Photoreceptor degeneration
Molecular pathways involved in PR degeneration
Stages of photoreceptor degeneration
Therapeutic approach: points to consider
Administration routes
Topical route
Systemic route
Intravitreal route
Treatments | Route of administration | Mechanism of action | State of progress towards clinical therapy |
---|---|---|---|
Compounds | |||
TUCDA | |||
UDCA | Intravitreal injection | FDA-approved; only one trial (NCT02841306) on retina among 151 studies listed in clinicaltrials.gov working on UDCA | |
MK-801 | Intravitreal injection | High efficacy compared to other NMDA blockers; side effects, including illusions, and memory deficits [179] | |
Brimonidine | Intravitreal implant, topical | 12 trials on retina out of 159 studies working on Brimonidine tartrate in clinicaltrials.gov, prescribed to treat glaucoma and ocular hypertension under trade name ALPHAGAN-P; side effects such as conjunctiva hyperemia, allergic conjunctivitis, and ocular pruritus | |
Tandospirone (AL-8309B) | Topical ocular | 5-HT1A receptor agonist (selective serotonin 1A receptor agonist) [181] | One trial completed NCT00890097 Prescribed to treat Dry macular degeneration |
Anti-amyloid β antibody (RN6G, Glatiramer acetate) | Intravenous, subcutaneous | Three studies on RN6G and six studies on Glatiramer acetate, listed in clinicaltrials.gov and completed on the retina | |
Corticosteroids | Intravitreal/subconjunctival, intraperitoneal injection, fasting-mediated stress [185], dietary supplement | Promoting myelination [186‐188], improving impaired axonal transport[189], increasing BDNF levels [190], reducing microglial and macrophage activity [191, 192], increasing inflammatory cytokine levels (IL-1β, TNF-α, IL-6, COX-2, and the p65 NF- κB subunit) [193], reducing edema, likely via action on aquaporin four expressions [194], reducing excitotoxicity by acting on the GABAA receptor [195, 196] and the NMDA response [197] | FDA-Approved but failed to pass phase III of clinical trials due to lack of methodological information, long term effects in the retina would have to be evaluated |
L-DOPA | Topical [198], dietary supplement | FDA-approved for Parkinson disease, eight studies on retina listed in clinicaltrials.gov; side-effects on eye must be considered, dosage needs to be optimized | |
GSK812 small molecule | Sustained induction of GDNF via Intravitreal injection of suspension solution instead of aqueous solution | Upregulation of GDNF mRNA (> 1.8-fold) and protein levels (> 2.8-fold) [204] | GDNF induces neuroprotective effects in retinal cells at concentrations as low as 30 nM |
Rasagiline (N-propargyl-1-(R)-aminoindan) | Dietary supplement | Already being used for Parkinson disease, one clinical trial (NCT02068625) on Rasagiline under trade name Azilect of patients with Macula-off Retinal Detachment and terminated due to the recruitment difficulties | |
Mycophenolate mofetil (MMF) | Intraperitoneal injection | Suppressing the cGMP-dependent cytotoxicity for photoreceptor cell death which occurs independently of the presence of hyperphysiological whole retinal cGMP levels [207] | FDA-approved, already being used off-label as an immunomodulatory agent for ocular inflammation treatment [208] |
Neurotrophic factors | |||
Intravitreal injection, encapsulated intravitreal implant | Five studies on retina listed in clinicaltrials.gov; delivering is challenging due to the instability and inability to cross blood-retina barriers, dosage, timing and target tissue need to be established | ||
LEDGF [222] | |||
Antioxidants | |||
Vitamin A, E and C | Hind leg muscle injection [223], dietary supplement | Body’s natural defense mechanisms against oxidative stress | 54 studies listed in clinicaltrials.gov, FDA-approved and easy to take; synergic effect of antioxidants combinations needs to be determined, regeneration efficiency needs to be improved |
Lutein | Dietary supplement | Preventing neurodegeneration induced by oxidative stress via affecting pathological pathways of inflammatory cytokines, such as IL-6 and angiotensin II signaling [224] | |
Docosahexaenoic acid (essential omega-3 FA family member) | DHA, is concentrated in the nervous system, particularly in photoreceptors and synaptic membranes, neuroprotectin D1, the DHA-derived bioactive lipids may be a mediator that promotes homeostatic modulation of cell integrity during photoreceptor renewal [216, 225, 226], delaying apoptosis and promotes differentiation of photoreceptor [227] | ||
Lyciumbarbarum Polysaccharides (LBP) [228] | Preventing the generation of reactive oxygen species (ROS), decreasing poly (ADP-ribose) polymerase (PARP14) | ||
Idebenone | Accelerating the recovery of visual acuity in patients with hereditary optic neuropathy (LHON) [229] | ||
Safranal [230] | Ameliorated the loss of both rods and cones, synaptic contacts between photoreceptors and bipolar or horizontal cells were preserved | One clinical trial ongoing (NCT01278277) | |
Rehabilitation methods | |||
Curcumin [1,7-bis (4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3, 5 dione] | Intraperitoneal injection | Suppressing N-methyl-N-nitrosourea-induced photoreceptor cell apoptosis in Sprague–Dawley rats through inhibition of DNA oxidative stress [231] | Crossing the blood–brain barrier due to its polyphenolic structure (two phenol rings connected by α, β-unsaturated carbonyl groups) [232]; poor solubility, bioavailability, and lack of stability at physiological conditions, degrading into different compounds such as ferulic acid, vanillin, ferulic aldehyde and feruloyl methane [233], adverse effects have seen on RPE at 10 μM dosage [234] |
Resveratrol (3,5,4′-trihydroxystilbene) | Intraperitoneal injection, dietary supplement | Natural compound, one clinical trial (NCT02625376) on age-related Macular Degeneration | |
Di-apocarotenoid norbixin (BIO201) | Systemic administrations Intraperitoneal injection | Reducing ocular A2E and lipofuscin accumulation [237] | Natural compound, well tolerated by human and animal |
Exercise | N/a | Five completed studies, voluntary exercise has been more beneficial than forced exercise for animal models[243]; intensity and duration must be optimized for each patient with a specific stage of degeneration; specialized equipment must be utilized for a patient with low vision | |
Transcorneal | Preserving function and structure, upregulation of neurotrophic factors; | Not FDA-approved Completed clinical trials showing vision improvement (NCT02019927) | |
Gene therapy | |||
Block of p75NTR, Lack of p75NTR [249] | Viral transgene | Preventing bFGF reduction, improving structural and functional photoreceptors survival | Clinical studies have been completed on Alzheimer disease |
APL-2 | Intravitreal injection | A complement C3 inhibitor, | One Clinical trial (NCT03525613) ongoing |
Lampalizumab [250] | An antibody against Complement factor D (CFD) | One clinical trial (NCT02247479) terminated | |
Metformin [251] | Activating adenosine monophosphate-activated protein kinase (AMPK), increasing mitochondrial biogenesis, reducing oxidative stress, reprogramming of metabolism | One Clinical trial (NCT02684578) ongoing | |
Adeno-associated viral vector serotype 1 | Intramuscular injection | Expressing human proinsulin | Requirement for repeated administration can be overcome; gene therapy vectors typically lead to insufficient photoreceptor transduction, may pathologically alter the retina environment |
FGF-5, FGF-18 [252] | Subretinal injection of adeno-associated virus vectors | Rescuing photoreceptors from apoptosis, mediating tyrosine kinase pathways | |
Calpain inhibitor (1S-1-((((1S)-1-benzyl-3-cyclopropylamino-2,3-di-oxopropyl) amino) carbonyl)-3-methylbutyl)carbamic acid 5-methoxy-3-oxapentyl ester (SNJ-1945) [15] | Intraperitoneal (IP) injection | Restoring basal autophagy and suppressing photoreceptor death induced by N-methyl-N-nitrosourea (MNU) | |
Methylene blue (MB) [253] | Dietary supplement | Decreasing photoreceptor cell survival and oxidative stress without correcting the energy deficit, normalizing the NAD + /NADH ratio and deactivating the mitochondrial stress response pathways, unfolding protein response and mitophagy | |
Sustained production of GDNF by electrotransfer of GDNF-encoding plasmid (30 μg) in the RCS rat ciliary muscle[254] | Non-viral gene therapy | Warning against toxic effect of high dose of GDNF administration in the retina, neuroprotective effect in RCS with RP | |
Cell therapy | |||
UCB-MSC | Subretinal injection | Secreting IL-6, bFGF, and BDNF, reducing functional deterioration in rodent model as well as photoreceptor degeneration | Unexpected pathology and cell differentiation into neurons were not observed [136] |
BM-MSC | Subretinal, epiretinal and intravitreal injection | ||
DPSC | Intravitreal injection | Secreting neurotrophic factors, Integrating into the photoreceptor layer, protecting the retinal morphology within two months | Differentiation potential of the transplanted cells needs to be investigated [141] |
Periocular route
Sub-tenon
Subconjunctival
Suprachoroidal
Sub-retinal
Carrier systems
Nanoparticle-based delivery systems
Polymeric carrier systems
Delivery challenges
Current approaches of photoreceptor regeneration
Neuroprotective strategies
Neurotrophic factors
Anti-stress compounds
Antioxidants
Synthetic bile acid
Steroid hormones
Dopamine
Rehabilitation methods
Gene therapy
Genome editing strategies: carriers and modalities
Viral vector
Retroviruses
Lentiviruses
Adenoviruses
Adeno-associated viruses
Non-viral vector
Liposomes-based methods
Naked DNA plasmid
Nanoparticle-based methods
Gene silencing (siRNA)
CRISPR/CAS9-mediated genome editing in the retina
Regenerative therapies using genetic modification
Phototransduction and visual cycle pathway
Ciliary proteins (Intracellular trafficking proteins)
Structural proteins (disk morphogenesis)
Optogenetic approaches
Cell based therapies
Current differentiation strategies
Different cell sources
Fetal cells
Cell source | Differentiation method | Culture medium condition | Cell types derived in vitro, specific markers (days) | Preclinical or clinical studies towards cell therapy |
---|---|---|---|---|
Human fetal neural stem cells (fNSC) | Direct differentiation | TGF-β3 | Photoreceptors, OPSIN (D15) | The transplanted cells in the rat model showed the extensive migration into the lesion area of the retina [460] |
Human exfoliated deciduous teeth (SHEDs) | Direct differentiation | N2,B27, FGF2, noggin, Dkk1, IGF-1, Shh, T3, RA | Photoreceptors, RECOVERIN, CRX, NRL (D24) | Injected SHEDs into the mouse eyes could differentiate into rod- and cone-like cells; retinal function improved, and photoreceptors were rescued for 3–5 months [468] |
hBM-MSC | Spontaneous differentiation, Direct differentiation | FGF2, EGF, BDNF | Photoreceptors, RHODOPSIN (D7) | Phase I trial was done in 3 patients with RP and two patients with cone-rod dystrophy 10 months after transplantation revealed no detectable structural or functional toxicity, demonstrating the short-term safety of the transplantation (NCT01068561) [492]. Phase II study enrolled 20 RD patients. Findings showed vision-related life quality improvement 3 months post treatment (NCT01560715) [493] |
hRSCs | Direct differentiation | FGF2, EGF | Rod photoreceptors, RHODOPSIN (D21) | After transplantation into the mouse eye, the cells showed photoreceptor morphology and expressed RHO marker; also able to integrate into different neuronal layers at appropriate developmental times [470] |
hRPCs | Direct differentiation | N2, B27, FGF2, EGF | Photoreceptors, RHODOPSIN and RECOVERIN (D14) | Transplantation in RCS rats revealed the integration and expression of specific markers. Also clinical study in retinitis pigmentosa 8 patients after 1–2 years post-transplantation clarified no obvious autofluorescence destruction in the macular area and also significant improvement in visual acuity. Although poor visual function of the patients prior to the study was detected. No immunological rejection was not observed after transplantation in both animal study and clinical trial [466, 494, 495] |
hESCs | Direct differentiation | N2, B27, FGF2, IGF-1, Dkk1, Noggin, COCO | Con Photoreceptors, CRX, S-OPSIN (D21) | Injected cell clamps into the vitreous of neonatal (P1) mice were presented in the PR nuclear layer by expression of S-opsin and the same morphology of host PRs [496] |
hiPSCs | Direct differentiation | N2, B27, IGF-1, Dkk1, Noggin, DAPT, FGF1 and 2 | Rod Photoreceptors, RECOVERIN (D90) and RHODOPSIN (D120) | Two weeks following transplantation into neonatal retinal degenerative Crb1 mutant mice, PR precursor cells were integrated into the outer nuclear layer and differentiated into morphologically and immunohistochemically recognizable PRs [497] |
hESCs/hiPSCs | Direct differentiation | N2, B27, Noggin, BDNF, CTNF, Insulin, DAPT, RA | Photoreceptors, CRX, NRL, NR2E3 (D90-100) | Three weeks post transplantation in the adult rd1 eye, the expression of mature PR markers and functional analysis indicated visual improvement [489] |
hESCs/ hiPSCs | Direct differentiation | N2, B27, FGF2, IGF-1, Dkk1, Noggin | Photoreceptors, CRX, NRL (120) RECOVERIN, RHODOPSIN, S-OPSIN (60) | |
hESCs/ RPE | Co-culture differentiation | N2, B27, FGF2, IGF-1, Dkk1, Noggin, Shh | Photoreceptors, RHODOPSIN, S-OPSIN (D40-50) | Following transplantation of Shh-treated retinal cells in eighteen adult albino rabbits for 4 weeks showed ERG improvement, and also cell incorporation into the retina, and finally visual restoration [491] |