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Human retinal gene therapy
for Leber congenital
amaurosis shows advancing
retinal degeneration despite
enduring visual improvement

Submitted to: Dr
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Important Terms
Human retinal gene therapy
• Retinal gene therapy holds a
promise in treating different forms
of non-inherited and inherited
blindness
...


Important Terms CONT…
...

• It results from both dysfunction
and degeneration of
photoreceptors
...

• The RPE65 protein is produced in a
thin layer of cells at the back of the
eye called the retinal pigment
epithelium (RPE)
...


Significance

The first retinal gene therapy in human blindness from
RPE65 mutations has focused on safety and efficacy, as
defined by improved vision
...
We show that gene therapy improves
vision for at least 3 y, but photoreceptor degeneration
progresses unabated in humans
...
The study shows
the need for combinatorial therapy to improve vision in
the short

Experiment Conducted
Human Subjects

Material
•

•

Patients (n = 23) with RPE65-LCA were
included
...


Methods
•
•

•
•

Retinal cross-sectional imaging and
analysis
...

Post acquisition processing of data was
performed with custom programs
(MatLab 7
...

Outer photoreceptor nuclear layer (ONL)
was segmented manually using a
combination of intensity and local slope
information of LRPs
...


Method
• face and retinal cross-sectional imaging
was performed with the dogs under
general anesthesia
• Custom programs (MatLab 7
...

• SD-OCT was performed with linear and
raster scans (RTVue-100 by Optovue or
Spectral is HRA+OCT)
...


CONT…
Human Subjects
•
•

•

•

ONL thickness measured at each location
by the mean normal ONL thickness at the
corresponding retinal location
Serial data from study eyes (both treated
and untreated retinal locations) of RPE65LCA were similarly processed to derive
ONL fraction
...


Dogs
• Dogs were dark-adapted overnight,
premedicated, and anesthetized
• In some case, high-energy flashes were
used to evoke photo responses
• Using the en face retinal images and ONL
topography maps as guides, eyes were
trimmed to section through the treated
and untreated regions
...


Observations
•

One of the key components of the visual cycle is the
retinoid isomerase encoded by the RPE-specific
protein 65 kDa (RPE65) gene
...

• RPE65-associated LCA (RPE65-LCA) is a complex
disease in which vision loss results from two
pathological mechanisms—dysfunction and
degeneration of photoreceptors
...


Results

•
•
•
•
•
•

Human RPE65-LCA: Natural History of Photoreceptor Degeneration
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Gene Therapy Does Not Slow the Progressive Retinal Degeneration in RPE65LCA
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Natural History of Photoreceptor Degeneration in RPE65-Mutant Dogs
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Graphical Results
Fig
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Natural history of disease in untreated human RPE65-LCA
...


Data from C replotted after horizontal shifts
accounting for differences in the onset of
degeneration at each retinal region
...

Results show a predictable natural history
underlying the progressive degeneration in
most patients
...
2
...
Green lines
demarcate the region superior to
the fovea that received a subretinal
injection and that visual function
measurements showed significant
improvements in sensitivity
...
ONL is
highlighted in blue for visibility
...


CONT…
ONL measures in control (Left)
and treated (Right) retinal
regions plotted on the natural
history of RPE65-LCA disease
defined in Fig
...
The progression
in control and treated regions is,
for
the
most
part,
indistinguishable
from
the
natural history

Visual sensitivities measured at
control (Left) and treated (Right)
retinal locations in the same
patients
...
Treated locations
show a dramatic improvement
after the surgery that is retained
over time

Fig
...
Natural history of retinal degeneration in Rpe65-mutant dogs shows regional effects
...
ONL thickness topography is mapped to a pseudo color scale
...
Reconstituted OCT scans along a superior–inferior meridian (line) are shown in Lower with the ONL
layer highlighted in blue
...
Note that
the OCTs shown are reconstituted from ultra-wide angle maps covering more than 80° × 80° (∼24 × 24 mm)
sampled at 1°
...
Gray symbols represent normal animals;
black symbols represent RPE65-mutant dogs
...

Hashed regions within gray lines show the dysfunction-only stage, and hashed regions within black lines show
the dysfunction and degeneration stage of RPE65 disease
...
Overlapping symbols have been moved
horizontally to aid in their visibility
...
2C)
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• We find that gene therapy causes substantial and durable vision improvement
but does not slow the natural history of photoreceptor degeneration
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• there is a need to advance the therapy by taking a step back to proof-ofconcept studies in animals at ages that better model the human patients



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