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Printable Handouts
Navigable Slide Index
- Introduction
- Adeno-associated virus for airway gene delivery
- Adeno-associated viral vectors
- History lesson: rAAV2 lung cystic fibrosis trials failed for several reasons (2000–2008)
- Unknowingly wrong preclinical model was used to evaluate rAAV2 (Rhesus monkey)
- Ubiquitin/proteasome system and rAAV2 transduction
- Proteasome inhibitors enhance nuclear trafficking of rAAV in polarized human airway epithelial cells
- Proteasome inhibitors can rescue functional rAAV2 following apical infection of human airway epithelia
- Cellular barriers for rAAV gene delivery
- Size matters with rAAV-CFTR vectors (fCFTR)
- Improving short synthetic promoters in rAAV
- Directed evolution of rAAV2 for airway transduction
- rAAV2.5T transduces ferret airway epithelium
- Solutions for neutralizing antibody response rAAV2.5T
- Solutions for neutralizing antibody response rAAV
- Human bocavirus 1 (HBoV1) (1)
- Human bocavirus 1 (HBoV1) (2)
- Wild type HBoV1 can infect children multiple times
- Unique properties of rHBoV vs rAAV vectors
- Impact of vector choice on CFTR gene therapy for cystic fibrosis
- rAAV2/HBoV1 demonstrates a preference for apical transduction of polarized HAE
- HBoV1 deliver genes to ciliated and non-ciliated cells without inhibition by human bronchioalveolar lavage antibodies
- rAAV2/HBoV1 transduces ferret airway
- RNA viral vectors for gene therapy
- Envelope screen on human and porcine primary cultures: preference for apical entry
- Lentiviral-mediated phenotypic correction of cystic fibrosis pigs
- Feline immunodeficiency virus (FIV-GP64) infection of neonatal ferrets
- Non-viral vectors for gene therapy of CF lung disease
- CF ferret models for testing gene therapy
- LNP mRNA delivery to ferret airways
- Typical gene therapy workflow to CF ferrets
- Mild disease CF ferret (~5 months off VX-770)
- Severe disease CF ferret (~9 months off VX-770)
- Mucolytics will be needed in severe disease states
- Mucociliary clearance endpoints in CF ferrets
- Summary
- Acknowledgements
Topics Covered
- Adeno-associated virus for airway gene delivery
- Directed evolution of rAAV2 for airway transduction
- rAAV2.5T transduces ferret airway epithelium
- Human bocavirus 1 (HBoV1)
- rAAV2/HBoV1 transduces ferret airway
- RNA viral vectors for gene therapy
- Lentiviral-mediated phenotypic correction of cystic fibrosis pigs
- Non-viral vectors for gene therapy of CF lung disease
- LNP mRNA delivery to ferret airways
- Mucolytics will be needed in severe disease states
Links
Series:
- Gene Transfer and Gene Therapy
- Periodic Reports: Advances in Clinical Interventions and Research Platforms
Categories:
Therapeutic Areas:
Talk Citation
Engelhardt, J.F. (2023, November 30). Advances in gene therapy for respiratory diseases 2 [Video file]. In The Biomedical & Life Sciences Collection, Henry Stewart Talks. Retrieved December 9, 2024, from https://doi.org/10.69645/ECEV3890.Export Citation (RIS)
Publication History
Financial Disclosures
- Prof. John F. Engelhardt has not informed HSTalks of any commercial/financial relationship that it is appropriate to disclose.
Advances in gene therapy for respiratory diseases 2
Published on November 30, 2023
41 min
Other Talks in the Series: Periodic Reports: Advances in Clinical Interventions and Research Platforms
Transcript
Please wait while the transcript is being prepared...
0:00
Welcome to Part 2, Advances
in Gene Therapy for
Respiratory Diseases.
0:08
Now, I'd like to
move into discussion
of viral vectors that
can be used for gene
therapy of cystic fibrosis.
Adeno-associated
virus, as shown here,
is a very simple single-stranded
DNA genome vector
that has a good safety profile
in human clinical trials,
it transduces both dividing
and non-dividing cells,
which is attractive
for the airway.
There are many
serotypes that exist.
There's persistent expression of
the transgene as an episome,
although if cells divide,
it's diluted with cell division
because there is
minimal integration.
The virus can be produced
at high yields for
both research and GMP
grade. The disadvantages
include the small
packaging size,
which is limited to
about 4.9 kb maximum
and at least for airway
applications there were
significant
intercellular block in
transport to the
nucleus that occurs,
which involves the ubiquitination
and the proteasome,
which I'll discuss briefly.
1:18
Now, adeno-associated viral
vectors are fairly simple.
The wild type genome,
shown here, contains two genes.
A 'rep' gene composed of
replication proteins
that encoded by
those mRNA transcripts and
the 'cap' gene that encodes
the capsid proteins.
These are flanked by two
inverted terminal repeats
that are involved in the
replication of the viral genome.
Now, a recombinant
adeno-associated virus removes
all these viral
genes and replace it
with a recombinant cDNA
in this particular KDR.
Now, there are many
serotypes of AAV
that exist, making
it attractive
to screen and find
vector systems
that can transduce the
appropriate cells in the lung,
and directed evolution is
a process in which
the shuffling of
capsid genes can be
performed in libraries made
that can be screened for
very selective tropisms
to cell types using
panning techniques.