Table1 Neuroprotective strategies for photoreceptor regeneration with an emphasis on clinical progress
From: Potential therapeutic strategies for photoreceptor degeneration: the path to restore vision
Treatments | Route of administration | Mechanism of action | State of progress towards clinical therapy |
|---|---|---|---|
Compounds | |||
 TUCDA | Intraperitoneal [162]; intravitreal injection of TUCD encapsulated microspheres [163]; intravitreal injection | Improving photoreceptor function and Structure [162,163,164,165,166,167,168], improving protein folding and trafficking [169], reducing oxidative stress and ER stress [167, 170], suppressing the pro-apoptotic P53 protein [171], anti-inflammatory effects [168, 172] | FDA-approved; no active clinical trial on Retina; well-tolerated by humans with few side effects [173, 174]; the optimal dose for animals (500 mg/kg) seems too high for human; systemic delivery is challenging |
 UDCA | Intravitreal injection | Breakdown of TUDCA to release taurine [175], stabilizing the mitochondrial membrane [176] | 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 | Alpha-2 adrenergic receptor agonist (Patent#US2001049369), cone neuroprotection [180], decreasing vitreoretinal vascular endothelial growth factor, inhibiting blood– retinal barrier breakdown [148] | 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 [186,187,188], 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 | Delaying AMD [199], anti-angiogenic [200], maintaining ERG function and photoreceptor cell counts [201], stimulating G protein coupled receptors (GPCR) like GPR143 in RPE [202, 203] | 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 | Selective monoamine oxidase B inhibitor [205], delaying activation of caspase 3 dependent apoptotic pathways and inducing the anti-apoptotic protein Bcl-XL [206] | 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 | Rescue photoreceptor from degeneration, activation of Jak/STAT, PI3K/Akt, and Ras/MAPK cell survival mechanisms [112], BDNF strengthen synaptic transmission following activation of neuronal firing [213,214,215] | 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 | Preventing photoreceptor cell death by upregulating FoxO family protein levels (FoxO1a, FoxO3a, FoxO4) and blocking caspase 3, 8 and, 9 activation [235, 236] | 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 | BDNF/TrkB signal transduction pathway [238], increasing BDNF [239, 240], blocking TrkB pathway activation using ANA-12, a TrkB inhibitor (K252a) [241, 242] | 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 | Stimulating and expressing bFGF, BDNF, and CNTF secretion in retinal layers [138, 139, 255], inhibiting photoreceptor apoptosis; thus slowing down retinal degeneration, integrating into ganglion cell layer to some extent [256] | In some cases, the injected cells had disappeared after transplantation [137, 139] |
 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] |