A Panel of 3 allele specific ASO's can be used to treat most Huntington Disease patients.

1. Potent and Selective
Antisense Oligonucleotides
Targeting Single-Nucleotide
Polymorphisms in the
Huntington Disease Gene/
Allele Specific Silencing of
Mutant Huntingtin
Carroll et al., 2011 (Both Jeffrey Carroll and Simon Warby
contributed equally)
Presented by Sveta Jagannathan

2. Presentation Overview
• Background
– Huntingtin
– Huntington’s Disease
– ASO’s
•Methods
•Major Findings
•Implications

3. Background- Huntingtin
• Huntingtin Protein made by Huntingtin
Gene (HTT)
• Wild-type HTT is unmutated allele
• Involved in development and maintaining
neuronal health

4. Background- Huntington’s
disease
• Huntington’s disease (HD) is a
neurodegenerative disorder
– Caused by gain-of-function mutation
– Mutation is a CAG-expansion in HTT gene
– Autosomal dominant mutation
• Currently has no cure/genetic therapy

5. Background- ASO’s
• ASO= Antisense Oligonucleotide(s)
• Can target single-nucleotide
polymorphisms (SNPs)
• Used in post-transcriptional gene silencing
• Effective in adult CNS neurons
• Possible method for HD treatment

6. Methods
• SNPs analyzed in 234 patients with HD via
custom genotyping assay
• Specific ASO’s that target 3 mutant HTT
alleles were developed and screened
– ASO’s binded to RNA and caused cleavage
• ASO’s modified to be more effective while
not harming the other DNA/RNA

7. Major Findings
• About 85% of people with HD have 1 of 3
specific mutant HTT alleles
• 50 potential SNP targets in HTT
• A single ASO can be used to treat 49% of
people with HD, but combining several
ASO’s is more effective

8. Major Findings Continued
• ASO’s can be modified by altering their
backbones
• Adult neurons from the CNS absorb ASO’s
without transfection reagents
• ASO’s work in vivo to silence mutant HTT

9. Implications
• A panel of 3 allele-specific ASO’s can be
used to treat most HD patients
• Modification to the ASO’s can be done to
treat these patients more effectively
• ASO’s can be explored as an option to
treat other autosomal dominant diseases
(particularly those affecting the CNS)