Advertisement

PentaVision

Glaucoma Physician

Article

Reversing Vision Loss With Neuromodulation

Numerous candidates could protect or restore vision after optic nerve injury.

By: Julie Y. Cho, MD, PhD, Jeffrey L. Goldberg, MD, PhD
Glaucoma Physician June 1, 2021 Vol Ophthalmology Management 25, Issue June 2021 Page(s): E1-E6

Related

Glaucoma remains the most common cause of irreversible vision loss worldwide, and together with other optic neuropathies — ischemic, traumatic, immunologic as in optic neuritis, and compressive as in optic nerve glioma — reflect loss of retinal ganglion cells (RGCs) and their axons in the optic nerve. Injury to RGC axons leads to progressive degeneration of RGC somata and Wallerian degeneration of their axons in the optic nerve.1 Because injured axons in the optic nerve do not spontaneously regenerate after injury, damage to and loss of RGCs ultimately lead to irreversible blindness. Effective therapies are critically needed to prevent degeneration of RGCs and to promote regeneration of their optic nerve axons.

Strategies to encourage the survival of RGCs, induce axonal regeneration, and promote the generation of new RGCs are of great interest in both understanding the neurodegenerative process and developing new therapies to maintain and even restore vision. Studies of molecular pathways regulating RGC development, survival, and regeneration have yielded multiple candidates to potentially reverse vision loss after optic nerve injury. This review summarizes several neuromodulatory strategies to reverse vision loss.

Inhibitory Factors in RGC Survival and Optic Nerve Regeneration

A number of factors inhibit RGC survival and axon regeneration in optic nerve injury or degeneration, including an inhibitory optic nerve glial environment2-4 and a developmental loss of the RGCs’ intrinsic capacity for rapid axon growth, which is initiated by presynaptic amacrine cells.5 Even more interesting has been work demonstrating the importance of electrical activity in enhancing RGCs’ responsiveness to peptide neurotrophic growth factors and thereby RGCs’ survival and growth.6

What happens to RGC activity after optic nerve injury? The data have varied in animal models and have been largely lacking in humans, but in general, measures of RGC activity, such as those in visually evoked potentials or electroretinogram studies in optic neuropathies, including glaucoma, show the loss of RGC activity, perhaps in advance of RGC death.7-9 These data are supported by data from animal models of glaucoma. For example, an early effect of ocular hypertension is retraction of RGC dendrites in the inner plexiform layer.10,11

Presynaptic to RGCs, amacrine cells respond to RGC axon injury in adult mice by becoming hyperactive. As the sole presynaptic source of inhibition of RGCs, amacrine hyperactivity leads to reduced RGC activity. Preventing hyperinhibition of RGCs, either by overexpression of inwardly rectifying potassium channels or by intravitreal injections of gamma aminobutyric acid (GABA) and glycine receptor blockers, increases RGC survival after optic nerve injury and induces modest axon regeneration.12 However, amacrine cell silencing was only effective in inducing long-distance axon regrowth in conjunction with trophic stimulation, such as with insulin-like growth factor 1 (IGF-1).12 In the mature retina, amacrine cells can further inhibit RGC survival and growth by releasing zinc, probably in synaptic vesicles, which is then taken up by injured RGCs. Blocking this pathway by genetic deletion of zinc transporter 3, a putative transporter of zinc into the synaptic vesicles, or by pharmacologic zinc chelation, leads to potent promotion of RGC survival and moderate regeneration of axons after optic nerve injury.13 Together, these results suggest that the retinal environment, and specifically inadequate levels of retinal activity normally stimulating RGCs, may indeed be a barrier to RGC survival and restoration of the optic nerve.

Thus, it may be critical to restore physiologic levels of activity, through electrical or visual stimulation, together with neurotrophic survival and growth signals, to optimally promote neuroprotection or vision restoration in glaucoma. Indeed, although generalized amacrine cell silencing is not a feasible strategy for the treatment of optic neuropathy given the important role that they play in retinal circuitry and proper visual function, strategies to reduce the activity of extrinsic inhibitory pathways are being pursued for their therapeutic potential.

Stimulation of the Retinal and Optic Nerve Circuitry to Promote Neuroprotection and Regeneration

Retinal ganglion cell electrical activity is important for cell growth and axon extension. During development, spontaneous and visually driven electrical activity refine RGC connections.14 Increasing electrical activity in RGCs confers survival benefits, but it also allows RGCs to respond to growth factors that normally would not stimulate axon outgrowth.6,12

Direct Pharmacologic Stimulation of Activity

In culture, increasing RGCs’ electrical activity by KCl depolarization or the elevating of adenosine 3’,5’-monophosphate (cAMP) levels increases responsiveness to trophic factors, including brain-derived neurotrophic factor (BDNF), ciliary neurotrophic factor (CNTF), and insulin, for survival15 and axon growth.6 Similarly, electrically stimulating RGCs in culture promotes trophic responsiveness, survival, and growth.6,16 Although intravitreal injection of cAMP analogs alone does not potentiate axon growth after crush injury in the adult animal,17 coadministration with CNTF synergistically improves axon regeneration.18 Furthermore, increasing RGC firing in the adult animal after optic nerve injury by activating receptors to upregulate activity pharmacologically19 or by melanopsin overexpression20 promotes regeneration and boosts the impact of molecular stimulants of axon growth. Enhancement of mTOR in combination with augmentation of cAMP and injections of oncomodulin promoted long-range regeneration of RGC axons21 in brain structures, including the visual cortex. Mice that received combined treatment of PTEN knockdown/cAMP increase/oncomodulin also recovered some visual function, although the connections eventually regressed.

Electrical Stimulation of Retinal Ganglion Cells

It is possible to electrically stimulate RGCs in vivo using extraocular electrodes. Transcorneal electrical stimulation using alternating currents (TcES) has been shown to exert neuroprotective and proregenerative effects in animal models of optic neuropathies, including acute nerve injury and glaucoma.22-24 Stimulation applied immediately after intraocular pressure elevation promoted RGC survival in an acute glaucoma model.22 The clinical value of alternating current stimulation (ACS) was tested in several controlled trials, in which patients with glaucoma or optic neuropathies received ACS, and treated patients showed statically significant improvement in visual field deficits that were stable for up to 2 months.25-27 However, it should be noted that recovery of vision was variable between patients and was limited by subjective assessment of improvement. Research in electrical stimulation is continuing, and improvements in delivery, dosing, durations, and intervals in these stimulation paradigms should be explored further.

Visual Stimulation of Retinal Ganglion Cells

Visual stimulation should in principle promote electrical stimulation of RGCs and could be used in lieu of electrical stimulation for neuroprotection and regeneration. Indeed, increasing RGC activity through forced visual stimulation, in the form of moving high-contrast white bars, promoted regeneration and boosted the impact of molecular stimulants of axon growth after optic nerve injury.19 Notably, the extreme treatment required a combination of mTOR activation, daily forced visual activation, and deprivation of the intact eye to produce long-distance axon regeneration that reached downstream targets and was shown to improve some vision-dependent behaviors, such as escape behavior in response to visual stimuli.19 There has not yet been a conclusive human study complementing these results, but use of virtual reality headsets to provide patients with visual stimulation paradigms to activate these pathways is entering human testing.

Stimulating Survival and Growth With Neurotrophic Factors

Strategies for neuromodulation and optic nerve stimulation may benefit from additional neurotrophic factor stimulation for significant neuroprotection and regeneration (and, in some cases, visual function). It is increasingly being recognized that these peptide trophic factors may be exerting their effects not only through directly stimulating RGC survival and axon growth but also by promoting RGCs’ dendrite and synapse health in the retina, thereby modulating RGC activity as well.

Neuromodulation of Retinal Ganglion Cell Dendrites

Increasing dendrite arborization also has been shown to modulate RGC activity. Dendrite retraction and synapse disassembly are signs of pathology in neurodegenerative disorders, and rapid retraction of dendrites is among the earliest pathological changes seen in RGCs in animal models of glaucoma.11 Insulin — a peptide factor that acts on insulin receptors but also, at higher concentrations, on IGF-1 receptors — led to dendrite regeneration and RGC survival and rescued RGC responses to light-driven stimulation.28 Given the significant results of the study and safety profile and availability of insulin as a systemic therapy, topical insulin drop therapy is being studied in clinical trials in human patients with glaucoma.29

Other Neurotrophic Factors as Candidates for Neuroprotection and Regeneration

Like insulin’s studied effects on dendrite growth, IGF-1 leads to modest axon regeneration when overexpressed using viral gene therapy following optic nerve injury12,30 and to more robust long-distance axon regrowth in conjunction with amacrine cell silencing.12 Other neurotrophic factors, such as BDNF and CNTF, reproducibly lead to RGC neuroprotection12,15,31 and axon regeneration, especially when used in combination with strategies to increase RGC activity.6 Candidate CNTF therapies are now in clinical trials for glaucoma,32,33 and other neurotrophic factors are also likely to be tested for glaucoma and other optic neuropathies in the future.

Conclusion

There are numerous exciting candidates to protect or restore vision after optic nerve injury. Major questions remain, however, including whether robust connection of regenerating RGCs can reach appropriate targets in the brain, whether restoration of useful visual function can be achieved, and the degree to which different candidate therapies enhance RGC function concomitant with promoting survival. Nevertheless, clinical testing is now viable in well-designed, randomized clinical trials, underscoring the many advances in the lab that can now be translated to human testing.

Julie Y. Cho, MD, PhD, and Jeffrey L. Goldberg, MD, PhD, are with the Spencer Center for Vision Research in the Byers Eye Institute department of ophthalmology at Stanford University in Palo Alto, California. The authors report no related disclosures.

References

  1. Chen H, Wei X, Cho KS, et al. Optic neuropathy due to microbead-induced elevated intraocular pressure in the mouse. Invest Ophthalmol Vis Sci. 2011;52(1):36-44. doi:10.1167/iovs.09-5115.
  2. Vidal-Sanz M, Bray GM, Villegas-Pérez MP, Thanos S, Aguayo AJ. Axonal regeneration and synapse formation in the superior colliculus by retinal ganglion cells in the adult rat. J Neurosci. 1987;7(9):2894-2909.
  3. Villegas-Pérez MP, Vidal-Sanz M, Bray GM, Aguayo AJ. Influences of peripheral nerve grafts on the survival and regrowth of axotomized retinal ganglion cells in adult rats. J Neurosci. 1988;8(1):265-280.
  4. Aguayo AJ, Rasminsky M, Bray GM, et al. Degenerative and regenerative responses of injured neurons in the central nervous system of adult mammals. Philos Trans R Soc Lond B Biol Sci. 1991;331(1261):337-343. doi:10.1098/rstb.1991.0025.
  5. Goldberg JL, Klassen MP, Hua Y, Barres BA. Amacrine-signaled loss of intrinsic axon growth ability by retinal ganglion cells. Science. 2002;296(5574):1860-1864. doi:10.1126/science.1068428.
  6. Goldberg JL, Espinosa JS, Xu Y, Davidson N, Kovacs GT, Barres BA. Retinal ganglion cells do not extend axons by default: promotion by neurotrophic signaling and electrical activity. Neuron. 2002;33(5):689-702.
  7. Porciatti V, Bosse B, Parekh PK, Shif OA, Feuer WJ, Ventura LM. Adaptation of the steady-state PERG in early glaucoma. J Glaucoma. 2014;23(8):494-500. doi:10.1097/IJG.0b013e318285fd95.
  8. Ventura LM, Porciatti V, Ishida K, Feuer WJ, Parrish RK 2nd. Pattern electroretinogram abnormality and glaucoma. Ophthalmology. 2005;112(1):10-19. doi:10.1016/j.ophtha.2004.07.018.
  9. Xu LJ, Zhang L, Li SL, Zemon V, Virgili G, Liang YB. Accuracy of isolated-check visual evoked potential technique for diagnosing primary open-angle glaucoma. Doc Ophthalmol. 2017;135(2):107-119. doi:10.1007/s10633-017-9598-6.
  10. El-Danaf RN, Huberman AD. Characteristic patterns of dendritic remodeling in early-stage glaucoma: evidence from genetically identified retinal ganglion cell types. J Neurosci. 2015;35(6):2329-2343. doi:10.1523/JNEUROSCI.1419-14.2015.
  11. Agostinone J, Di Polo A. Retinal ganglion cell dendrite pathology and synapse loss: Implications for glaucoma. Prog Brain Res. 2015;220:199-216. doi:10.1016/bs.pbr.2015.04.012.
  12. Zhang Y, Williams PR, Jacobi A, et al. Elevating growth factor responsiveness and axon regeneration by modulating presynaptic inputs. Neuron. 2019;103(1):39-51 e35. doi:10.1016/j.neuron.2019.04.033.
  13. Li Y, Andereggen L, Yuki K, et al. Mobile zinc increases rapidly in the retina after optic nerve injury and regulates ganglion cell survival and optic nerve regeneration. Proc Natl Acad Sci U S A. 2017;114(2):E209-E218. doi:10.1073/pnas.1616811114.
  14. Huberman AD, Feller MD, Chapman B. Mechanisms underlying development of visual maps and receptive fields. Annu Rev Neurosci. 31;2008:479-509. doi:10.1146/annurev.neuro.31.060407.125533.
  15. Meyer-Franke A, Kaplan MR, Pfrieger FW, Barres BA. Characterization of the signaling interactions that promote the survival and growth of developing retinal ganglion cells in culture. Neuron. 1995;15(4):805-819. doi:10.1016/0896-6273(95)90172-8.
  16. Corredor RG, Trakhtenberg EF, Pita-Thomas W, Jin X, Hu Y, Goldberg JL. Soluble adenylyl cyclase activity is necessary for retinal ganglion cell survival and axon growth. J Neurosci. 2012;32(22):7734-7744. doi:10.1523/JNEUROSCI.5288-11.2012.
  17. Monsul NT, Geisendorfer AR, Han PJ, et al. Intraocular injection of dibutyryl cyclic AMP promotes axon regeneration in rat optic nerve. Exp Neurol. 2014;186(2):124-133. doi:10.1016/S0014-4886(03)00311-X.
  18. Cui H, Green RD. Regulation of the cAMP-elevating effects of isoproterenol and forskolin in cardiac myocytes by treatments that cause increases in cAMP. Biochem Biophys Res Commun. 2003;307(1):119-126. doi:10.1016/s0006-291x(03)01130-6.
  19. Lim JH, Stafford BK, Nguyen PL, et al. Neural activity promotes long-distance, target-specific regeneration of adult retinal axons. Nat Neurosci. 2016;19(8):1073-1084. doi:10.1038/nn.4340.
  20. Li S, Yang C, Zhang L, et al. Promoting axon regeneration in the adult CNS by modulation of the melanopsin/GPCR signaling. Proc Natl Acad Sci U S A. 2016;113(7):1937-1942. doi:10.1073/pnas.1523645113.
  21. de Lima S, Koriyama Y, Kurimoto T, et al. Full-length axon regeneration in the adult mouse optic nerve and partial recovery of simple visual behaviors. Proc Natl Acad Sci U S A. 2012;109(23):9149-9154. doi:10.1073/pnas.1119449109.
  22. Fu L, Fung FK, Lo AC, et al. Transcorneal electrical stimulation inhibits retinal microglial activation and enhances retinal ganglion cell survival after acute ocular hypertensive injury. Transl Vis Sci Technol. 2018;7(3):7. doi:10.1167/tvst.7.3.7.
  23. Morimoto T, Miyoshi T, Matsuda S, Tano Y, Fujikado T, Fukuda Y. Transcorneal electrical stimulation rescues axotomized retinal ganglion cells by activating endogenous retinal IGF-1 system. Invest Ophthalmol Vis Sci. 2005;46(6):2147-2155. doi:10.1167/iovs.04-1339.
  24. Tagami Y, Kurimoto T, Miyoshi T, Morimoto T, Sawai H, Mimura O. Axonal regeneration induced by repetitive electrical stimulation of crushed optic nerve in adult rats. Jpn J Ophthalmol. 2009;53(3):257-266. doi:10.1007/s10384-009-0657-8.
  25. Gall C, Sgorzaly S, Schmidt S, Brandt S, Fedorov A, Sabel BA. Noninvasive transorbital alternating current stimulation improves subjective visual functioning and vision-related quality of life in optic neuropathy. Brain Stimul. 2011;4(4):175-188. doi:10.1016/j.brs.2011.07.003.
  26. Sabel BA, Fedorov AB, Naue N, Borrmann A, Herrmann C, Gall C. Non-invasive alternating current stimulation improves vision in optic neuropathy. Restor Neurol Neurosci. 2011;29(6):493-505. doi:10.3233/RNN-2011-0624.
  27. Gall C, Schmidt S, Schittkowski MP, et al. Alternating current stimulation for vision restoration after optic nerve damage: a randomized clinical trial. PLoS One. 2016;11(6):e0156134. doi:10.1371/journal.pone.0156134.
  28. Agostinone J, Alarcon-Martinez L, Gamlin C, Yu WQ, Wong ROL, Di Polo A. Insulin signalling promotes dendrite and synapse regeneration and restores circuit function after axonal injury. Brain. 2018;141(7):1963-1980. doi:10.1093/brain/awy142.
  29. Safety of topical insulin drops for open-angle glaucoma. Clinicaltrials.gov identifier: NCT04118920. https://clinicaltrials.gov/ct2/show/NCT04118920 . Updated July 16, 2020. Accessed April 30, 2021.
  30. Duan X, Qiao M, Bei F, Kim I-J, He Z, Sanes JR. Subtype-specific regeneration of retinal ganglion cells following axotomy: effects of osteopontin and mTOR signaling. Neuron. 2015;85(6):1244-1256. doi:10.1016/j.neuron.2015.02.017.
  31. Leaver SG, Cui Q, Plant GW, et al. AAV-mediated expression of CNTF promotes long-term survival and regeneration of adult rat retinal ganglion cells. Gene Ther. 2006;13(18):1328-1341. doi:10.1038/sj.gt.3302791.
  32. NT-501 CNTF implant for ischemic optic neuropathy: safety, neuroprotection and neuroenhancement. Clinicaltrials.gov identifier: NCT01411657. https://clinicaltrials.gov/ct2/show/NCT01411657 . Updated August 2, 2016. Accessed April 30, 2021.
  33. NT-501 CNTF implant for glaucoma: safety, neuroprotection and neuroenhancement. Clinicaltrials.gov identifier: NCT01408472. https://clinicaltrials.gov/ct2/show/NCT01408472 . Updated August 2, 2016. Accessed April 30, 2021.

What to Read Next