Science - USA (2020-05-22)

SCIENCE sciencemag.org

By John E. Dowling

S

urveys consistently report that peo-

ple fear total blindness more than

any other disability, and currently

the major cause of untreatable blind-

ness is retinal disease. The retina, a

part of the brain that extends into

the eye during development, initiates vi-

sion by first detecting light with the rod

and cone photoreceptors. Four classes of

retinal neurons then begin the analysis of

visual images. Defects in the optical me-

dia that transmit and focus light rays onto

the retina (lens and cornea) can usually be

dealt with surgically, although such treat-

ments are not available in some parts of the

world, resulting in as many as 20 to 30 mil-

lion legally blind individuals worldwide.

Untreatable retinal disease potentially

causes legal or total blindness in more

than 11 million people in the United

States alone, but progress in treatments

raises the possibility of restoring vision

in several types of retinal blindness ( 1 ).

Retinal neurons comprise bipolar and

horizontal cells, which are second-order

neurons that receive signals from the pho-

toreceptors in the outer retina. Third-order

amacrine and retinal ganglion cells are ac-

tivated in the inner retina by bipolar cells.

Axons from the ganglion cells form the op-

tic nerve and carry the visual message to the

rest of the brain (see the figure). The cells

most susceptible to blinding retinal disease

are the photoreceptors and ganglion cells.

Whereas progress has been made in com-

bating blindness caused by photoreceptor

degeneration, little can be done currently

to address ganglion cell loss, such as occurs

in glaucoma.

The approach that has been most suc-

cessful in restoring photoreceptor loss that

results in complete blindness is the use of

retinal prosthetic devices, with two now

approved for clinical use ( 2 ). These devices

electrically stimulate either bipolar or gan-

glion cells. They require goggles that have

a camera that converts visual stimuli into

electrical stimuli that activate the device,

which in turn stimulates the retinal cells.

Several hundred of these devices have

been implanted in blind or virtually blind

individuals, 70 to 80% of whom report im-

provement in quality of life. For those who

are completely blind, the ability to experi-

ence again at least some visual function is

viewed as a miracle.

There are substantial limitations to the

devices, however. The best visual acuity

attained so far is poor (20/500) and visual

field size is limited, but many improve-

ments, mainly technical, are being devel-

oped and tested, including the potential use

of electronic low-vision devices to increase

visual field size and acuity ( 3 ). Retinal pros-

theses are not useful for patients who are

blind because of loss of ganglion cells and/

or the optic nerve, but prostheses that by-

pass the retina and stimulate more central

visual structures, including the lateral ge-

niculate nucleus (the intermediary between

retina and cortex) and visual cortex, are

being developed and tested in humans ( 4 ).

There remain considerable technical issues,

but preliminary data indicate that such de-

vices are feasible.

A second approach to treat photorecep-

tor degeneration and potential blindness,

now in the clinic, is gene therapy ( 5 ). This

involves injecting a viral construct into

the eye that contains a normal gene to

replace an abnormal one. Success so far

has been limited to the treatment of Leber

congenital amaurosis (LCA) type 2, a rare

form of retinitis pigmentosa in which the

gene whose product is required to form the

correct isomer of vitamin A aldehyde, the

chromophore of the visual pigments, is mu-

tated. Little of the correct isomer is made

in LCA patients, resulting in substantial

loss of photoreceptor light sensitivity. This

is reversed when viral constructs encoding

the normal gene are injected deep into the

eye between the photoreceptors and pig-

ment epithelium.

Two factors make this approach feasible

in LCA: The genetic defect is monogenic,

and many of the photoreceptors in the pa-

tients remain alive, although compromised.

Thus, how broadly feasible gene therapy

will be for treating the enormous range of

inherited retinal diseases now known to ex-

ist (~300) remains to be seen. But at least a

dozen other gene therapy trials on mono-

genic inherited eye diseases similar to LCA

are under way ( 6 ). Other methods to ma-

nipulate genes are now available, including

CRISPR-mediated editing of retinal genes.

So far, the experiments have been mainly on

isolated cells or retinas, but these powerful

techniques are likely to have eventual clini-

cal applications.

A variation on the use of gene therapy

techniques is optogenetics, in which light-

sensitive molecules are introduced into

non- photosensitive retinal cells. This ap-

proach holds much promise for restoring

vision to totally blind individuals whose

photoreceptors have been lost. Using

viruses to insert genes encoding light-

sensitive molecules into bipolar and

ganglion cells, as well as surviving

photoreceptor cells that are no longer

photosensitive, has been accomplished

in animals and shown to restore some

vision ( 7 ). Again, technical issues remain:

The cells made light-sensitive require

bright light stimuli, and the light-sensitive

cells do not adapt. That is, whereas pho-

toreceptors normally allow vision over as

much as 10 log units of light intensity, the

cells made light-sensitive respond only to a

range of 2 to 3 log units. Various methods

to overcome these limitations are now be-

ing developed, and at least one clinical trial

is under way. Experiments to make cortical

neurons sensitive to light or other stimuli

that better penetrate the skull—magnetic

fields or ultrasound, for example—are also

being developed and tested in animals.

Other promising approaches to restore

vision are being explored. In cold-blooded

vertebrates, retinal cells (in fish) and even

the entire retina (in amphibians) can re-

generate endogenously after damage.

Regeneration of retinal cells in zebrafish is

now quite well understood ( 8 ). The regener-

ated neurons come from the major glial cell

in the retina, the Müller cell. After retinal

damage, Müller cells reenter the cell cycle

and divide asymmetrically to self-renew

and produce a progenitor cell that prolif-

erates to produce a pool of cells capable of

differentiating into new retinal cells that

repair the retina.

A number of transcription factors and

NEUROSCIENCE

Restoring vision to the blind

Ideas abound to restore vision to people blinded by retinal disease

Department of Molecular and Cellular Biology, Harvard

University, Cambridge, MA 02138, USA. Email: dowling@

mcb.harvard.edu

“...progress in treatments raises the

possibility of restoring vision in several

types of retinal blindness .”

22 MAY 2020 • VOL 368 ISSUE 6493 827

Published by AAAS