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Printable Handouts
Navigable Slide Index
- Introduction
- Coagulation and hemophilia
- Hemophilic knee bleed
- Hemophilia in queen Victoria's family tree
- Sequencing the mutation in the royal family
- Hemophilia treatment in the 20th century
- Current treatment of hemophilia
- 21st century goals
- Goals of gene transfer for genetic disease
- Viruses can be engineered to deliver genes
- Two strategies to achieve long-term expression
- Successes in gene therapy-integrating vectors
- In vivo transduction strategy
- AAV structure and composition
- Adeno-associated virus (AAV)
- AAV vectors: two viewing standpoints
- Scientific and medical/therapeutic questions
- Paradigm for novel therapeutics in genetic disease
- Expression of F.IX in mice with AAV-hF.IX
- AAV-F.IX vectors
- AAV2-based gene transfer for hemophilia B
- Animal studies may not predict side effects
- PCR on DNA extracted from semen samples
- Risk of germline transmission
- Risk of inadvertent germline transmission
- Gene experiment comes to cross ethicists' line
- Results: week 3 to week 5
- Semen analysis for vector DNA
- Animal model for risk of germline transmission
- PCR analysis of rabbit semen after IV rAAV
- Trial protocol amended to mitigate risk
- Second phase I/II trial
- Coagulation studies (subject E)
- Observations from infusion in humans
- Human subjects differ from animal models
- Transient transaminitis (subject E)
- AAV vectors: simple structure and 2 antigens
- Loss of F.IX expression in clinical trial
- Peptide library based on AAV-2 and F.IX
- Positive T cell response to viral capsid
- Working model
- Liver enzyme and capsid-specific CD8+ T cells
- Transaminitis and decrease in F.IX levels
- Neutralizing antibodies to AAV block transduction
- Advances in first trial
- Next steps
- UCL/St. Jude trial
- Self-complementary DNA and F.IX synthesis
- AAV8-F.IX trial (UCL/Royal Free/St. Jude's)
- Titering discrepancy with sc vectors
- Re-titering of vectors
- Factor IX levels in UCL/St. Jude trial
- Plasma F.IX levels: low dose
- Plasma F.IX levels: high dose (P5)
- Further dose elevation (P5)
- Plasma F.IX levels: high dosage (P6)
- Clinical results of high dose cohort
- High dose cohort
- Advances in second trial
- AAV-mediated gene transfer for hemophilia
- Anti-AAV NAb in adults with hemophilia B
- Strategies to overcome immunity to AAV
- Empty capsids hypothesis
- Rationale for use of empty capsids
- Mouse model of NAb in humans
- Empty capsids overcome transduction barrier
- Safety issue of the empty capsids
- Vector engineering enhances safety of approach
- Current trial ongoing at CHOP and Pittsburgh
- Current results of CHOP clinical trial (subject 1)
- Current results of CHOP clinical trial (subject 2)
- Three AAV-Factor IX trials now open
- Pending questions/future directions
- Acknowledgments
Topics Covered
- Hemophilia treatment past and present
- Gene transfer for genetic disease
- Viruses engineered to deliver genes
- Gene therapy using integrating vectors
- Adeno-associated virus (AAV) structure and composition
- AAV-Factor IX vectors
- AAV-mediated gene transfer for hemophilia
- Risk of germline transmission
- Peptide library based on AAV and Factor IX
- Transaminitis and liver enzymes
- Neutralizing antibodies to AAV
- Self-complementary DNA and Factor IX synthesis
- Strategies to overcome immunity to AAV
- Use of empty capsids
Links
Series:
Categories:
Therapeutic Areas:
Talk Citation
High, K. (2014, August 5). Gene therapy for hemophilia [Video file]. In The Biomedical & Life Sciences Collection, Henry Stewart Talks. Retrieved December 8, 2024, from https://doi.org/10.69645/HXNH2558.Export Citation (RIS)
Publication History
Financial Disclosures
- Prof. Katherine High has not informed HSTalks of any commercial/financial relationship that it is appropriate to disclose.
A selection of talks on Clinical Practice
Transcript
Please wait while the transcript is being prepared...
0:00
The title of this talk is
Gene Therapy for Hemophilia.
My name is Katherine High, and
I'm a professor of pediatrics
at the University of
Pennsylvania School of Medicine
and an investigator of the
Howard Hughes Medical Institute.
0:18
I'll begin by providing
some background
on blood coagulation and hemophilia.
Hemophilia is the
x-linked bleeding disorder
that is caused by the absence of
functional factor VIII, which is
called hemophilia A, or factor
IX, which is called hemophilia B.
These diseases are
clinically indistinguishable
and were not separated in the
laboratory until the 1950s.
Both diseases are characterized
by frequent bleeding episodes,
primarily into the joints,
also other soft tissues,
and less frequently
but more seriously,
into critical closed spaces,
such as the intercranial space.
Hemophilia affects one
in 5000 male births,
with hemophilia A approximately
five to six times more common
than hemophilia B.
And clinically the disease is
divided into those who are severely
affected who have less
than 1% normal circulating
levels of factor VIII or factor IX.
Those who are moderately
affected with levels of 1% to 5%
and those who are mildly affected
with levels of 5% or greater.
1:31
For individuals who have never
seen a hemophilic knee bleed,
you can see in this slide
that the bleed can greatly
distend the joint, and
in fact, an untreated bleed
will continue to bleed until
the back pressure from the field
that joint space exerts enough
pressure to stop the bleeding.
It's easy to imagine that
this would be very painful
and that repeated bleeds
like this would result
in a chronic arthropathy
in the joint.