SCIENCE sciencemag.org
NEUROSCIENCEUnblinding with infrared
nanosensors
Gene therapy and nanotechnology come together
to fight degenerative blindness
By Katrin Franke and Anna VlasitsM
any cases of blindness result from
progressive loss of photoreceptors,
which are the light-sensing cells in
the eye. For individuals with such
progressive blindness, potential
therapies aim at restoring vision by
making the retina light-sensitive again while
minimally interfering with any healthy pho-
toreceptors—goals that are usually contradic-
tory. Many current therapeutic strategies in-
terfere with remaining vision, making them
primarily suitable for patients who have lost
all light sensitivity. On page 1108 of this issue,
Nelidova et al. ( 1 ) present a potential solution to
this conundrum: making the retina sensitive
to infrared light, which is largely undetect-
able by human photoreceptors. They use en-
gineered nanoparticle sensors and gene ther-
apy to induce infrared light sensitivity in mice
with inherited degenerative blindness and in
postmortem human retinas. This approach
might avoid damage to functional photore-
ceptors by preventing saturation or hyper-
activation while inducing light sensitivity in
patients with partial retinal degeneration.
At the level of the retina, a multilayered ar-
ray of more than 100 types of neurons sorts
complex visual features, such as motion and
color, into separate channels to send to the
brain ( 2 ). When photoreceptors fail, the en-
tire downstream network is affected, and
restoring the visual system’s physiological
function becomes challenging. In addition,
mammalian rod and cone photoreceptors,
unlike those of some species in the animal
kingdom, cannot regenerate. For patients
with degenerative blindness, the aim of ther-
apy is therefore twofold: to slow degenera-
tion while preserving remaining vision, and
to restore some vision once degeneration is
complete. Several types of therapies show
promise in slowing degenerative blindness,
including targeted gene therapies and stem
cell–based approaches ( 3 , 4 ). One example
is Leber congenital amaurosis, a disease for
which a gene therapy has led to an improve-ment in patients’ visual function ( 5 ). Other
therapeutic strategies include electrical im-
plants and optogenetic gene therapies, which
aim at restoring vision ( 4 , 6 ).
The optogenetic approach induces the
expression of light-sensitive ion channels
through gene therapy to restore light sensi-
tivity to retinal neurons. Several molecular
candidates can restore light sensitivity in ani-
mals and in postmortem human retinas ( 7 ),
and some are now in clinical trials. But cur-
rently these molecules require much more
light than normal photoreceptors to become
activated, and most therapies would require
video goggles to boost the effective bright-
ness of incoming images. For patients with
some remaining vision, this strategy would
saturate or possibly even damage their re-
maining functional photoreceptors.
Nelidova et al. circumvent these problems
by making the retina sensitive to infrared
light, which is light beyond the visible spec-
trum and emitted by, for example, warm ob-
jects. Their approach combines gene therapy
with the use of gold nanorods, an emerging
nanotechnology for activating molecules
in the human body ( 8 ). Nelidova et al. use
gold nanorods as antennae for infrared light,
transforming the light into heat through a
process called surface plasmon resonance.
Genetic constructs injected into the eye then
cause the expression of temperature-sensitive
transient receptor potential (TRP) channels
in photoreceptors. Such TRP channels are
normally found in mammalian heat-sensing
nerves in the skin, as well as in the infrared-
sensing organs of some snakes and vampire
bats, and are able to transform heat into elec-
trical changes in the membranes of cells ( 9 ).
The authors use antibodies to link the heat-
emitting gold nanorods to heat-sensitive TRP
channels. Thus, infrared light can activate
photoreceptors (see the figure).
To test whether this strategy can restore
visual function, Nelidova et al. express TRP
channels in cone photoreceptors of a mouse
model of degenerative blindness. They find
that neural activity measured in the retina
and visual cortex correlated with infrared
light stimuli. In addition, they show that
treated blind mice can use their infrared light
sensitivity to learn a simple visually guidedInstitute for Ophthalmic Research, Bernstein Center
for Computational Neuroscience, Center for Integrative
Neuroscience, Tübingen University, 72076 Tübingen,
Germany. Email: [email protected]metallic spectral features begin to reveal
themselves at concentrations lower than
when the solution begins to visually appear
metallic bronze.
On the dilute side of the concentration
range (only one solvated electron or one
solvated dielectron), ab initio molecular dy-
namics provide structures of the electron and
dielectron solvated by ammonia molecules.
These structures are then used for high-level
vertical dissociation energy computations.
Performing ab initio molecular dynamics of
an excess electron or dielectron in bulk am-
monia is a substantial computational feat
and advances the field beyond previous static
cluster calculations to reveal a diffuse ammo-
nia solvation shell that is similar for both the
electron and the dielectron. The spin densi-
ties suggest that the ammoniated electron
resides within a cavity that is less structured
than that of the hydrated electron. The high-
level vertical dissociation energy calculations
show that the energies to ionize the electron
and the dielectron both fall within the mea-
sured photoelectron signal.
With greatly increased computational re-
sources, ab initio molecular dynamics simu-
lations could be expanded to a larger scale
to include metal ions dissolved in ammonia
at a variety of concentrations. Studies such
as these may be necessary to resolve some
of the remaining controversy of the localized
versus delocalized nature of the hydrated
and ammoniated electron ( 10 – 13 ). These re-
sults would provide additional atomistic and
electronic details of the electrolyte-to-metal
transition. For now, the spectroscopic stud-
ies by Buttersack et al. provide the missing
energetic and spectroscopic link and reveal
the gradual transition to metallic behavior
before our eyes can see it. j
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ACKNOWLEDGMENTS
The author is supported by grants from the U.S. Department
of Energy, Basic Energy Sciences, Computational and
Theoretical Chemistry and Condensed Phase and Interfacial
Molecular Science programs (DE-SC0019053 and
DE-SC0020203).
10.1126/science.abb97175 JUNE 2020 • VOL 368 ISSUE 6495 1057
Published by AAAS