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Each form of Batten (Neuronal Ceroid Lipofuscinoses - NCL-) is caused by
a mutation in the patient’s DNA that renders a gene defective.
Gene transfer is the idea of replacing the defective gene with a working
copy of the gene.
The INCL mice recapitulate the major features of the disease. Neurological
deficits appear at 4.5 months (20 weeks old) with premature death occurring
around 8 months old (normal mice live 24 months).
A single intrathecal (IT) injection of an AAV vector carrying the CLN1 gene
was administered via lumbar puncture to mice at different ages, each one
corresponding to a different stage in the disease progression and relevant for
the design of a clinical trial: 1 week old (modeling dosing soon after birth in a
human), 4 weeks old (pre-symptomatic), 20 weeks old (early-symptomatic) or
26 weeks old (symptomatic).
A low dose (LD) and a high dose (HD) were compared.
I. Direct brain injection
Needles are inserted by a neurosurgeon through holes
drilled in the skull.
A. The vector can be injected into multiple areas of the
brain. This is the approach being utilized for the ongoing
CLN2 clinical trial with AAV.
B. Vector can be injected into the cerebrospinal fluid
(CSF) that surrounds and runs through the brain.
II. Intravenous injection
Uses a vector that can reach the brain by
crossing the Blood-Brain barrier (newer
AAV can do this).
This delivery route is utilized for the
ongoing Spinal Muscular Atrophy (SMA)
and MPS IIIA clinical trials.
Getting the vector to the brain
Some forms of Batten (including Infantile NCL) involve genes that make a
In this case, the enzyme produced and secreted by 1 cell can be taken up
by neighboring cells. This is called cross-correction.
With cross-correction, a few treated cells can provide enough enzyme to
have far-reaching beneficial effects.
Enzyme producing cell
Cross-corrected cell Uncorrected cell
At the low dose (LD), mice treated at 20 weeks or later did not show
therapeutic benefits; however, mice treated at 4 weeks survived to
approximately twice their expected lifespan (16 months) concurrent with
improvement of their quality of life. Mice treated at 1 week are currently 15
months old and in good health.
Treatment with the high dose (HD) did provide some modest benefit in
survival and quality of life when administered after the onset of symptoms;
still, the outcome was better the earlier the mice were treated.
Our preliminary findings suggest this approach could be
advanced as a treatment for INCL that is likely to provide the
most benefit when administered early in the disease
Our results would not predict a meaningful benefit for patients
at an advanced stage of the disease.
Gene Therapy For Infantile NCL
Steven Gray, Alejandra Rozenberg, Gene Therapy Center, University of North Carolina at Chapel Hill
What is Gene Therapy?
The new healthy copy of the gene has to be delivered to the cells in the
patient somehow. Anything that is used to move the DNA into the cells is
called a vector.
The most successful vectors so far for Batten Disease have been modified
The most prominent and widely
used vector for Batten Disease and
other brain disorders is the Adeno-
Associated Virus (AAV).
Used in over 75 human clinical trials,
including Parkinson’s, Batten and
How does gene transfer work?
Acknowledgments and funding
Intrathecal Gene Therapy in
The objective of the study was to directly test a gene
therapy treatment approach for Infantile Batten Disease
(INCL), trying to establish the optimal dose and
determine how late in the course of the disease the
treatment is effective.
There are three main delivery routes:
Gene transfer should correct the disease at the source of the problem,
rather than just treating symptoms.
“Gene transfer” becomes gene therapy when the new gene fixes some
aspect of the disease and it helps the patient.
Since the gene is corrected, one treatment can be a permanent fix.
0 4 8 12 16 20 24
DeathBirth Onset of
Birth Onset of
DeathBirth Onset of
DeathBirth Onset of
Birth Onset of
26 weeks- LD
LD Low Dose
HD High Dose
* Schematic representation. 1 week-HD and
4 weeks-HD treatments not shown (mice still
too young to see benefits).
Treatment benefits comparison*
Much work has been done to
modify existing viruses to work as
gene therapy vectors, or “molecular
cell makes protein
using new gene
These results clearly demonstrate the importance of early intervention.
UNC Vector Core
UNC Mouse Behavioral Phenotyping Core
Contributors at UNC
III. Intrathecal injection
(A needle is inserted through the skin and into the
CSF at the lumbar region of the spine).
Vector will flow through the fluid that surrounds
the brain and spinal cord (CSF) and distribute
throughout the brain.
This has been demonstrated in monkeys with
AAV, but there are no published results in humans.
Used for the CLN6 and Giant Axonal Neuropathy
(GAN) clinical trials.