Neuroprotective agents


Many inherited forms of sight loss are caused by genetic changes that lead to progressive degeneration of the retinaoptic nerve and/or cornea. As a result, patients experience gradual but permanent visual impairment as these specialised cells do not regenerate once they die. 

Conditions that ultimately lead to gradual degeneration of the photoreceptor cells in the retina are collectively termed inherited retinal dystrophies (IRD), while those that cause optic nerve degeneration are called hereditary optic neuropathies. The most common IRD is retinitis pigmentosa (RP), affecting 1 in 4000 individuals worldwide[1], and there is much ongoing research on potential therapies for this blinding condition. In terms of hereditary optic neuropathy, a number of researches are currently focused on Leber hereditary optic neuropathy (LHON)Corneal dystrophies are a group of conditions characterised by gradual degeneration of the corneal cells, out of which the most common is Fuchs endothelial corneal dystrophy.  

One area of current research is the use of neuroprotective agents. They encompass a broad range of therapies that aim to slow or halt the degenerative process by promoting cell survival and preserving their function. A few selected neuroprotective agents that are either approved for clinical use or are undergoing human clinical trials will be discussed herein. 

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1) N-acetylcysteine (NAC)/ N-acetylcysteine-amide (NACA)

There are two types of photoreceptors in the retina called rods and cones. In humans, there are significantly more rods compared to cones. The rods are responsible for vision in dim light and peripheral vision (side vision) while cones are responsible for central (reading) vision, along with helping us to see colour and objects in detail under bright light. In RP, the rods are affected earlier and more severely compared to cones. 

It is hypothesised that when large amounts of rods die in RP, oxygen consumption in the retina is severely reduced, leading to large amounts of toxic free radicals being generated. These compounds are harmful to the remaining cone photoreceptors.[2]

Both NAC and its more potent form, NACA are medications with powerful antioxidant effect (able to “clean up” the generated free radicals). NAC is a safe and common drug used in patients with certain lung conditions and paracetamol overdose. Both drugs have been shown in animal models of RP to preserve cone structure and function.[3,4]

In a phase 1 trial investigating daily oral NAC intake in RP patients for 6 months (FIGHT-RP1), an improvement in visual function was observed during the treatment period. This improvement subsequently diminished after treatment was stopped at the end of the study. NAC was well-tolerated and the main associated side effects were nausea, stomach upset, diarrhoea and vomiting, all of which resolved on their own. The FIGHT-RP1 study has since been extended (NCT 03999021) and a phase 2 trial is being planned for orally administered NACA

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2) Neurotrophic factors

Neurotrophic factors are proteins in our bodies that support cell growth, development, regeneration and survival. Multiple neurotrophic factors have been shown to slow photoreceptor loss but only two have been or are being translated to human clinical trials.[5-7]

Ciliary neurotrophic factor (CNTF)

CNTF was investigated in two separate phase 2 clinical trials for both early and end-stage RP. The treatment was delivered into the eye as an encapsulated implant that releases CNTF continuously to the photoreceptor cells. Although there were no major side effects reported and continuous CNTF release from the implant was achieved, patients did not experience any improvement in visual function in the long-term (60-96 months)

Rod-derived Cone Viability Factor (RdCVF)

RdCVF is a protein that was first described by a group of French researchers, led by Dr Thierry Léveillard.[8] By conducting experiments in animal models of RP, they learned that rod photoreceptors are crucial in keeping cones healthy due to the production of RdCVF.[9] RdCVF enables cones to uptake glucose (sugars) to produce energy and stay healthy, hence in its absence, cones are essentially starved. Injections of RdCVF into the retina and blood circulation of mice with RP showed preservation of cone structure and function.[10] A clinical trial is being planned to investigate its safety and effectiveness in humans. If proven successful, RdCVF-based therapies may enable us to address a wide range of IRDs in addition to RP. 

3) Tauroursodeoxycholate acid (TUDCA)

TUDCA and its original derivative, ursodeoxycholate acid (UDCA) are naturally occurring bile acids found in hibernating bears that have been utilised in traditional Chinese medicine for various conditions, ranging from liver detoxification to improving vision.[11] In modern medicine, synthetic UDCA is an approved treatment for a liver condition called primary biliary cholangitis.

Further research into both TUDCA and UDCA revealed that both drugs exert a protective effect on nerve cells (including photoreceptors) through multiple mechanisms[11]:

  • Preventing premature programmed cell death (medically known as apoptosis)
  • Preventing sustained activation of a natural chemical response in cells that triggers apoptosis if the proteins created are dysfunctional and cannot be repaired within a certain time span (medically know as endoplasmic reticulum stress) 
  • Reducing production of toxic oxygen free radicals
  • Reduce inflammation in cells 

Most ongoing clinical trials for TUDCA are in neurological conditions that progressively deteriorate (neurodegenerative conditions) such as Alzheimer disease, multiple sclerosis and motor neuron disease.

Although injections of TUDCA into the blood stream of various mouse models[12-16] of RP have resulted in significant preservation of photoreceptor structure and function, this has not translated into human clinical trials mainly because the dosages used in animal studies are extremely high for humans. Hence, an alternative approach such as direct injections into the eye (e.g intravitreal injections) is preferable as the dosage can be reduced and there is less risk of systemic side effects. 

Injection of a drug into the clear jelly (vitreous) of the eye.
Intravitreal injection

One such approach that has been trialled involved encapsulating TUDCA in a biodegradable material which was then slowly but continuously released once injected into the eye. An increased number of surviving photoreceptor cells and visual function improvement were observed when injected into mice affected by RP.[17]  

4) Idebenone (Raxone)

Idebenone is an antioxidant approved for the treatment of LHON in the UK and the European Union (EU).This is mainly based on the result of a clinical trial where patients were randomly assigned to receive idebenone or placebo tablets for 6 months.[18] The results suggested that treatment with idebenone most likely benefit patients with discordant visual acuity (different visual acuity in the two eyes of a patient), who are probably at the early stages of the disease course. The study also reported that in 20% of idebenone-treated patients who could not read the visual acuity chart at start of the study, they could read at least one line on the chart by the end of the study. 

A standard visual acuity measuring chart with letters arranged vertically in decreasing sizes.
A standard Snellen chart used to measure visual acuity

A follow-up study of a sub-group of these patients showed that the treatment effect persisted despite idebenone has been stopped for a median of 2.5 years.[18] The authors hypothesised that idebenone can preserve or re-establish retinal ganglion cell (collection of these cells form the optic nerve) connection during the initial stages of the disease, protecting it from irreversible damage. 

A microscopic view of the cells in the retina. The cone-shaped and rod-shaped photoreceptors are situated deepest and supported by the RPE cells. Other cells above the photoreceptors are responsible for transmitting electrical signals to the brain to generate vision.
Microscopic view of the cells in the retina: The rod and cone photoreceptors are at the bottom supported by the retinal pigment epithelium. The other cell types above the photoreceptors relay electrical signals to the brain

Other studies observed that it can take an average of 17 months for visual recovery in patients who were continuously kept on idebenone treatment.[19,20] This means that prolonged treatment may result in some degree of visual recovery even in patients with established disease. Current data also suggest that idebenone treatment has the most visual impact if initiated early in the disease course.[20]  

There is an ongoing phase 4 trial (NCT 02774005; LEROS) assessing the long-term safety and efficacy of idebenone treatment in LHON.  

5) Antioxidants in corneal dystrophies

Toxic free radicals generated from oxygen consumption by corneal cells have been implicated as the underlying disease mechanisms of Fuchs endothelial corneal dystrophy.[21-23] A few anti-oxidants have been identified as potential treatments for Fuchs endothelial corneal dystrophy but further studies are required to confirm these findings. The potential medications are: 

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  2.  Campochiaro PA, Mir TA. The mechanism of cone cell death in Retinitis Pigmentosa. Prog Retin Eye Res. Jan 2018;62:24-37. doi:10.1016/j.preteyeres.2017.08.004
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  4.  Dong A, Stevens R, Hackett S, Campochiaro PA. Compared with N-acetylcysteine (NAC), N-Acetylcysteine Amide (NACA) Provides Increased Protection of Cone Function in a Model of Retinitis Pigmentosa. Investigative Ophthalmology & Visual Science. 2014;55(13):1736-1736.
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  8.  Léveillard T, Mohand-Saïd S, Lorentz O, et al. Identification and characterization of rod-derived cone viability factor. Nat Genet. Jul 2004;36(7):755-9. doi:10.1038/ng1386
  9.  Aït-Ali N, Fridlich R, Millet-Puel G, et al. Rod-derived cone viability factor promotes cone survival by stimulating aerobic glycolysis. Cell. May 7 2015;161(4):817-32. doi:10.1016/j.cell.2015.03.023
  10.  Sahel JA, Léveillard T. Maintaining Cone Function in Rod-Cone Dystrophies. Adv Exp Med Biol. 2018;1074:499-509. doi:10.1007/978-3-319-75402-4_62
  11.  Pardue MT, Allen RS. Neuroprotective strategies for retinal disease. Prog Retin Eye Res. Jul 2018;65:50-76. doi:10.1016/j.preteyeres.2018.02.002
  12.  Pardue MT, Allen RS. Neuroprotective strategies for retinal disease. Prog Retin Eye Res. Jul 2018;65:50-76. doi:10.1016/j.preteyeres.2018.02.002
  13.  Lawson EC, Bhatia SK, Han MK, et al. Tauroursodeoxycholic Acid Protects Retinal Function and Structure in rd1 Mice. Adv Exp Med Biol. 2016;854:431-6. doi:10.1007/978-3-319-17121-0_57
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  15.  Drack AV, Dumitrescu AV, Bhattarai S, et al. TUDCA slows retinal degeneration in two different mouse models of retinitis pigmentosa and prevents obesity in Bardet-Biedl syndrome type 1 mice. Invest Ophthalmol Vis Sci. Jan 5 2012;53(1):100-6. doi:10.1167/iovs.11-8544
  16.  Fernández-Sánchez L, Lax P, Pinilla I, Martín-Nieto J, Cuenca N. Tauroursodeoxycholic acid prevents retinal degeneration in transgenic P23H rats. Invest Ophthalmol Vis Sci. Jul 1 2011;52(8):4998-5008. doi:10.1167/iovs.11-7496
  17.  Zhang X, Shahani U, Reilly J, Shu X. Disease mechanisms and neuroprotection by tauroursodeoxycholic acid in Rpgr knockout mice. J Cell Physiol. Aug 2019;234(10):18801-18812. doi:10.1002/jcp.28519
  18.  Fernández-Sánchez L, Bravo-Osuna I, Lax P, et al. Controlled delivery of tauroursodeoxycholic acid from biodegradable microspheres slows retinal degeneration and vision loss in P23H rats. PLoS One. 2017;12(5):e0177998. doi:10.1371/journal.pone.0177998
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  21.  Carelli V, La Morgia C, Valentino ML, et al. Idebenone treatment in Leber’s hereditary optic neuropathy. Brain. Sep 2011;134(Pt 9):e188. doi:10.1093/brain/awr180
  22.  Jurkunas UV, Bitar MS, Funaki T, Azizi B. Evidence of oxidative stress in the pathogenesis of fuchs endothelial corneal dystrophy. Am J Pathol. Nov 2010;177(5):2278-89. doi:10.2353/ajpath.2010.100279
  23.  Engler C, Kelliher C, Spitze AR, Speck CL, Eberhart CG, Jun AS. Unfolded protein response in fuchs endothelial corneal dystrophy: a unifying pathogenic pathway? Am J Ophthalmol. Feb 2010;149(2):194-202.e2. doi:10.1016/j.ajo.2009.09.009
  24.  Borderie VM, Baudrimont M, Vallée A, Ereau TL, Gray F, Laroche L. Corneal endothelial cell apoptosis in patients with Fuchs’ dystrophy. Invest Ophthalmol Vis Sci. Aug 2000;41(9):2501-5.

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Updated on November 30, 2020
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