REMYELINATION BY THERAPEUTICALLY ENHANCED OLIGODENDROGENESIS

 

Myelin, made by oligodendrocytes enwrapping axons with lipid-rich membranes, is essential for proper central nervous system (CNS) function. Loss of oligodendrocytes and myelin, known as demyelination, induces severe delay and failure of action potential propagation, leaves neurons and their axons vulnerable to degeneration, and causes motor, sensory, and cognitive impairment.

Demyelination is typically followed by a period of heightened new myelin formation known as remyelination, which can restore action potential propagation and prevent neurodegeneration. Remyelination is carried out primarily by newly formed oligodendrocytes.

However, the endogenous remyelination response is often incomplete, resulting in chronic demyelination and limited functional recovery.

Myelin loss, including in visual gray matter, is a common feature of several neurodegenerative diseases and injury conditions, and is present in normal aging. In addition, myelin is malformed or present in insufficient levels in several neurodevelopmental and neuropsychiatric disorders. By promoting the formation of new oligodendrocytes and myelin, remyelination therapies may be clinically important for numerous neurological conditions.

Researchers have shown that endogenous remyelination is driven by recent oligodendrocyte loss and is highly efficacious following mild demyelination, but fails to restore the oligodendrocyte population when high rates of oligodendrocyte loss occur quickly.

Treatment with a high dose of LL-341070 substantially increased regenerative oligodendrogenesis during remyelination. Thus, incomplete remyelination via therapeutically enhanced oligodendrogenesis is sufficient to recover visual cortical function.

The authors concluded that oligodendrocyte gain rate during remyelination is driven by recent oligodendrocyte loss, rather than a drive to reestablish oligodendrocyte numbers, indicating that acute signaling around the time of the loss of myelinating oligodendrocytes induces new oligodendrocyte formation. However, the exact source of the signal is unknown, and it is unclear if it involves direct signaling from damaged oligodendrocytes or is mediated by other cell types.

REFERENCE:

Della-Flora Nunes, G., Osso, L.A., Haynes, J.A. et al. Incomplete remyelination via therapeutically enhanced oligodendrogenesis is sufficient to recover visual cortical function. Nat Commun 16, 732 (2025). https://doi.org/10.1038/s41467-025-56092-6.

 

ANTIBODY-MEDIATED TREATMENT OF GLAUCOMA

 

Early-onset familial glaucoma is attributed to nonsynonymous mutations in the gene encoding myocilin. The protein myocilin is secreted at relatively high levels in the trabecular meshwork (TM) extracellular matrix. Mutant myocilin aggregates intracellularly in the endoplasmic reticulum (ER). Subsequent ER stress causes cytotoxicity that hastens dysregulation of intraocular pressure, the primary risk factor for most forms of glaucoma.

Recombinant antibodies represent an emerging class of versatile and powerful therapeutics to treat protein conformational and misfolding associated with neurodegenerative diseases. Glaucoma management has entered a new phase with the development of antibodies targeting the aggregation-prone β-propeller olfactomedin (OLF) domain of myocilin, variants of which comprise the strongest genetic link to glaucoma.

These new antibodies target the domain of myocilin that misfolds in the ER and causes pathogenic cytotoxicity. These antibodies degrade aggregating mutant myocilin in situ by rerouting mutant myocilin for lysosomal degradation.

Clearance of OLF-resident myocilin mutants is hindered by aberrant interactions with molecular chaperones such as glucose-regulated protein 94 (Grp94), leading to the accumulation of misfolded proteins, ER stress, and subsequent TM cell death.

Multi-centric research by Ma and colleagues has discovered two recombinant antibodies: anti-OLF1 recognizes a linear epitope, while anti-OLF2 is selective for natively folded OLF and inhibits aggregation in vitro. By binding OLF, these antibodies engage autophagy/lysosomal degradation to promote degradation of two pathogenic mutant myocilins.

The interaction between Grp94 and mutant myocilin can be abrogated with selective small molecules targeting Grp94 or by downregulation of Grp94 with siRNA.

Treatment with Grp94-targeted small molecules or siRNA leads to the clearance of mutant myocilin by autophagy, similar to what is observed with anti-OLF1 and anti-OLF2.

This research shows the promise of antibodies in the treatment of familial open-angle glaucoma associated with myocilin.

REFERENCE:

Ma MT, Qerqez AN, Hill KR, Azouz LR, Youngblood HA, Hill SE, Ku Y, Peters DM, Maynard JA, Lieberman RL. Antibody-mediated clearance of an ER-resident aggregate that causes glaucoma. PNAS Nexus. 2024 Dec 10;4(1):pgae556. doi: 10.1093/pnasnexus/pgae556. PMID: 39726989; PMCID: PMC11670252.

VASCULAR DENSITY AND PERFUSION IN GLAUCOMA

 

Optical coherence tomography angiography (OCTA) is a fast, noninvasive imaging technique that offers quantitative and volumetric evaluations of both the structural and vascular features of the retina and optic nerve. The changes observed in OCTA correlate topographically with the functional alterations identified through visual field assessments and the structural modifications noted on OCT.

There have been a couple of studies to analyze the radial peripapillary capillary vessel density (RPC VD) in glaucoma.

Joseph et al. have studied the peripapillary and macular perfusion densities in 20 eyes of POAG patients, 20 of NTG, and 15 of NTG, and compared them with normal eyes by OCTA analysis.  

All POAG, PACG, and NTG patients showed a lesser peripapillary perfusion density (PD) compared to normal subjects in all quadrants, which was statistically significant (P < 0.002).

Also, all POAG, PACG, and NTG patients showed a lesser superficial perifoveal plexus PD compared to normal subjects in all zones, which was statistically significant (P < 0.004).

In NTG, the peripapillary PD of the superior quadrant showed the least PD (P < 0.001), and in PACG, the inferior, nasal, and temporal quadrants showed the least PD, which was statistically significant (P < 0.002).

The mean peripapillary flux index of the outer zone was lowest in the PACG group, which was statistically significant (P < 0.001).

All forms of glaucoma (POAG, PACG, and NTG) were associated with decreased blood supply to the ONH and the perifoveal zone.

Apart from the mechanical damage to the optic nerve head, PACG is associated with significant retinal microvascular impairment.

Significant microvascular impairment in the perifoveal area in NTG is characterized by decreased PD in the outer and full zones.

Ashour et al have shown that RPC VD is reduced in eyes with glaucomatous cupping, and not in those with physiological cupping or in normal eyes. The study included 98 eyes from 98 patients, divided into 3 groups. Group 1 included 30 eyes with primary open-angle glaucoma, group 2 included 28 normal eyes with physiological cupping (normal OCT and no evidence of glaucoma), and group 3 included 40 age-matched normal eyes (vertical cup/disc ratio ≤0.5).

The study found significantly lower RPC VD across all retinal quadrants, compared to the other groups (P<0.001) in Group 1. But no significant differences were found between Groups 2 and 3 (P=0.559). Therefore, OCTA can be used to differentiate between glaucomatous and physiological cupping.

REFERENCES:

Joseph, Rachel; Apoorva, N.; Nayak, Lakshmi D.. Comparison of vascular parameters in primary open-angle glaucoma, primary angle closure glaucoma, and normal tension glaucoma with healthy subjects using optical coherence tomography angiography. The Pan-American Journal of Ophthalmology 7(1):143, April 2025. | DOI: 10.4103/pajo.pajo_23_25

Ashour DM, Madkour NS, Ebeid WM, Mahmoud RA. Peripapillary Vascular Density Differentiates Glaucomatous Cupping From Physiological Cupping Using Optical Coherence Tomography Angiography. J Glaucoma. 2025 May 1;34(5):415-420. doi: 10.1097/IJG.0000000000002530. Epub 2024 Dec 16. PMID: 39670861.

OPTIC DISC-RNFL IN PEDIATRIC POPULATION

Optic disc and retinal nerve fiber layer (RNFL) measurements by optical coherence tomography (OCT) are important investigations in detecting glaucoma. However, the results of the OCT measurements are influenced by a normative database with which the measurements are compared. 

The results of the OCT findings in adults are reliable because of the large and stable database. However, in children below 18 years of age, the database is usually not robust, and so the OCT results are not clear.

There have been a few studies of OCT in children, and the results of those studies are being presented here.

Adem et al. reported the average peri-papillary RNFL thickness in children between 6 to 16 years of age was 106.45 9.41 μm; the average macular thickness was 326.44 14.17 μm; and the average macular volume was 0.257 0.011 mm³. The aforementioned OCT measurements were not significantly correlated with age, SE, or AL values (P > .05 for all). [Turk A, Ceylan OM, Arici C, Keskin S, Erdurman C, Durukan AH, Mutlu FM, Altinsoy HI. Evaluation of the nerve fiber layer and macula in the eyes of healthy children using spectral-domain optical coherence tomography. Am J Ophthalmol. 2012 Mar;153(3):552-559.e1.]

Patel et al. have reported the average retinal nerve fiber layer (RNFL) thickness measured with spectral-domain (SD) OCT in children between 5 and 18 years of age to be 102 to 113μm. [Patel A, Purohit R, Lee H, Sheth V, Maconachie G, Papageorgiou E, McLean RJ, Gottlob I, Proudlock FA. Optic Nerve Head Development in Healthy Infants and Children Using Handheld Spectral-Domain Optical Coherence Tomography. Ophthalmology. 2016 Oct;123(10):2147-57.] Susan et al. found the mean peripapillary RNFL thickness in children aged 5 to 15 years to be 107.6 ± 1.2 μm. [Yanni SE, Wang J, Cheng CS, Locke KI, Wen Y, Birch DG, Birch EE. Normative reference ranges for the retinal nerve fiber layer, macula, and retinal layer thicknesses in children. Am J Ophthalmol. 2013 Feb;155(2):354-360.e1.] In a study by Raffa regarding the normative OCT reference ranges in healthy Saudi children, the mean values for RNFL thickness, disc area, rim area, and cup volume were 93.9 μm, 2 mm², 1.6 mm², and 0.3 mm³, respectively. The vertical ratio of cup to disc was 0.4. [Raffa L, AlSwealh SS. Normative optical coherence tomography reference ranges of the optic nerve head, nerve fiber layer, and macula in healthy Saudi children. Saudi Med J. 2023 Nov 28;44(12):1269-1276.] An OCT study of 113 healthy children aged 6 to 17 years with no ocular abnormality except refractive error showed the mean RNFL thickness was 95.6+/-8.7 μm. [Al-Haddad C, Barikian A, Jaroudi M, Massoud V, Tamim H, Noureddin B. Spectral domain optical coherence tomography in children: normative data and biometric correlations. BMC Ophthalmol. 2014 Apr 22;14:53.] A multi-center Spanish study in normal children reported the following data: The mean global RNFL thickness was 97.40 ± 9.0 μm (range, 77-121.7 μm). [Barrio-Barrio J, Noval S, Galdós M, Ruiz-Canela M, Bonet E, Capote M, Lopez M. Multicenter Spanish study of spectral-domain optical coherence tomography in normal children. Acta Ophthalmol. 2013 Feb;91(1):e56-63.]

This study is by Hassan et al. from Iran, 9051 eyes of 4784 children were analyzed.

Vertical cup-to-disc ratio	0.45±0.15(0.45–0.46) mm
Average cup-to-disc ratio	0.43±0.14 (0.42–0.43) mm
Rim area	1.46±0.25 (1.45–1.47) mm2
Disc area	1.92±0.35 (1.91–1.93) mm2
Cup volume	0.14±0.14 (0.14–0.15) mm3

The mean±SD and 95% confidence intervals (in parentheses)

Hashemi, Hassan; Khabazkhoob, Mehdi; Heydarian, Samira; Emamian, Mohammad Hassan; Fotouhi, Akbar. Optic Disc Measurements in Children by Optical Coherence Tomography. Journal of Glaucoma 32(5):p 361-368, May 2023.

ALCOHOL AND OPEN-ANGLE GLAUCOMA

 

A study by Leo et al, based on the National Institutes of Health All of Us (AoU) Research Program, has reported a significant association between the frequency of consumption of alcoholic drinks and primary open-angle glaucoma (POAG).

The retrospective study utilized the diverse All of Us Research Program. A randomized 1:4 case/control ratio was utilized for POAG patients and randomly selected control patients. χ², bivariable, and multivariable regression were utilized to examine the associations between alcohol use and POAG.

Of the 3876 POAG patients, 2015 (52%) were female, 1943 (50%) were White, 1152 (30%) were Black, 117 (3%) were Asian, and 584 (15%) were Hispanic.

Alcohol use of 4 or more drinks per week was significantly higher in the glaucoma cohort relative to controls (15% vs. 12%, P<0.001). On bivariate analysis, diagnosed alcohol misuse was associated with higher odds of POAG [odds ratio (OR): 1.20, 95% CI: 1.17–1.23, P<0.001].

In multivariable regression, more frequent alcohol use was associated with higher odds of glaucoma; alcohol use with a frequency of 4 or more drinks per week was significantly associated with increased odds of glaucoma (OR: 1.22, 95% CI: 1.03–1.44, P=0.023).

This dose-response relationship was also observed and more pronounced for female participants, where alcohol use frequency of monthly or less was already associated with increased odds of glaucoma (OR: 1.21, 95% CI: 1.002–1.46, P=0.048).

RESULT:

According to this study, there was a dose-response relationship between alcohol consumption and POAG risk, which was more pronounced in female participants. Overall, a higher frequency of alcohol consumption was associated with an increased risk of POAG; 4 or more drinks per week was significantly associated with a higher risk of glaucoma.

REFERENCE:

Meller LLT, Saseendrakumar BR, Mahmoudinezhad G, Tavakoli K, Wu JH, Parikh A, Bhanvadia S, Moghimi S, Zangwill L, Weinreb RN, Baxter SL. Association Between Alcohol Use and Primary Open Angle Glaucoma. J Glaucoma. 2025 Feb 1;34(2):69-76. doi: 10.1097/IJG.0000000000002529. Epub 2024 Dec 16. PMID: 39670849.

 

LEOS (LASER ENDOSCOPY OPHTHALMIC SYSTEM)

 

BVI Medical, a leading global ophthalmic device company, has received 510(k) clearance from the U.S. Food and Drug Administration (FDA) for its innovative glaucoma surgical system, Leos™ (Laser Endoscopy Ophthalmic System).

Leos™ introduces a novel, more intuitive laser endoscopic cyclophotocoagulation (ECP) procedure that integrates seamlessly into the surgical workflow.

This laser system lowers intraocular pressure by addressing aqueous humor production in a minimally invasive ab interno procedure.

It incorporates unique endoscopic capabilities to provide superior visualization of the eye anatomy in a way not seen in the past, or with the latest imaging systems.

https://www.bvimedical.com/bvi-medical-announces-approval-of-breakthrough-technology-fda-510k-clearance-of-its-laser-endoscopy-ophthalmic-system-leos/

DIRECT SELECTIVE LASER TRABECULOPLASTY (DSLT)

Selective Laser Trabeculoplasty (SLT) is an effective first-line treatment option for patients with open-angle glaucoma and normal-tension glaucoma.

Alcon has improved the delivery system of SLT machines with the development of the Voyager Direct Selective Laser Trabeculoplasty (DSLT) system.

Voyager™ DSLT is designed to automatically deliver 120 laser pulses directly through the limbus to the trabecular meshwork, thereby improving aqueous outflow and reducing intraocular pressure.

The GLAUrious Study comparing DSLT and SLT did not find inferiority of the DSLT procedure at 6 and 12 months of follow-up.

The study demonstrated that DSLT with the Eagle device is effective in providing a clinically meaningful reduction in IOP at 6 months that is sustained out to 12 months.

The protocol included DSLT: 120 shots, 3 ns, 400 µm spot size, energy 1.4–1.8 mJ delivered at the limbus over 2 s. SLT: approximately 100 shots, 3 ns, 400 µm spot size administered 360 degrees at the limbus using any gonioscopy lens, energy 0.3–2.6 mJ.

According to the authors, a sample size of 164 is sufficient to detect a non- inferiority margin of 1.95 mm Hg for change from baseline IOP.

REFERENCE:

Congdon N, Azuara-Blanco A, Solberg Y, Traverso CE, Iester M, Cutolo CA, Bagnis A, Aung T, Fudemberg SJ, Lindstrom R, Samuelson T, Singh K, Blumenthal EZ, Gazzard G; GLAUrious study group. Direct selective laser trabeculoplasty in open angle glaucoma study design: a multicentre, randomised, controlled, investigator-masked trial (GLAUrious). Br J Ophthalmol. 2023 Jan;107(1):62-65. doi: 10.1136/bjophthalmol-2021-319379. Epub 2021 Aug 25. PMID: 34433548; PMCID: PMC9763163.