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other factors identified as being involved in

retinal regeneration in zebrafish have been

shown to stimulate some Müller cell prolif-

eration and neuronal regeneration in mice.

Regenerated bipolar and amacrine cells,

as well as rod photoreceptors, have so far

been identified in mouse retinas, and these

cells are responsive to light stimuli ( 9 , 10 ).

Further, cells postsynaptic to the regener-

ated neurons are activated by light stimuli,

indicating that the regenerated neurons

have been incorporated into the retinal

neural circuitry. So far, the regenerative ca-

pacity of mammalian Müller cells is limited,

but directed differentiation of specific types

of neurons with a mix of factors appears to

be a possibility. Regrowth of ganglion cell

axons after the optic nerve is disrupted is

also under active investigation, and al-

though the number of axons regrowing is

low (~10%), those that do regrow establish

synaptic connections with their correct tar-

gets ( 11 ). Therefore, endogenous regenera-

tion is still far from clinical testing, but sub-

stantial progress has occurred.

A long-studied area of research is trans-

plantation of retinal cells, particularly

photoreceptors, into diseased retinas. In

experiments with mice, transplanted post-

mitotic rod photoreceptor precursor cells

derived from embryonic retinas or from

stem cells appeared to integrate into dis-

eased retinas in reasonable numbers and

to be functional. A surprising and unex-

pected complication in the interpretation

of these experiments was recently discov-

ered. Rather than integrating into diseased

retinas, the donor cells appear to pass

material (RNA or protein) into remain-

ing host photoreceptor cells, rejuvenating

them, and these appear to be most of the

functional cells ( 12 ). The current evidence

suggests that only a small proportion of

the donor cells integrate, but progress in

overcoming this setback is being made.

More success has been reported with

stem cells induced to become pigment epi-

thelial (PE) cells, which provide essential

support for photoreceptors. A number of

blinding retinal diseases relate to the de-

generation of the PE cells, and replacement

using such cells—in a suspension or on a

scaffold—is being actively pursued. PE cells

do not need to integrate synaptically with

retinal cells; they simply need to contact the

photoreceptor cells. This is achieved when

PE cells are placed between the retina and

the back of the eye. Early clinical trials sug-

gest that the transplants are safe, but reti-

nal detachment, a serious complication, can

occur and efficacy has yet to be shown ( 13 ).

The finding that donor photoreceptor

cells can help diseased host retinal cells

to recover function suggests that certain

substances can provide neuroprotection.

Indeed, a substantial number of such neu-

roprotective molecules have been shown to

affect retinal disease progression, especially

degeneration of photoreceptor cells. No one

factor has been shown to be effective gener-

ally, but two have received much attention.

One, ciliary neurotrophic factor (CNTF),

promotes photoreceptor survival in light-

induced photoreceptor degeneration and in

several other models of retinal degeneration

( 14 ). Some evidence suggests that CNTF acts

primarily on Müller cells, but how it works,

and on what cells, is still unclear. The other

factor, rod-derived cone viability (RDCV)

factor, has received less research attention,

but with recent industrial support, it is now

being advanced to the clinic. Current evi-

dence indicates that RCDV factor protects

cones after rod degeneration.

Two of the most common retinal dis-

eases in developed countries—age-related

macular degeneration (AMD), the leading

cause of legal blindness (visual acuity of

less than 20/200), and glaucoma, the lead-

ing cause of total blindness—are not mono-

genic diseases, and so genetic treatments

for them are not obvious. Attempts to un-

derstand the etiology of these diseases are

under way, but currently their underlying

causes are still unclear. A difficulty pre-

sented by AMD is that no animal model is

readily available, because it is a disease of

the fovea, which mediates high-acuity vi-

sion. Except for primates, other mammals

do not possess this small critical retinal

area. Whereas large primates are not fea-

sible for extensive cellular or molecular

studies, small primates such as marmosets

that have a fovea are potential models but

have not been used much to date.

Other approaches for restoring vision

have been suggested and have even yielded

some progress. From both normal hu-

mans and those with an inherited retinal

disease, skin biopsy cells can be induced

to form tiny retinal eyecups called organ-

oids ( 15 ). Containing all retinal cell types,

these structures could be a source of reti-

nal cells for studying retinal disease devel-

opment and possible therapies, as well as

for cell transplantation. A fovea has not

been observed in any organoid so far, but

this is not beyond the realm of possibility.

Another suggested approach is to surgi-

cally transplant whole eyes into blind indi-

viduals. This appears feasible, but whether

there is sufficient optic nerve regrowth re-

mains an open question. j

REFERENCES AND NOTES

1. J. E. Dowling, K. M. Wright, Eds., special issue on
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2. J. O. Mills, A. Jalil, P. E. Stanga, Eye 31 , 1383 (2017).


3. A. D. Deemer et al., Optom. Vis. Sci. 95 , 694 (2018).


4. E. Fernández, R. A. Normann, in Artificial Vision, V. P.
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5. S. Russell et al., Lancet 390 , 849 (2017).


6. A. V. Garafalo et al., Prog. Ret. Eye Res. 10.1016/
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7. J.-A. Sahel, J. Bennett, B. Roska, Sci. Transl. Med. 11 ,
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8. J. F. Martin, R. A. Poché, Development 146 , dev182642
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9. N. L. Jorstad et al., Nature 548 , 103 (2017).
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10. S. G. Varadarajan, A. D. Huberman, Curr. Opin. Neurobiol.
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11. R. A. Pearson et al., Nat. Commun. 7 , 13029 (2016).


12. M. S. Mehat et al., Ophthalmology 125 , 1765 (2018).


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ACKNOWLEDGMENTS

I am gr ateful to the participants of the Lasker/IRRF study on

Restoring Vision to the Blind ( 1 ) who provided recent findings

in the field.

10.1126/science.aba2623

INSIGHTS | PERSPECTIVES

GRAPHIC: N. CARY/

SCIENCE

Retina

Cornea

Iris

Visual axis

Lens

Fovea
Sclera

Pigment
epithelium Optic nerve

RGCs

Amacrine cells

Bipolar cells

Horizontal cells

Photoreceptors

Rod

Cone

Müller cells

Pigment

epithelium

The eye and retina

The retina lines the back of the eye and consists of rod and cone photoreceptors, as well as four types of neuron:

second-order bipolar and horizontal cells and third-order retinal ganglion cells (RGCs) and amacrine cells.

Müller glial cells fill the spaces between the neurons. The pigment epithelium, critical for photoreceptor function,

underlies the retina. Photoreceptors and RGCs are most susceptible to blinding retinal disease. Progress in

combating photoreceptor degeneration has been made, but there are few strategies to address RGC loss.

828 22 MAY 2020 • VOL 368 ISSUE 6493

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