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1. Introduction
2. Repeat expansion diseases
3. Polyglutamine (polyQ) repeat diseases
4. Huntington’s disease (1)
5. Huntington’s disease (2)
6. Effects of mutant huntingtin protein
7. RNAi-pathway
8. Reducing mt protein expression reverses disease
9. Vectors for delivering genetic material to brain
10. AAVs for delivering RNAi
11. Distribution of cells expressing reporter (GFP)
12. Types of cells expressing the reporter (GFP)
13. Preclinical rodent data
14. RNAi reduces target gene expression in vivo
15. RNAi improves rotarod performance in HD mice
16. Testing the efficacy of RNAi
17. RNAi that reduce expression of both alleles
18. Artificial miRNAs
19. Testing miHD for efficacy
20. miHD improves the rotarod phenotype
21. miHD treated mice show improved survival
22. miHD reduces wt and mutant htt mRNA levels
23. Off-target silencing
24. Off-target silencing pathway
25. How to make RNAi safer
26. Moving RNAi towards the clinic
27. MRI-guided delivery of AAV into primates
28. In vivo assessment of AAV.miHDS1 efficacy
29. Non-human primate and huntingtin
30. Study design
31. Suppression of HTT does not alter behavior
32. Motor rating scale developed for primates
33. Lifesaver test: assess manual dexterity
34. Reduction of HTT does not alter fine motor skills
35. HTT suppression and the Question Mark Task
36. HTT levels are reduced
37. Building a convergence of evidence
38. Summary of pre-clinical proof-of-principle studies
39. Summary I
40. Other gain-of function diseases
41. Spinocerebellar ataxias
42. Polyglutamine-based SCAs
43. Spinocerebellar Ataxia Type 1
44. Silencing of ataxin-1 by miRNA
45. Targeted infusion for broad coverage
46. B05 transgenic mouse model (Orr lab)
47. AAV.miS1 expression and ataxin-1 silencing
48. AAV.miS1: experimental design
49. AAV.miS1 silencing of ataxin-1: after 35 weeks
50. AAV.miS1 & AAV.HAtxn1L improve motor skills
51. Hindlimb clasping
52. Ledge test
53. AAV.miS1, AAV.HAtxn1L and Purkinje cells
54. AAV.miS1 improves molecular layer thickness
55. SCA1 knock-in mouse model & silencing ataxin-1
56. Nonallele specific silencing: experimental design
57. Expression and activity of miSCA1 (1)
58. Expression and activity of miSCA1 (2)
59. miSCA1 improves motor phenotypes
60. miSCA1 preserves molecular layers
61. Summary II
62. Acknowledgements

Topics Covered

• Repeat expansion diseases
• Polyglutamine (polyQ) repeat diseases
• Huntington’s disease
• Vectors for delivering genetic material to brain
• AAVs for delivering RNAi for reducing gene expression
• Artificial miRNAs
• Testing miHD for efficacy
• Off-target silencing
• MRI-guided delivery of AAV into primates
• HTT suppression
• Other gain-of function diseases
• Targeted infusion for broad coverage
• Silencing ataxin-1
• Nonallele specific silencing: experimental design
• Expression and activity of miSCA1

Links

Series:

• Gene Transfer and Gene Therapy
• RNA Interference

Categories:

• Genetics & Epigenetics
• Neuroscience

Therapeutic Areas:

• Neurology

Talk Citation

Publication History

• Published on August 5, 2014

Financial Disclosures

• Prof. Beverly L. Davidson has not informed HSTalks of any commercial/financial relationship that it is appropriate to disclose.