genes. Using the latest repeat genotyping algorithms and the T2T-CHM13/hs1 reference assembly, I will catalogue the human CGG STRs. With an additional step of repeat detection in indel variant data, I aim to extend the CGG catalogue beyond the constraints of the reference. Further, I will use whole-genome sequencing (WGS) data to establish a population baseline of STR length and variation, before assessing NDD population WGS data to identify potentially pathogenic STRs. Once STR expansion targets are identified, a group of NDD trios will be experimentally investigated by long-read sequencing. Until now, the epigenetic changes accompanying STR mutations have been presented as an all-or-nothing effect. In this project, I will challenge this dogma and define epigenetic changes associated with the full range of CGG STRs lengths. In addition, I will explore the biological and functional role of CGG STRs by assessing their mosaic differences across different brain tissues and correlating this with transcriptomic data.

Researcher(s)

Research team(s)

Project type(s)

  • Research Project