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Printable Handouts
Navigable Slide Index
- Introduction
- Gene therapy: concept and current status
- Adeno-associated virus (AAV)
- Adeno-associated viral vectors
- Recent breakthroughs in AAV gene therapy
- AAV success in Leber’s congenital amaurosis
- Gene delivery problems (1)
- Gene delivery problems (2)
- Criteria for success in nature vs. medicine
- Directed evolution of AAV
- Challenges when using viruses
- Barriers to gene transfer (1)
- Antibody neutralization of AAV vectors
- AAV evolution for antibody evasion
- Analysis in an animal model (1)
- Analysis in an animal model (2)
- Where are the mutations?
- Novel library construction (1)
- Selection for “viable” chimeras (1)
- Selection for “viable” chimeras (2)
- Novel library construction (2)
- Evolution of IVIG-resistant AAV
- Evolution of IVIG-resistant AAV variants
- Resistance to serum of Hemophilia B patients
- Barriers to gene transfer (2)
- Cystic fibrosis
- Directed evolution of novel tropism
- Evolved variant yields high level gene expression
- AAV-CFTR corrected CF airway epithelia
- Current responses of CF airway epithelia
- Current responses after AAV-CFTR treatment
- Barriers to gene transfer (3)
- Retina
- Retinal degenerations
- Subretinal injections in LCA trial
- intravitreal injection to transduce Muller glia
- Directed evolution to infect glia
- Gene delivery to striatal region of the brain
- Intravitreal injection
- Rat model of retinal degeneration
- Intravitreal injection of Shh10-GDNF
- Treated retinas 5 months post-injection
- Transducing photoreceptors from the vitreous
- In vivo directed evolution (1)
- AAV evolution to reach and infect photoreceptors
- GFP expression in mouse retina with AAV7m8
- Using photoreceptor specific promoter (Rho)
- Retinoschisis
- Mouse model of retinoschisis
- Functional rescue in retinoschisis model
- 7m8-RPE65 treats murine model of LCA2
- 7m8 in non-human primate
- 7m8 reaches photoreceptors
- Intensity comparison
- Summary
- Acknowledgments
- Thank you
Topics Covered
- Recent successes in gene therapy
- Problems in the field with naturally derived vectors
- Directed evolution as an approach to engineer optimal viral vector variants that meet clinical needs
- Examples: development of variants to evade neutralizing antibodies and evolution for enhanced delivery in the retina
Links
Series:
Categories:
Therapeutic Areas:
Talk Citation
Schaffer, D. (2014, August 5). Directed evolution of novel adeno-associated viral vectors for gene therapy [Video file]. In The Biomedical & Life Sciences Collection, Henry Stewart Talks. Retrieved December 14, 2024, from https://doi.org/10.69645/HUCJ8496.Export Citation (RIS)
Publication History
Financial Disclosures
- Prof. David Schaffer has not informed HSTalks of any commercial/financial relationship that it is appropriate to disclose.
Directed evolution of novel adeno-associated viral vectors for gene therapy
A selection of talks on Ophthalmology
Transcript
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0:00
This is David Schaffer.
I'm a professor at the University of
California at Berkeley in Chemical
and Biomolecular Engineering,
Bioengineering, and the Helen Wills
Neuroscience Institute,
as well as director
of the Berkeley Stem Cell Center.
In addition, I'm co-founder of the
company, 4D Molecular Therapeutics.
And I'm going to be talking
about directed evolution
of novel adeno-associated
viral vectors for gene therapy.
0:23
So if we assess the current status
of the field of gene therapy,
which can be defined as the
introduction or delivery
of genetic material to
the cells of an individual
for therapeutic benefit.
There have been a number-- an
increasing number of successes
over the past few
years, and these include
bona fide clinical
successes for the treatment
of Leber's congenital
amaurosis, hemophilia B,
as well as familial
lipoprotein lipase
deficiency and x-linked
adrenoleukodystrophy.
Now the first three
indications I mentioned
were made possible through
adeno-associated viral vector
technology, which has been
increasingly successful as we
mentioned over the past few years.
Despite all of these
successes however,
a number of disease
targets are still
beyond the reach of current
gene transfer technology.
And that technology
must be made better,
which is the focus of my talk today.
1:09
So if we zoom into more detail next
slide on adeno-associated virus,
we see that this virus has
a relatively simple genome.
It simply contains
two Cis elements--
the inverted terminal repeats
that flank the genome.
And the genome only has two genes
that are open reading frames-- REP,
which encodes several proteins, as
well as CAP, which encodes three
proteins, as well
as a fourth protein
and an alternative reading frame.
Now this virus encodes as I
mentioned several versions
or several variants of the cap
protein-- 60 copies of which will
self assemble to create this
beautiful icosahedral structure--
and the rep protein which
is responsible for mediating
the replication as well as of
other functions of the viral genome
will then load this capsid with
it's viral genome payload for cargo.
So this virus is non-pathogenic.
It's never been associated
with human disease.
It's among the smallest of viruses
both in terms of genome size
at around 4.9 kilobases
of information,
as well as the dimensions
of the particle--
around 25 nanometers in size.
And a number of natural
variants of the virus
have been isolated, which
typically have variations
in the amino-acid sequence or
identity on these exposed loop
regions that you can see on
the viral capsid structure.
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