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DISEASES OF INTEREST

  • Spinal and bulbar muscular atrophy

  • Neuromuscular diseases

  • Spinal muscular atrophy

  • Cerebellar ataxias

  • Rare neurological diseases

  • Repeat expansion diseases

RESEARCH THEMES

THEME 1. MECHANISMS OF ENHANCER ACTIVITY IN HEALTH AND DISEASE

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Enhancers play a pivotal role in governing gene expression, and their disruption is increasingly recognized as a key driver of diseases. Chromosomal rearrangements can prompt aberrant gene expression by affecting enhancers, genetic variants within enhancers may influence a transcription factor binding site, and mutations in enhancer-binding transcription factors can modify enhancer activity. Our strategy involves employing cutting-edge gene editing techniques and advanced single-cell microscopy to interrogate enhancer function in neuromuscular diseases. By delving into the intricacies of enhancer function, our goal is to precisely modulate enhancer activity to fine-tune gene expression patterns and offer treatment opportunities for these diseases.

THEME 2. UNDERSTANDING TRANSCRIPTOME DIVERSITY IN THE MOTOR UNIT

Transcriptome complexity and diversity, including patterns of differential isoform expression, non-canonical transcripts, diversity of non-coding RNAs, and RNA editing e.g. by adenosine deaminases acting on RNA (ADAR) enzymes, play fundamental roles in both normal physiological function and disease mechanisms. Owing to its paramount biological importance, alternative splicing is intricately regulated in a tissue- and developmental stage-specific manner. The central nervous system and skeletal muscle stand out for harbouring an exceptional level of transcriptome complexity. Understanding these aspects of the transcriptome is crucial for advancing our knowledge of biology and developing targeted therapeutic approaches.

THEME 3. DEVELOPMENT OF GENE THERAPY TOOLS FOR BRAIN DISEASES

Gene-targeted therapies (i.e. gene replacement, gene silencing, and genome-editing) for neurological diseases involve unique challenges, including delivery to target tissues (brain, spinal cord, and/or skeletal muscle) and restricting therapeutic activity in a cell type-specific and spatially-controlled manner to avoid off-targets. We aim to accelerate progress in three key areas: 1) Improving delivery and distribution; 2) Understanding and evading the immune response upon gene-targeted therapy administration; and 3) Development of controllable genome-editing tools that respond to endogenous signatures in a cell-type and cell-state specific fashion.

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