The Latest Articles on Glaucoma and Neurodegenerative Diseases
Our staff editors continue to share exciting, interesting, and thought-provoking reading material in the recommended articles series.
This week, we would like to share several latest articles on Glaucoma and Neurodegenerative Diseases.
Title: Safety and Target Engagement of C1q Inhibitor ANX007 in Neurodegenerative Eye Disease:Results from Phase 1 Studies in Glaucoma
Authors: Yang Sun, David Wirta, Wendy Murahashi, Vidhu Mathur, Sethu Sankaranarayanan, Lori K. Taylor, Ted Yednock, Donald S. Fong, Jeffrey L. Goldberg
Type: Research Article
Abstract:
Purpose
C1q, the initiating molecule of the classical complement cascade, is involved in synapse elimination and neuronal loss in neurodegenerative diseases including glaucoma. Here we report an evaluation of the safety, tolerability, and ocular pharmacokinetics and pharmacodynamics of intravitreal (IVT) injections of ANX007, an anti-C1q monoclonal antibody fragment that blocks activation of the classical complement cascade.
Design
An open-label, single-dose-escalation phase 1a study followed by a double-masked, randomized, sham-controlled, repeat-injection phase 1b study.
Participants
A total of 26 patients with primary open-angle glaucoma.
Methods
Nine patients with primary open-angle glaucoma (mean Humphrey visual field deviation between –3 and –18 dB) were enrolled in phase 1a and received single doses of ANX007 (1.0 mg, n = 3; 2.5 mg, n = 3; or 5.0 mg, n = 3). Seventeen patients (mean Humphrey visual field deviation between –3 and –24 dB) were enrolled in phase 1b and randomized to 2 monthly doses of ANX007 (sham, n = 6; 2.5 mg ANX007, n = 6; or 5 mg ANX007, n = 5).
Main Outcome Measures
Safety and tolerability (including laboratory evaluation of urinalysis, complete blood count, and serum chemistries), ANX007 pharmacokinetics, target engagement, and immunogenicity.
Results
The mean age overall was 70 years in phase 1a and 68 years in phase 1b. In both studies, no serious adverse events were observed, no non-ocular treatment-emergent adverse events (TEAEs) attributable to study drug were reported, and ocular TEAEs were mild. IOP returned to normal levels for all patients within 45 minutes of IVT injection. No clinically significant deviations in laboratory results were observed. In the phase 1b study, C1q in the aqueous humor was reduced to undetectable levels in both the 2.5 mg and 5 mg cohorts 4 weeks after the first ANX007 dose.
Conclusions
In these studies, single and repeat IVT ANX007 injections were well tolerated and demonstrated full target engagement 4 weeks after dosing with both low and high doses, supporting monthly or less-frequent dosing. Further investigation in neurodegenerative ocular diseases is warranted.
Access this article: https://doi.org/10.1016/j.xops.2023.100290
Title: Risk of dementia in newly diagnosed glaucoma: a nationwide cohort study in Korea
Authors: Do Young Park, Mina Kim, Yoonjong Bae, Hyemin Jang, Dong Hui Lim
Type: Research Article
Abstract:
Purpose
To investigate the risk of dementia in participants with newly diagnosed glaucoma.
Design
A nationwide cohort study using authorized data provided by the Korean National Health Insurance Service (NHIS).
Participants
A total of 788,961 participants aged ≥ 45 years in 2006, who did not have dementia or glaucoma between 2002 and 2005, were included.
Methods
Data were collected from a nationwide population-based retrospective cohort study using the Korean NHIS database. From January 2006 to December 2017, participants were tracked for the diagnosis of glaucoma or dementia using claims data. The prospective association between newly diagnosed glaucoma and the risk of dementia was investigated using a multivariable Cox proportional hazard model adjusted for age, sex, behavioral factors, and systemic and ocular comorbidities.
Main Outcome Measures
Hazard ratios and 95% confidence intervals for dementia development according to the parameters, including glaucoma diagnosis.
Results
Overall, 7.0% of the participants developed dementia after an average of 7.4 years. A newly diagnosed glaucoma was associated with a higher risk of dementia (hazards ratio [HR] 1.89, 95% confidence interval [CI] 1.57 to 2.27) independent of age, sex, body mass index, income, smoking and drinking status, visual acuity, and other systemic comorbidities, such as diabetes, hypertension, stroke, and depression. An association between the risk of dementia and glaucoma was noted in participants with Alzheimer’s disease (AD) but not in those with vascular dementia. The risk of dementia in relation to glaucoma was higher in older participants (HR = 3.15 (≥ 65 years) vs. 1.56 (< 65 years), P < 0.0001).
Conclusion
This nationwide cohort study found that individuals with newly diagnosed glaucoma were at a higher risk of developing dementia, particularly AD. This association was greater among older individuals in the studied population.
Access this article: https://doi.org/10.1016/j.ophtha.2023.02.017
Title: Pathways to healing: Plants with therapeutic potential for neurodegenerative diseases
Authors: Sheena E.B. Tyler, Luke D.K. Tyler
Type: Research Article
Abstract:
Some of the greatest challenges in medicine are the neurodegenerative diseases (NDs), which remain without a cure and mostly progress to death. A companion study employed a toolkit methodology to document 2001 plant species with ethnomedicinal uses for alleviating pathologies relevant to NDs, focusing on its relevance to Alzheimer’s disease (AD). This study aimed to find plants with therapeutic bioactivities for a range of NDs. 1339 of the 2001 plant species were found to have a bioactivity from the literature of therapeutic relevance to NDs such as Parkinson’s disease, Huntington’s disease, AD, motor neurone diseases, multiple sclerosis, prion diseases, Neimann-Pick disease, glaucoma, Friedreich's ataxia and Batten disease. 43 types of bioactivities were found, such as reducing protein misfolding, neuroinflammation, oxidative stress and cell death, and promoting neurogenesis, mitochondrial biogenesis, autophagy, longevity, and anti-microbial activity. Ethno-led plant selection was more effective than random selection of plant species. Our findings indicate that ethnomedicinal plants provide a large resource of ND therapeutic potential. The extensive range of bioactivities validate the usefulness of the toolkit methodology in the mining of this data. We found that a number of the documented plants are able to modulate molecular mechanisms underlying various key ND pathologies, revealing a promising and even profound capacity to halt and reverse the processes of neurodegeneration.
Access this article: https://doi.org/10.1016/j.ibneur.2023.01.006
Title: Differential Effects of SARM1 Inhibition in Traumatic Glaucoma and EAE Optic Neuropathies
Authors: Pingting Liu, Wei Chen, Haowen Jiang, Haoliang Huang, Liping Liu, Fang Fang, Liang Li, Xue Feng, Dong Liu, Roopa Dalal, Yang Sun, Paymaan Jafar-Nejad, Karen Ling, Frank Rigo, Jiangbin Ye, Yang Hu
Type: Research Article
Abstract:
Optic neuropathy is a group of optic nerve (ON) diseases with progressive degeneration of ON and retinal ganglion cells (RGCs). The lack of neuroprotective treatments is a central challenge for this leading cause of irreversible blindness. SARM1 has intrinsic NAD+ hydrolase activity that causes axon degeneration by degrading axonal NAD+ significantly after activation by axon injury. SARM1 deletion is neuroprotective in many but not all neurodegenerative disease models. Here we compare two therapy strategies for SARM1 inhibition, antisense oligonucleotide (ASO) and CRISPR, to germline SARM1 deletion in neuroprotection of three optic neuropathy mouse models. This study reveals that, similar to germline SARM1 knockout in every cell, local retinal SARM1 ASO delivery and AAV-mediated RGC-specific CRISPR knockdown of SARM1 provide comparable neuroprotection to both RGC somata and axons in the SOHU glaucoma model, but only protect RGC axons, not somata, after traumatic ON injury. Surprisingly, neither of these two therapy strategies of SARM1 inhibition, nor SARM1 germline KO, benefits RGC or ON survival in the EAE/optic neuritis model. Our studies therefore suggest that SARM1 inhibition by local ASO delivery or AAV-mediated CRISPR is a promising neuroprotective gene therapy strategy for traumatic and glaucomatous optic neuropathies, but not for demyelinating optic neuritis.
Access this article: https://doi.org/10.1016/j.omtn.2023.02.029
Title: Activation of retinal glial cells contributes to the degeneration of ganglion cells in experimental glaucoma
Authors: Yanying Miao, Guo-Li Zhao, Shuo Cheng, Zhongfeng Wang, Xiong-Li Yang
Type: Review
Abstract:
Elevation of intraocular pressure (IOP) is a major risk factor for neurodegeneration in glaucoma. Glial cells, which play an important role in normal functioning of retinal neurons, are well involved into retinal ganglion cell (RGC) degeneration in experimental glaucoma animal models generated by elevated IOP. In response to elevated IOP, mGluR I is first activated and Kir4.1 channels are subsequently inhibited, which leads to the activation of Müller cells. Müller cell activation is followed by a complex process, including proliferation, release of inflammatory and growth factors (gliosis). Gliosis is further regulated by several factors. Activated Müller cells contribute to RGC degeneration through generating glutamate receptor-mediated excitotoxicity, releasing cytotoxic factors and inducing microglia activation. Elevated IOP activates microglia, and following morphological and functional changes, these cells, as resident immune cells in the retina, show adaptive immune responses, including an enhanced release of pro-inflammatory factors (tumor neurosis factor-α, interleukins, etc.). These ATP and Toll-like receptor-mediated responses are further regulated by heat shock proteins, CD200R, chemokine receptors, and metabotropic purinergic receptors, may aggravate RGC loss. In the optic nerve head, astrogliosis is initiated and regulated by a complex reaction process, including purines, transmitters, chemokines, growth factors and cytokines, which contributes to RGC axon injury through releasing pro-inflammatory factors and changing extracellular matrix in glaucoma. The effects of activated glial cells on RGCs are further modified by the interplay among different types of glial cells. This review is concluded by presenting an in-depth discussion of possible research directions in this field in the future.
Access this article: https://doi.org/10.1016/j.preteyeres.2023.101169
