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- Principles and general themes
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1. Oncolytic viruses: strategies, applications and challenges
- Dr. Stephen J. Russell
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2. Directed evolution of AAV delivery systems for clinical gene therapy
- Prof. David Schaffer
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6. The host response: adaptive immune response to viral vector delivery
- Prof. Roland W. Herzog
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7. Gene therapy and virotherapy in the treatment of cancer
- Prof. Leonard Seymour
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8. Gene therapy for the muscular dystrophies
- Prof. Jeff Chamberlain
- Major gene transfer platforms and gene therapy strategies
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9. Gammaretroviral vectors: biology, design and applications
- Prof. Axel Schambach
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13. Surface-mediated targeting of lentiviral vectors
- Prof. Dr. Christian Buchholz
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14. Gene transfer and gene therapy
- Dr. David A. Williams
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15. Tracking vector insertion sites to explore the biology of transduced cells in vivo
- Prof. Dr. Christof Von Kalle
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16. Advances in gene therapy for respiratory diseases 1
- Prof. John F. Engelhardt
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17. Advances in gene therapy for respiratory diseases 2
- Prof. John F. Engelhardt
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20. Gene therapy for hemophilia
- Prof. Katherine High
- New technologies for sequence-specific editing of gene expression
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21. Helper-dependent adenoviral vectors for gene therapy
- Prof. Nicola Brunetti-Pierri
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22. HSV vectors: approaches to the treatment of chronic pain
- Prof. Joseph C. Glorioso
- Archived Lectures *These may not cover the latest advances in the field
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23. RNAi for neurological diseases
- Prof. Beverly L. Davidson
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24. Directed evolution of novel adeno-associated viral vectors for gene therapy
- Prof. David Schaffer
Printable Handouts
Navigable Slide Index
- Introduction
- Repeat expansion diseases
- Polyglutamine (polyQ) repeat diseases
- Huntington’s disease (1)
- Huntington’s disease (2)
- Effects of mutant huntingtin protein
- RNAi-pathway
- Reducing mt protein expression reverses disease
- Vectors for delivering genetic material to brain
- AAVs for delivering RNAi
- Distribution of cells expressing reporter (GFP)
- Types of cells expressing the reporter (GFP)
- Preclinical rodent data
- RNAi reduces target gene expression in vivo
- RNAi improves rotarod performance in HD mice
- Testing the efficacy of RNAi
- RNAi that reduce expression of both alleles
- Artificial miRNAs
- Testing miHD for efficacy
- miHD improves the rotarod phenotype
- miHD treated mice show improved survival
- miHD reduces wt and mutant htt mRNA levels
- Off-target silencing
- Off-target silencing pathway
- How to make RNAi safer
- Moving RNAi towards the clinic
- MRI-guided delivery of AAV into primates
- In vivo assessment of AAV.miHDS1 efficacy
- Non-human primate and huntingtin
- Study design
- Suppression of HTT does not alter behavior
- Motor rating scale developed for primates
- Lifesaver test: assess manual dexterity
- Reduction of HTT does not alter fine motor skills
- HTT suppression and the Question Mark Task
- HTT levels are reduced
- Building a convergence of evidence
- Summary of pre-clinical proof-of-principle studies
- Summary I
- Other gain-of function diseases
- Spinocerebellar ataxias
- Polyglutamine-based SCAs
- Spinocerebellar Ataxia Type 1
- Silencing of ataxin-1 by miRNA
- Targeted infusion for broad coverage
- B05 transgenic mouse model (Orr lab)
- AAV.miS1 expression and ataxin-1 silencing
- AAV.miS1: experimental design
- AAV.miS1 silencing of ataxin-1: after 35 weeks
- AAV.miS1 & AAV.HAtxn1L improve motor skills
- Hindlimb clasping
- Ledge test
- AAV.miS1, AAV.HAtxn1L and Purkinje cells
- AAV.miS1 improves molecular layer thickness
- SCA1 knock-in mouse model & silencing ataxin-1
- Nonallele specific silencing: experimental design
- Expression and activity of miSCA1 (1)
- Expression and activity of miSCA1 (2)
- miSCA1 improves motor phenotypes
- miSCA1 preserves molecular layers
- Summary II
- 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:
Categories:
Therapeutic Areas:
Talk Citation
Davidson, B.L. (2014, August 5). RNAi for neurological diseases [Video file]. In The Biomedical & Life Sciences Collection, Henry Stewart Talks. Retrieved November 12, 2024, from https://doi.org/10.69645/YDFW9009.Export Citation (RIS)
Publication History
Financial Disclosures
- Prof. Beverly L. Davidson has not informed HSTalks of any commercial/financial relationship that it is appropriate to disclose.
A selection of talks on Genetics & Epigenetics
Transcript
Please wait while the transcript is being prepared...
0:00
RNAi for Neurological Diseases.
My name is Beverly Davidson.
I work at the Center for
Cell and Molecular Therapy
at the Children's
Hospital of Philadelphia.
0:11
I'm going to talk today
about RNAi interference
for repeat expansion diseases.
Shown is a schematic of a gene
indicating a disease repeat
sequence in the location of
the repeat within the gene.
For example, all but
one CAG repeat, SCA12
is in the protein coding region.
These, therefore, encode
polyglutamine in the disease
containing proteins.
Other repeats, for example
the GAA in Friereich's Ataxia,
is in a non-coding region, in this
instance, in the intronic region.
There are examples of other repeats,
for example CTG repeats in three
prime UTRs in mitotic
dystrophy, also known as DM1.
And also CGG repeats
in the Fragile X locus.
These occur in the five prime UTR.
Purposes of today's talk, I'm
going to focus on the repeat
expansion diseases that are due
to polyglutamine expansion, or CAG
repeat expansion, in the
genes that, when mutated,
caused the diseases known
as spinocerebellar ataxia
or SCA type one, type
two, type six, type
seven, or Huntington's
disease, denoted here as HD.
I will only be presenting data
on SCA1 and Huntington's disease
today, although in my
laboratory work on all of those
that are highlighted below.