Retinitis Pigmentosa

Main Moderator – Prof. S. N. Askari

Assistant Moderator – Dr. Abdul Waris

Presenter – Dr. Rupankar Sarkar

• Broad set of disorders
• Affect the photoreceptors and Retinal Pigment
epithelium
• Progressive visual dysfunction
Rod-Cone Dystrophy
• Rods affected earlier and more
severely
• Cones affected in end-stage
• Progressive night blindness
• Visual field constriction
• Visual acuity minimally
affected initially
Cone-Rod Dystrophy
• Cones affected earlier
• Affects central vision early and
peripheral vision later
• Poor acuity, reduced color
vision
• Visual prognosis is better than
rod-cone dystrophy.
 ‘itis’
• Inflammatory ?
Symptoms
• Night-blindness
• Prolonged dark adaptation – problem in dimly
lit places.
• Patients may appear clumsy as they collide with
door frame or a person walking alongside
because of unrecognized tunnel vision.
• End-stage disease results in loss of both central
and peripheral vision
Ocular Findings
• Thinning and atrophy of the RPE in the mid-
and far-peripheral retina
• Relative preservation of RPE in the macula
• Waxy pallor of optic disc (gliosis)
• Bone-spicule intraretinal pigment
• Arteriolar attenuation
• Cystoid macular edema(CME)
• Posterior subcapsular cataract
• Usually bilateral
• Unilateral retinitis pigmentosa – one eye lags in
differentiation; both eyes invariably show
involvement on careful examination
• Weller et al., 2014 have presented a case report of a
female patient with unilateral retinitis pigmentosa (RP),
who presented first in 1984 at the age of 43 years. At the
beginning, there were cells in the vitreous leading to the
diagnosis of uveitis with vasculitis in one eye. Within
30 years, the complete clinical manifestation of RP
developed with bone spicule-shaped pigment deposits,
pale optic disc, narrowed arterioles, cystoid macular
edema, posterior subcapsular cataract, concentric
narrowing of the visual field and undetectable
electroretinogram signal in that eye. At the age of
72 years, there were still no signs of retinal dystrophy in
the other eye.

• Weller, J.M., Michelson, G., and Juenemann, A.G. (2014).

Unilateral retinitis pigmentosa: 30 years follow-up. BMJ Case Rep.
2014.
X linked Retinitis Pigmentosa
• Has features of typical retinitis pigmentosa
• Rate of vision loss is rapid, major functional loss
of vision by 30 years of age, blindness by 40
years of age
• Dark adapted thresholds are elevated (1000-fold
sensitivity loss)
• Night blindness is severe by mid teenage
• Cone vision is affected to a greater extent
• Prominent parafoveal atrophy may be present
Retinitis Pigmentosa Inversa
• Retinitis pigmentosa inversa is a rare variant of
this disorder characterized by areas of choroidal
degeneration with pigment migration and bony
spicule formation in the macular area.
• In contrast to more typical forms of RP, this
anomaly destroys central vision, leaving
peripheral vision intact.
• Normal person looking at the menu
• a person with a central vision loss looking at a
menu
• that same person looking at the waitresses face
INVESTIGATIONS
• Color Vision Tests
• Fransworth D-15 panel
• Tritan (blue-yellow) color
discrimination loss is
sensitive for early foveal
cone involvement.
• Ishihara color charts are less useful as it was
made for detecting congenital red-green color
blindness.
Dark Adaptation Test

• Goldmann-Weekers dark
adaptometer
• In a dark room
• Patient detects the
dimmest (threshold)
light, which gets dimmer
with time
• Final absolute threshold
sensitivity reached after
30-40 minutes
• DA time is prolonged in
RP
Visual Field Testing
• Goldmann perimetry
• Testing out to 90 ̊ in temporal periphery
• Mid-peripheral retina involved first in rod-cone
type
• Peripheral field loss to small I4e target in rod-
cone type
• Cone-rod disease leaves the peripheral fields
more intact.
• In rod-cone disease, Goldmann visual fields are
relatively large with the large V4e target but
considerably constricted to I4e target
• In cone-rod disease, fields initially remain full
with V4e targets and constricted slightly to I4e
target
• Macular dysfunction may be detected by testing
the central visual field using automated static
perimeters.
Electroretinography
• Rod b-wave amplitudes are reduced in the
earliest stages of disease, when the retina may
appear clinically normal
• Scotopic b-waves are reduced by 50% - indicates
progressive disease
• Early cone system disease reduces the amplitude
of 30 Hz flicker before photopic b-wave
responses to single flashes
• Delayed flicker implicit time (from flash to
response peak) – highly sensitive measure of
abnormality. Implicit times maybe prolonged
even with normal flicker amplitude
• ERG maybe repeated 1-2 years after the first test
 To confirm ERG findings
 Determine rate of progression
 Monitoring of effects of therapy
Genetics
• Can be inherited in autosomal dominant,
autosomal recessive and X-linked fashion
• Many a times no other family members are
affected (sporadic retinitis pigmentosa)
• Rhodopsin – first RP gene to be indentified.
• Most other genes identified are associated with
the phototransduction cascade within the rod
cells (transducin, phosphodiesterase, arrestin,
recoverin and G-protein coupled Na-K channel)
• Farrar et al. 1991 had identified a three basepair
deletion in rds gene which led to the loss of a
highly conserved cysteine residue in the
structure of peripherin and had suggested that
mutant peripherin gene gave rise to retinitis
pigmentosa

• Farrar, G. J., P. Kenna, S. A. Jordan, R. Kumar-Singh, M. M.

Humphries, E. M. Sharp, D. M. Sheils, and P. Humphries. 1991. “A
Three-Base-Pair Deletion in the Peripherin-RDS Gene in One Form
of Retinitis Pigmentosa.” Nature 354 (6353): 478–80.
https://doi.org/10.1038/354478a0.
• Swain et al. 1997 mapped the cone-rod homeobox
(CRX) gene to chromosome 19q13 and suggested
that mutations in the CRX gene co segregated with
the disease phenotype of retinitis pigmentosa. The
authors also suggested in their study that CRX
protein is necessary for the maintenance of normal
photoreceptor function and that mutations in CRX
gene are associated with photoreceptor
degeneration.

• Swain, P. K., S. Chen, Q. L. Wang, L. M. Affatigato, C. L. Coats, K.

D. Brady, G. A. Fishman, et al. 1997. “Mutations in the Cone-Rod
Homeobox Gene Are Associated with the Cone-Rod Dystrophy
Photoreceptor Degeneration.” Neuron 19 (6): 1329–36.
• Tanackovic et al. 2011 has concluded from their
study that Proteins PRPF31, PRPF3 and PRPF8
(RP-PRPFs) are ubiquitously expressed components
of the spliceosome, a macromolecular complex that
processes nearly all pre-mRNAs, when mutated, can
cause inefficient splicing of about 9% of
endogenously expressed introns and such aberrant
splicing play a role in PRPF-linked retinitis
pigmentosa.

• Tanackovic, Goranka, Adriana Ransijn, Philippe Thibault, Sherif Abou

Elela, Roscoe Klinck, Eliot L. Berson, Benoit Chabot, and Carlo Rivolta.
2011. “PRPF Mutations Are Associated with Generalized Defects in
Spliceosome Formation and Pre-MRNA Splicing in Patients with
Retinitis Pigmentosa.” Human Molecular Genetics 20 (11): 2116–30.
https://doi.org/10.1093/hmg/ddr094.
• Chang et al. 1993 in their study had provided
evidence that apoptosis is the final common
pathway for photoreceptor death.
• Kang et al. 2012 have identified a signalling
pathway mediated by cdk5 and mekk1 required for
ER-stress-induced apoptosis. Inactivation of these
genes specifically suppressed apoptosis. The authors
also found that disruption of this pathway can delay
the course of retinal degeneration in a Drosophila
model of ADRP.
• Chang, Guo-Qing, Ying Hao, and Fulton Wong. 1993. “Apoptosis: Final
Common Pathway of Photoreceptor Death in Rd, Rds, and Mutant
Mice.” Neuron 11 (4): 595–605. https://doi.org/10.1016/0896-
6273(93)90072-Y.
• Kang, Min-Ji, Jaehoon Chung, and Hyung Don Ryoo. 2012. “CDK5 and
MEKK1 Mediate Pro-Apoptotic Signalling Following Endoplasmic
Reticulum Stress in an Autosomal Dominant Retinitis Pigmentosa
Model.” Nature Cell Biology 14 (4): 409–15.
https://doi.org/10.1038/ncb2447.
Differential Diagnosis
• Leber Congenital Amaurosis
• Congenital Stationary Nightblindness
• Usher’s syndrome
• Bardet-Beidl Syndrome
• Refsum Disease
• Kearns Sayre Syndrome
• Senior – Loken Syndrome
• Toxic Retinopathy (chloroquine, thioridazine)
• Postinfectious Retinopathy (syphilis, rubella)
• Melanoma Associated Retinopathy
• Cancer Associated Retinopathy
Lebers Congenital Amaurosis
• Autosomal recessive
• RPE65 gene defect
• Very early onset severe disease
• Nystagmus is usually the first sign
• Phosphenes on rubbing the eyes (oculo-digital
sign) in severe visual loss
• Fundus – marked vascular attenuation
• Variable pigmentation
• ERG – amplitude of the responses are markedly
reduced
Congenital Stationary Night Blindness
• Symptoms of night blindness, often severe from
birth (DD of XLRP)
• Color discrimination is unaffected
• Visual acuity is mildly affected
• X-linked CSNB is most common
• Vision remains ‘stationary’ in contrast to XLRP
• ERG – preserved scotopic a-wave amplitude but
reduced b-wave amplitude; broad flat bottom
trough to photopic a-wave
Usher Syndrome
• AR inheritance
• RP like retinal degenerations
• Sensorineural hearing loss
Bardet-Biedl Syndrome
• AR inheritance
• RP-like retinal degeneration – early onset
• Blindness by 30 years of age
• Obesity
• Mental retardation
• Diabetes
• Renal and cardiac malformations
• Brachydactyly, hexadactyly and syndactyly
• Hypogonadotropic hypogonadism
Refsum Disease
• AR inheritance
• Classic tetrad –
1. Peripheral neuropathy
2. RP like degenerations
3. Cerebellar ataxia
4. Elevated CSF proteins

• Progressive distal sensory loss and weakness in legs leading to

footdrop by their 20s
• Subsequently proximal leg and arm muscles may become
weak
• Sensorineural hearing loss
• Cardiac conduction defects
• Ichthyosis
• Anosmia
• Serum phytanic acid levels are elevated
Kearns Sayre Syndrome
• Caused by single Mitochondrial DNA deletions
• Triad of clinical findings:
1. Onset before age 20 years
2. Chronic Progressive External Ophthalmoplegia
3. Pigmentary retinopathy
With one or more of:
• Complete heart block
• Cerebrospinal fluid (CSF) protein > 100 mg/dL
• Cerebellar ataxia
o Endocrine abnormalities are common – gonadal
dysfunction, short stature and infertility; diabetes
mellitus in 13% of cases
o Diagnosis by EMG and muscle biopsy (ragged red
fibers, highlited on oxidative enzyme stains)
Senior – Loken Syndrome
• Juvenile and adolescent forms of
nephronophthisis
• RP like retinal degeneration
• Progressive kidney failure and volume depletion
lead to growth retardation
Postinfectious Retinopathy
• Syphilis, Rubella
• Syphilitic chorioretinitis is associated with
vitritis; retinitis has ‘ground glass appearance.
• Rubella – salt pepper pigmentary retinitis
• Differentiation by associated systemic features
• Serological test
 Chloroquine retinopathy
• Earliest symtoms are
scotomas in central 10
degrees of fixation.
• Subsequently scotomas
enlarge, multiply and
may involve fixation.
• Fundus –
 Irregular macular
pigmentation
 Blunting of foveal reflex
 Concentric zone of
hypopigmentation
surrounding the macula.
(horizontally oval and
more prominent
inferiorly)
 End-stage similar to
cone-rod dystrophy.
Treatment
Vitamin A
• Berson et al., 1993 had performed a randomized
controlled trial in which patients receiving 15000
IU vitamin A daily were 32% less likely to have a
decline in amplitude of 50% or more from baseline
in a given year than those not receiving this dosage,
while those receiving 400 IU/d of vitamin E were
42% more likely to have a decline in amplitude of
50% or more from baseline than those not receiving
this dosage.

• Berson, E.L., Rosner, B., Sandberg, M.A., Hayes, K.C., Nicholson, B.W.,
Weigel-DiFranco, C., and Willett, W. (1993). A Randomized Trial of Vitamin
A and Vitamin E Supplementation for Retinitis Pigmentosa. Arch.
Ophthalmol. 111, 761–772.
Lutein
• Lutein (as yellow macular pigment) is thought to
screen the foveal cone photoreceptors from
short-wavelength light to minimize chromatic
aberration and enhance visual acuity.
• In rod outer segments lutein may serve as an
antioxidant to quench free radicals produced by
high-energy short-wavelength illumination and
thereby minimize light-induced retinal damage
• Berson et al., 2010 performed a randomized controlled trial in
order to determine whether lutein supplementation alongside
15000 IU/d Vitamin A will slow visual function decline in
patients with retinitis pigmentosa.
• In this trial, no significant difference in rate of decline was
found between the lutein + vitamin A and control + vitamin A
groups over a 4-year interval for the HFA 30-2 program.
• However, for the HFA 60-4 program, a decrease in mean rate
of sensitivity loss was observed in the lutein + vitamin A
group.
• The authors didn’t find any toxic side effects of lutein.
• The authors concluded that Lutein supplementation 12
mg/d slows loss of midperipheral visual field on
average among adults with retinitis pigmentosa
taking vitamin A.

• Berson, E.L., Rosner, B., Sandberg, M.A., Weigel-DiFranco, C., Brockhurst, R.J.,
Hayes, K.C., Johnson, E.J., Anderson, E.J., Johnson, C.A., Gaudio, A.R., et al. (2010).
Clinical Trial of Lutein in Patients with Retinitis Pigmentosa Receiving Vitamin A.
Arch. Ophthalmol. 128, 403–411.
Docosahexaenoic Acid (DHA)
• Docosahexaenoic acid is the most abundant fatty
acid in the retina. This fatty acid can increase
membrane fluidity and modify the mobility of vital
proteins and activities of retinal enzymes, promote
photoreceptor differentiation and antiapoptotic
activity. The highly unsaturated nature of DHA
makes it a potential target for free radical oxidative
damage.
• Abnormal cholesterol and serum lipid levels have
been reported in some RP cases and DHA levels are
particularly and somewhat consistently low in X
linked RP patients
• Hoffman et al., 2014 did a four-year placebo-
controlled trial of Docosahexaenoic acid (30
mg/kg/day) in X linked retinitis pigmentosa.
The authors found that long term DHA
supplementation was not effective in
slowing the loss of cone or rod ERG
function associated with X-linked retinitis
pigmentosa.

• Hoffman, D.R., Hughbanks-Wheaton, D.K., Pearson, N.S., Fish, G.E.,

Spencer, R., Takacs, A., Klein, M., Locke, K.G., and Birch, D.G. (2014).
Four-Year Placebo-Controlled Trial of Docosahexaenoic Acid in X-Linked
Retinitis Pigmentosa (DHAX Trial): A Randomized Clinical Trial. JAMA
Ophthalmol. 132, 866–873.
• Rayapudi et al., 2013 published a review article in which they
included three trials; One trial evaluated the effect of vitamin
A alone, one trial evaluated DHA alone, and a third trial
evaluated DHA and vitamin A versus vitamin A alone.
• The three trials included a total of 866 participants aged four
to 55 years with RP of all forms of genetic predisposition.

• Based on the results of three RCTs, there is no clear

evidence for benefit of treatment with vitamin A
and/or DHA for people with RP, in terms of the mean
change in visual field and ERG amplitudes at one year and the
mean change in visual acuity at five years follow-up

• Rayapudi, S., Schwartz, S.G., Wang, X., and Chavis, P. (2013). Vitamin A and
fish oils for retinitis pigmentosa. Cochrane Database Syst. Rev. 12.
Low Vision Aids
• They can be optical or optical and electronic.
• Optical
• These are aids that have optical properties capable of promoting
better visual performance through lenses.
• Types of optical aids for
 Distance
 Intermediate distance
 Near
• Optical Aids for Distance and Intermediate Distance
• The telescopic system (TS) or telescope is an optical instrument that
improves the resolution of an object by increasing the size of the
image projected on the retina, making it closer. (Faye, 1984). It is
available for far, near, and middle distances
• A telescope enables greater participation in daily and social
activities
• On the other hand, restriction of visual field and illumination,
difficulty in locating and focusing on objects quickly, and limited
focus depth are disadvantages of the telescopes.
Near low-vision aids:
• High-plus spectacles (microscopes)
• Hand-held magnifier
• Stand magnifier
 • Current treatments are limited to
1. Vitamin A palmitate @ 15000 IU/d
2. Lutein @ 12 mg/d
3. Fish oils (DHA)
4. Avoiding vitamin E
• But these adjustments only delay the
degeneration
Emerging Treatments

Ray of Hope?
LIN et al., 2015 reviewed the following emerging
treatments for Retinitis Pigmentosa

• Gene Therapy
• Stem Cell Transplantation
• Neurotrophic Factors
• Retinal Prosthesis (Bionic Eye)

• LIN, M.K., TSAI, Y.-T., and TSANG, S.H. (2015). Emerging Treatments
for Retinitis Pigmentosa. Retin. Physician 12, 52–55, 70.
Gene Therapy
• Gene therapy uses the machinery of a virus to insert
normal genes into patients’ cells. This is a potentially
effective method of treating genetic diseases with
recessive mutations, in which no functional protein is
produced.

• The adeno-associated virus (AAV) has been the vector of

choice for a number of gene therapy trials due to its lack
of pathogenicity and its ability to infect many types of
human cells at an efficient rate.

• The successful administration of gene therapy is

performed by subretinal injection of fluid containing the
virus, inducing a small retinal detachment that
generally resolves within 14 hours
• Pellissier et al., 2015 applied CRB1 and CRB2 gene therapy
vectors in CRB-1 Retinitis Pigmentosa mouse models.
• Mutations in the Crumbs-homologue-1 (CRB1) gene lead to
severe recessive inherited retinal dystrophies.
• In human retinas, CRB1 is expressed at the subapical region
above the adherens junctions in Müller glial cells and cone and
rod photoreceptors, while CRB2 is localized at the subapical
region only in Müller glial cells.
• The authors tested if CRB expression restricted to Müller glial
cells or photoreceptors or co-expression in both is required to
recover retinal function. The authors showed that targeting both
Müller glial cells and photoreceptors with CRB2 ameliorated
retinal function and structure in Crb1 mouse models.
Surprisingly, targeting a single cell type or all cell types with
CRB1 reduced retinal function.

• Pellissier, L.P., Quinn, P.M., Alves, C.H., Vos, R.M., Klooster, J., Flannery, J.G., Heimel,
J.A., and Wijnholds, J. (2015). Gene therapy into photoreceptors and Müller glial cells
restores retinal structure and function in CRB1 retinitis pigmentosa mouse models.
Hum. Mol. Genet. 24, 3104–3118.
• Beltran et al., 2015 have shown that Gene Augmentation
with Full-Length Human RPGR (ex1-ORF15) prevents
disease onset in a canine model of X linked RP.
• The authors have also shown that Gene Augmentation with
Full-Length Human RPGR (ex1-ORF15) rescues
photoreceptors in another canine model of X linked RP,
when delivered at early and mid-stages of disease.
• Availability of two complementary canine models that
recapitulate distinct spatiotemporal features of the
phenotypes reported in human RPGR-XLRP patients has
enabled the authors to establish initial proof of concept that
a corrective gene augmentation approach may be sufficient
to both prevent and stop the degenerative process of rods
and cones.

• Beltran, W.A., Cideciyan, A.V., Lewin, A.S., Hauswirth, W.W., Jacobson, S.G.,
and Aguirre, G.D. (2015). Gene Augmentation for X-Linked Retinitis
Pigmentosa Caused by Mutations in RPGR. Cold Spring Harb. Perspect. Med. 5,
a017392.
Neurotrophic Factors
• Kucharska et al., 2014 demonstrated that the molecule
Cyr61 protects RP in an indirect way, most likely through
stimulation of macular ganglion cells and RPE cells, which
in turn most likely secrete a variety of neuroprotective
factors supporting PR survival. A similarly complex
signalling pattern was described for Cyr61 activity in the
context of cutaneous wound healing (Chen et al. 2001).
• The results of this study indicate that application of Cyr61 to
the degenerating retina is neuroprotective and opens the
possibility of future in vivo characterizations of Cyr61 action
within the retina
• The authors focused on Cyr61 as this molecule has a
documented pro-survival potential in different cancer cells

• Kucharska, J., Río, P. del, Arango‐Gonzalez, B., Gorza, M., Feuchtinger,

A., Hauck, S.M., and Ueffing, M. (2014). Cyr61 activates retinal cells and
prolongs photoreceptor survival in rd1 mouse model of retinitis
pigmentosa. J. Neurochem. 130, 227–240.
Ciliary Neurotrophic Factor
• Ciliary neurotrophic factor decreases photoreceptor
loss during retinal degeneration (Faktorovich et al.,
1990; LaVail et al., 1992, 1998)
• Although its intrinsic function is not fully
understood, exogenous ciliary neurotrophic factor
affects the survival and differentiation of cells in the
nervous system, including retinal cells (Fuhrmann
et al., 2003)
• Further, ciliary neurotrophic factor has passed
appropriate milestones in a phase 1 human clinical
study of RP. (Sieving et al., 2006)
• The key question for patients and clinicians is
whether it can be used safely in the treatment of
retinal degeneration in humans.
• Faktorovich, E.G., Steinberg, R.H., Yasumura, D., Matthes, M.T.,
and LaVail, M.M. (1990). Photoreceptor degeneration in inherited
retinal dystrophy delayed by basic fibroblast growth factor. Nature
347, 83–86.
• Fuhrmann, S., Grabosch, K., Kirsch, M., and Hofmann, H.-D.
(2003). Distribution of CNTF receptor α protein in the central
nervous system of the chick embryo. J. Comp. Neurol. 461, 111–122.
• LaVail, M.M., Unoki, K., Yasumura, D., Matthes, M.T., Yancopoulos,
G.D., and Steinberg, R.H. (1992). Multiple growth factors, cytokines,
and neurotrophins rescue photoreceptors from the damaging effects
of constant light. Proc. Natl. Acad. Sci. 89, 11249–11253.
• LaVail, M.M., Yasumura, D., Matthes, M.T., Lau-Villacorta, C.,
Unoki, K., Sung, C.H., and Steinberg, R.H. (1998). Protection of
mouse photoreceptors by survival factors in retinal degenerations.
Invest. Ophthalmol. Vis. Sci. 39, 592–602.
• Sieving, P.A., Caruso, R.C., Tao, W., Coleman, H.R., Thompson,
D.J.S., Fullmer, K.R., and Bush, R.A. (2006). Ciliary neurotrophic
factor (CNTF) for human retinal degeneration: Phase I trial of CNTF
delivered by encapsulated cell intraocular implants. Proc. Natl.
Acad. Sci. 103, 3896–3901.
Stem Cell Therapy
• Cell replacement is one approach for restoration of
vision in RP. Because visual loss usually occurs when the
outer retinal photoreceptor layer is lost, therapeutic
timing should be at this stage of disease.
• Singh et al., 2013 have demonstrated using a murine
model of severe human retinitis pigmentosa, that at a
stage when no host rod cells are remaining, transplanted
rod precursors can reestablish an anatomically distinct
and appropriately polarized outer nuclear layer.
• In their study, restoration of a trilaminar retinal
organization was restored to hosts with only two retinal
layers before treatment. The introduced rod precursors
continued to develop in the host niche to become mature
rods complete with lightsensitive outer segments and
connections to host neurons downstream.
• Visual function was also restored.
• These findings indicated that stem cell therapy may
reinstate a light-sensitive cell layer de novo and
restore structurally damaged visual circuits.
• In this model, total photoreceptor layer
reconstruction is one approach to further develop
cell-based strategies for retinal repair
• Two types of stem cells may be utilized to produce
retinal progenitor cells.

 Firstly, Embryonic stem cells (ESC) and

 secondly, induced pluripotent stem (IPS) cells.

• Both types of cells are pluripotent and capable of

becoming any cell type.
• ESC’s are derived from embryos while IPS cells are
obtained from a variety of adult tissues such as skin,
bone marrow, teeth.
• IPS cells, if successfully implanted and optimized, can
potentially provide an unlimited supply of stem cells for
transplantation.
• ESC’s have been shown to generate functional
photoreceptor cells restoring light response of
photoreceptor-deficient mice, but there is concern over
the risk for tumor formation using ESC.
• Li et al., 2013 have successfully cultured
Nestin(+)Sox2(+)Pax6(+) multipotent retinal stem cells
(RSCs) from the adult mouse retina. These ESC’s are
capable of producing functional photoreceptor cells that
restore light response of photoreceptor-deficient mutant
mice.
• After several cycles of expansion using growth factors,
cultured RSCs still maintained proliferation and
differentiation potential
• Li et al., 2012 showed that along similar lines,
autologous IPS cells are being developed for
stem cell transplantation.
• The lack of immunogenicity confers an
important advantage. Because IPS cells are
autologous or derived from the same organism,
they do not incite immunological reaction nor
require use of immunosuppressive medication.
• The use of retinal progenitor sheet transplantation
is another promising approach.
• Seiler and Aramant, 2012 demonstrated that when
freshly dissected sheets of fetal-derived retinal
progenitor cells are mixed with RPE and
transplanted subretinally, improvements of visual
acuity are observed among animals and humans.
• Visual improvement in this model is attributed to
restoration of synaptic connections between
transplant and host when transplant processes
proliferate into the inner plexiform layer of the host
retina and presumably form synapses.
• One drawback of widespread use of this method is
limited supply of fetal donor tissue.
• Future areas for stem cell development include
methods for optimizing stem cell production and
delivery. The use of specific extracellular matrix
can stimulate the development of human
pluripotent stem cells into transient organized
neuroepithelum with rapid differentiation into
retinal progenitor cells
• Li, T., Lewallen, M., Chen, S., Yu, W., Zhang, N., and Xie, T. (2013).
Multipotent stem cells isolated from the adult mouse retina are
capable of producing functional photoreceptor cells. Cell Res. 23,
788–802.
• Li, Y., Tsai, Y.-T., Hsu, C.-W., Erol, D., Yang, J., Wu, W.-H., Davis,
R.J., Egli, D., and Tsang, S.H. (2012). Long-term Safety and Efficacy
of Human-Induced Pluripotent Stem Cell (iPS) Grafts in a
Preclinical Model of Retinitis Pigmentosa. Mol. Med. 18, 1312–1319.
• Seiler, M.J., and Aramant, R.B. (2012). Cell replacement and visual
restoration by retinal sheet transplants. Prog. Retin. Eye Res. 31,
661–687.
• Singh, M.S., Issa, P.C., Butler, R., Martin, C., Lipinski, D.M.,
Sekaran, S., Barnard, A.R., and MacLaren, R.E. (2013). Reversal of
end-stage retinal degeneration and restoration of visual function by
photoreceptor transplantation. Proc. Natl. Acad. Sci. 110, 1101–1106.
• Brief Report: Self‐Organizing Neuroepithelium from Human
Pluripotent Stem Cells Facilitates Derivation of Photoreceptors -
Boucherie - 2013 - STEM CELLS - Wiley Online Library.
Retinal Prosthesis
• Retinal prostheses are being developed to replace
the photoreceptor of the eye in cases with severe
retinal degeneration.
• The mechanism of prosthesis as it relates to
photoreceptors of the eye is to utilize an artificial
device to detect and transform light energy into an
electrical signal, conveying the electrical signal to
the unaffected areas of the inner retinal neurons to
evoke downstream visual pathway.
• In other words, through electrical stimulation of the
inner retinal layers, degenerative diseases of the
outer retina are bypassed and substituted
• Electronic retinal prostheses are neither able to
restore full visual acuity nor all visual functions
because the high density of photoreceptors in
the fovea cannot be completely replaced by
current microelectronic devices.
• These devices are intended to only improve
visual acuity from blindness into low vision.
• Although there are several different types of
retinal implants, all of them contain an image
capture unit with either a microphoto diode
array or an external camera plus an array of
electrodes for stimulation of the inner retinal
neurons to mediate the luminance and spatial
information of images.
Subretinal Prosthesis
• Subretinal prostheses are implanted in that common
location where photoreceptors are typically found.
These prostheses can be divided into passive and
active systems.
• Light energy is converted into electrical signal from
either an external camera or an implanted imaging
component in different systems.
• For external cameras, data are transmitted
wirelessly to the implant. The implant generates a
stimulation pattern based on the light pattern on the
camera and delivers this stimulation pattern to the
multielectrode array itself and contains an external
power supply.
• In most of these prostheses, the photoreceptor
component and the electrode array are combined
into one subretinal chip
Epiretinal Prosthesis
• The epiretinal prosthesis is implanted on top of
the ganglion cell layer with the electrode array
fixed to the retina with retinal tacks.
• Thus, the ganglion cells are stimulated directly
without mediation of the inner nuclear layer,
whereas the image information comes from an
external camera mounted on glasses and is
mediated wirelessly through an inductive coil to
the intraocular electrode array.
• All epiretinal visual implants are provided with
an external battery system for power supply
Prostheses Argus II EPI-RET 3 Intelligent Alpha-
type Medical Institute for
Implants Microelectro
nics
Stuttgart

Image capture External External External 1500-pixel

camera camera camera Multi-
photodiode
array
Location Epiretinal Epiretinal Epiretinal Subretinal