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- Principles and general themes
-
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
-
7. Gene therapy and virotherapy in the treatment of cancer
- Prof. Leonard Seymour
-
8. Gene therapy for the muscular dystrophies
- Prof. Jeff Chamberlain
- Major gene transfer platforms and gene therapy strategies
-
9. Gammaretroviral vectors: biology, design and applications
- Prof. Axel Schambach
-
13. Surface-mediated targeting of lentiviral vectors
- Prof. Dr. Christian Buchholz
-
14. Gene transfer and gene therapy
- Dr. David A. Williams
-
15. Tracking vector insertion sites to explore the biology of transduced cells in vivo
- Prof. Dr. Christof Von Kalle
-
16. Advances in gene therapy for respiratory diseases 1
- Prof. John F. Engelhardt
-
17. Advances in gene therapy for respiratory diseases 2
- Prof. John F. Engelhardt
-
20. Gene therapy for hemophilia
- Prof. Katherine High
- New technologies for sequence-specific editing of gene expression
-
21. Helper-dependent adenoviral vectors for gene therapy
- Prof. Nicola Brunetti-Pierri
-
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
-
23. RNAi for neurological diseases
- Prof. Beverly L. Davidson
-
24. Directed evolution of novel adeno-associated viral vectors for gene therapy
- Prof. David Schaffer
Printable Handouts
Navigable Slide Index
- Introduction
- Metachromatic Leukodystrophy (MLD)
- HCT for lysosomal storage disorders (LSDs)
- HCT for LSDs and metabolic correction
- Improving HCT efficacy - myeloid infiltration
- The role of brain pre-conditioning
- Mechanisms of microglia turnover
- Improving efficacy by appropriate conditioning
- Improving HCT efficacy - enzyme production
- Gene therapy (GT) modulates enzyme release
- HSC-GT of LSDs in the murine models
- Treatment efficacy in the murine models
- HSC gene therapy for MLD: clinical testing
- HSC gene therapy for MLD: treatment plan
- HSC gene therapy for MLD: inclusion criteria
- HSC gene therapy for MLD: study objectives
- First three patients - data before treatment
- First three patients - treatment
- Post-HCT hematopoietic reconstitution
- Stable engraftment of the transduced cells
- LV integration site analysis
- Stem cells analysis
- Shared integration sites between multiple lineages
- Stable ARSA activity reconstitution
- ARSA delivery to the CNS
- Effect on cerebral demyelination
- Effect on peripheral demyelination
- Motor function by GMFM
- HSC gene therapy for MLD: conclusions
- Acknowledgments
Topics Covered
- Metachromatic Leukodystrophy (MLD)
- Hematopoietic stem cell therapy (HCT) for lysosomal storage disorders (LSDs)
- Improving HCT efficacy
- The role of brain pre-conditioning
- Mechanisms of microglia turnover
- Gene therapy (GT) & enzyme release
- Gene therapy in murine models
- HSC gene therapy for MLD
- Lentivirus integration site analysis
- Stem cells analysis
- ARSA activity and delivery to the CNS
- Cerebral and peripheral demyelination
- Motor function testing (GMFM)
Links
Series:
Categories:
Therapeutic Areas:
Talk Citation
Biffi, A. (2014, September 3). Hematopoietic stem cell gene therapy for the treatment of metachromatic leukodystrophy [Video file]. In The Biomedical & Life Sciences Collection, Henry Stewart Talks. Retrieved December 3, 2024, from https://doi.org/10.69645/BCRL7609.Export Citation (RIS)
Publication History
Financial Disclosures
- Dr. Alessandra Biffi has not informed HSTalks of any commercial/financial relationship that it is appropriate to disclose.
Hematopoietic stem cell gene therapy for the treatment of metachromatic leukodystrophy
Published on September 3, 2014
37 min
A selection of talks on Genetics & Epigenetics
Transcript
Please wait while the transcript is being prepared...
0:00
I'm Alessandra Biffi, MD.
I'm working at the San
Raffaele Telethon Institute
for Gene Therapy in Milano, Italy.
And my talk is going to be
dedicated to the presentation
of our recent results in the
development of hematopoietic stem
cell gene therapy for the treatment
of metachromatic leukodystrophy.
0:25
Metachromatic leukodystrophy is
a demyelinating lysosomal storage
disorder.
It is due to the deficiency of
the activity of the arylsulfatase
A enzyme, which is a
lysosomal enzyme that plays
a key role in the
maintenance of myelin sheaths
in the center and
peripheral nervous system.
Arylsulfatase A indeed is critical
for the metabolize of sulfatides
that are major components
of myelin, again,
both present in the central
and peripheral nervous system.
It is a disease that is inherited
in an autosomal recessive fashion.
It's a rare disorder, with an
overall frequency of one affected
children over 40,000 live
births, and it is characterized
by quite variable
clinical presentations.
In particular, we recognize four
different variants of the disease
that are distinguished
according to the age at onset
of the first symptoms of
the disease and include
the late infantile variant, with
symptom onset before two years
of age; the early juvenile MLD
variant, in which the disease
manifests in between two
and six years of age;
late juvenile MLD, in which symptom
onset occurs between six age
and puberty; and the adult variant,
in which the onset of symptom
occurs from puberty on.
All of these disease
variants are characterized
by clinical manifestations
related to the myelin damage
occurring in the nervous
system, and so they basically
present with signs of dysfunction of
the central and peripheral nervous
system that, in children,
are manifest in the form
of developmental delay, so delay
in the acquisition of motor
and cognitive milestones
and early loss of previously
acquired motor and cognitive skills.
Whereas in adults, mostly manifests
in the form of deterioration
of cognitive abilities and,
later on, motor abilities,
and the psychiatric manifestations.
Whatever the disease
variant, the MLD
is characterized by a very severe
prognosis and is fatal, basically,
in all of the patients within
a few years from disease onset.
At the moment, that are
few therapeutic options
available for MLD.
In particular, we do have the
opportunity of hematopoietic stem
cell transplantation, which
is available for a minority
of patients and which has been
shown to stabilize disease evolution
mostly in late-onset MLD variants
and when the transplant is
performed very early in
the course of the disease.
Then we have some experimental
treatments under testing
which include gene therapy and
enzyme replacement therapy.
Enzyme replacement therapy, which
consists in the administration
of the recombinant
arylsulfatase A to the patients,
failed to exert a benefit
when administered systemically
whereas is under phase one clinical
testing upon administration
into the thecal space-- so
within the cerebrospinal fluid.
Gene therapy is under testing
with two different approaches,
the first one being an in
vivo gene therapy approach,
namely administration
of gene therapy vectors
within the brain parenchyma, and
the other one being hematopoietic
stem cell gene therapy,
so the approach
we are going to discuss
during this presentation.
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