Thesis
Personalised Therapeutics for Motor Neuron Disease Patients: Preliminary Genomic, Transcriptomic and Phenotypic Investigation of Two Early Onset Motor Neuron Disease Patients
Honours, Murdoch University
2024
Abstract
Amyloid Lateral sclerosis is a fatal neurodegenerative disease characterised by the progressive loss of upper and lower motor neurons resulting in muscle weakness and eventual paralysis. In this study, two patients in Perth were clinically diagnosed with early onset bulbar MND. Commercial genetic analysis revealed patient A contained a G4C2 expansion of 25 repeats within the C9ORF72 gene, suggestive of C9ORF72-ALS, while patient B was classified as having sporadic ALS with no genetic mutations in known ALS genes. Further interrogation of these patients genomic and transcriptomic data conducted through whole genome sequencing and RNA sequencing using patient DNA and RNA, respectively, to elucidate the genetic basis of their disease. While our analysis exploring C9ORF72-ALS phenotypic traits in patient A fibroblasts yielded inconclusive results, our study identified novel variants in SYPL1 and PRKCD, as well as significant dysregulation of the following genes, SEC14L5, CYP7B1, CYP24A1 and multiple members of the HOX gene family. Despite inconclusive characterisation of C9ORF72-ALS, preliminary therapeutic investigation using a C9ORF72 antisense oligonucleotide successfully reduced expression of the likely pathogenic C9ORF72 variant 3 in patient A fibroblasts. This study highlights potentially new points of interest as potential targets for personalized antisense-oligonucleotide development. Future studies with larger sample sizes are warranted to validate the genomic and transcriptomic results in ALS populations.
Details
- Title
- Personalised Therapeutics for Motor Neuron Disease Patients: Preliminary Genomic, Transcriptomic and Phenotypic Investigation of Two Early Onset Motor Neuron Disease Patients
- Authors/Creators
- Sebastian Drysdale
- Contributors
- Ianthe Pitout (Supervisor) - Murdoch University, Centre for Molecular Medicine and Innovative TherapeuticsSue Fletcher (Supervisor) - Murdoch University, Health Futures InstituteNiall Keegan (Supervisor)Leon Larcher (Supervisor) - Murdoch University, Centre for Molecular Medicine and Innovative Therapeutics
- Awarding Institution
- Murdoch University; Honours
- Identifiers
- 991005732483407891
- Murdoch Affiliation
- Centre for Molecular Medicine and Innovative Therapeutics
- Resource Type
- Thesis
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