Poster Presentation Australasian RNA Biology and Biotechnology Association 2025 Conference

Childhood Dementia Theratyping: Evaluating Variant Suitability For Antisense Oligonucleotide Therapy Development (#45)

Sujit S Krishnan 1 , Arlene D'Silva 1 2 , Andrei Smolnikov 3 , Childhood Dementia Working Group 1 2 3 4 5 6 7 8 9 , May Aung-Htut 10 , Emily C Oates 3 4 , Michelle A Farrar 1 2 11
  1. Discipline of Paediatrics and Child Health, School of Clinical Medicine UNSW, Sydney, NSW, Australia
  2. Department of Neurology, Sydney Children’s Hospital Network, Sydney, NSW, Australia
  3. School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW , Australia
  4. Centre for Clinical Genetics, Sydney Children’s Hospital Network, Sydney, NSW , Australia
  5. Centre for Population Genomics, Garvan Institute of Medical Research and University of New South Wales, Sydney, NSW, Australia
  6. Centre for Population Genomics, Murdoch Children's Research Institute, Melbourne, VIC, Australia
  7. Structural Biology Facility, Mark Wainwright Analytical Centre, University of New South Wales, Sydney, NSW, Australia
  8. Genetic Metabolic Disorders Service, Sydney Children’s Hospital Network, Sydney, NSW, Australia
  9. Department of Neurology, John Hunter Children’s Hospital, Sydney, NSW, Australia
  10. Centre for Molecular Medicine + Innovative Therapeutics, Murdoch University, Perth, WA, Australia
  11. RNA Institute, University of New South Wales, Sydney, NSW , Australia

Background & Aim

Childhood dementias (CD) are a clinically and genetically heterogeneous group of neurodegenerative disorders. Less than 5% have effective treatments. Antisense oligonucleotides (ASOs) are small nucleic acid molecules that modulate the RNA-level impacts of genetic variants and hold great promise as future CD treatments.  This study aimed to identify potentially ASO-targetable disease-causing variants in a well-characterised CD cohort.

Methods 

Clinical, demographic and causative variant data from a cohort of children with genetically confirmed CD were analysed. Bioinformatic tools were used to predict the RNA- and protein-level impacts of all cohort member variants. Existing ASO theratyping frameworks and additional expert opinion were then leveraged to determine which variants were potentially amenable to ASO-based treatments.

Results 

The CD cohort comprised 30 children with 38 disease-causing variants in 22 nuclear and three mitochondrial genes. Overall, ten children from seven families had at least one variant potentially amenable to ASO treatment. This included 1) six children with an intronic variant amenable to ASO-masking aimed at restoring full-length protein expression, and 2) four children with an exonic variant amenable to ASO-induced exon skipping aimed at feasibly producing a shorter, partially functional protein. Additionally, eight children had variants requiring more nuanced consideration of ASO treatment options.

Conclusions

We have consolidated and applied an effective ASO theratyping methodology that incorporates comprehensive in silico predictive analyses and a clinically useful decision-making framework. This approach could evaluate the ASO-targetability of other rare disease-causing variants in the context of an Australian-led ASO treatment discovery, development, and translational pipeline.