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Scientists Found a New Abnormality Inside Human Glaucoma Nerve Cells — Could It Lead to a New Treatment? · Glaucoma, Vision & Longevity: Supplements & Science

• 0:00
  SPEAKER_00: Scientists found a new abnormality inside human glaucoma nerve cells.
• 0:04
  SPEAKER_00: Could it lead to a new treatment?
• 0:07
  SPEAKER_00: Short answer: possibly, but the evidence is still early.
• 0:11
  SPEAKER_00: A newly published human donor retina study found that glaucoma was associated with less sphingomyelin inside retinal ganglion cells, more acid sphingomyelinase protein, and greater activity of the lysosomal form of that enzyme.
• 0:25
  SPEAKER_00: The study also found more retinal ganglion cells containing ceramide aggregates, although total ceramide was not significantly higher overall.
• 0:33
  SPEAKER_00: That pattern is biologically interesting because acid sphingomyelinase can break down sphingomyelin into ceramide.
• 0:39
  SPEAKER_00: Excessive or mislocalized ceramide can disturb lysosomes, cell membranes, autophagy, mitochondria, inflammatory signaling, and programmed cell death.
• 0:49
  SPEAKER_00: However, the human study is observational and post-mortem.
• 0:53
  SPEAKER_00: It does not prove that acid sphingomyelinase starts glaucoma or that inhibiting it will preserve vision.
• 0:59
  SPEAKER_00: The strongest evidence for causality still comes from animal and cell studies, not from patients.
• 1:06
  SPEAKER_00: My overall interpretation, acid sphingomyelinase is a credible contributor to retinal ganglion cell injury in at least a subset of glaucoma, but it is unlikely to be the only cause or a universal treatment target.
• 1:19
  SPEAKER_00: What the new human study actually found.
• 1:22
  SPEAKER_00: The newest study published online on August 31, 2026, examined donated human retinas from people with and without a glaucoma diagnosis.
• 1:31
  SPEAKER_00: It used a sphingomyelin binding probe called enhanced green fluorescent protein conjugated non-toxic lysinin and identified retinal ganglion cells using the retinal ganglion cell marker RNA binding protein with multiple splicing.
• 1:45
  SPEAKER_00: The researchers also measured acid sphingomyelinase, neutral sphingomyelinase, sphingomyelin synthase 1, sphingomyelin synthase 2, enzyme activity, and ceramide distribution.
• 1:57
  SPEAKER_00: Human glaucoma donor retina study.
• 1:59
  SPEAKER_00: What can be determined from the currently accessible report?
• 2:03
  SPEAKER_00: For the full table, please open this article on VisualFieldtest.com.
• 2:08
  SPEAKER_00: The article is currently labeled an early accepted version that may undergo further editing before the final version of record.
• 2:15
  SPEAKER_00: Therefore, exact numeric values should be taken from the full downloadable article and supplementary data once they are accessible in a stable form, rather than reconstructed from figures or secondary summaries.
• 2:26
  SPEAKER_00: Scientific Reports article page.
• 2:29
  SPEAKER_00: The most important negative finding.
• 2:32
  SPEAKER_00: The study did not show a simple uniform increase in total ceramide throughout the retina.
• 2:37
  SPEAKER_00: That matters.
• 2:38
  SPEAKER_00: A straightforward model would predict more acid sphingomyelinase, less sphingomyelin, more total ceramide.
• 2:46
  SPEAKER_00: Instead, the study found less phenomyelin in retinal ganglion cells, more acid sphingomyelinase, more ceramide-containing aggregates, but no statistically significant increase in total retinal ganglion cell ceramide.
• 3:01
  SPEAKER_00: This suggests that the important abnormality may be local ceramide clustering rather than a large increase in the average ceramide concentration across the whole retina.
• 3:11
  SPEAKER_00: That is biologically plausible because ceramide can act as a membrane organizing signal.
• 3:16
  SPEAKER_00: A small amount concentrated in the wrong lysosomal or plasma membrane domain may be more damaging than a larger amount dispersed throughout the cell.
• 3:25
  SPEAKER_00: Why the study is interesting, but not yet proof of cause.
• 3:29
  SPEAKER_00: The human findings support a coherent mechanism, but several alternative explanations remain possible.
• 3:36
  SPEAKER_00: Acid sphingomyelinase may increase because retinal ganglion cells are already dying.
• 3:41
  SPEAKER_00: Damaged neurons often activate lysosomal enzymes, inflammatory pathways, and membrane recycling systems.
• 3:48
  SPEAKER_00: Therefore, increased acid sphingomyelinase could be an early cause of retinal ganglion cell injury, a response to mechanical, vascular, or metabolic injury, or a late consequence of degeneration.
• 4:00
  SPEAKER_00: The human study cannot determine the timing because postmortem tissue provides only one snapshot.
• 4:06
  SPEAKER_00: Lower sphingomyelin may partly reflect cell loss.
• 4:10
  SPEAKER_00: Glaucomatous retinas contain fewer retinal ganglion cells.
• 4:13
  SPEAKER_00: A whole retina dot blot can therefore show lower sphingomyelin simply because the tissue contains fewer sphingomyelin-rich neurons.
• 4:22
  SPEAKER_00: The cell level analysis is stronger because it compares sphingomyelin labeling in identified retinal ganglion cells.
• 4:29
  SPEAKER_00: Even then, survivor bias remains possible.
• 4:31
  SPEAKER_00: The analysis may compare surviving glaucoma retinal ganglion cells with healthy cells while missing the most severely damaged cells that have already disappeared.
• 4:41
  SPEAKER_00: The lysinin probe does not measure every sphingomyelin species equally.
• 4:47
  SPEAKER_00: Enhanced green fluorescent protein conjugated lysinin preferentially binds certain, especially longer chain, sphingomyelin species.
• 4:56
  SPEAKER_00: It is therefore best interpreted as a measure of accessible membrane-associated sphingomyelin, not necessarily a complete measurement of every sphingomyelin molecule in the cell.
• 5:05
  SPEAKER_00: Visualizing sphingomyelin in the retina.
• 5:08
  SPEAKER_00: Postmortem tissue is vulnerable to artificial biochemical changes.
• 5:12
  SPEAKER_00: Important limitations include postmortem delay, which can alter lysosomal pH and enzyme activity, hypoxia or agonal illness before death, systemic infection, diabetes, vascular disease or inflammation, cause of death, age and sex differences, glaucoma medications, antidepressant or antihistamine exposure, retinal regions sampled, fixation and tissue processing differences, incomplete removal of vitreous or other surrounding tissue, loss of fragile or already degenerated cells, uncertainty about the exact glaucoma subtype, and severity.
• 5:46
  SPEAKER_00: These factors are particularly important because acid sphingomyelinase is a stress-responsive enzyme.
• 5:52
  SPEAKER_00: Reconstructing the proposed pathway, the proposed pathway is acid sphingomyelinase activation, sphingomyelin breakdown, ceramide generation and clustering, lysosomal and membrane dysfunction, mitochondrial stress, apoptosis, retinal ganglion cell, and axon loss.
• 6:10
  SPEAKER_00: Each step has a different level of evidence.
• 6:12
  SPEAKER_00: Step 1.
• 6:13
  SPEAKER_00: Acid sphingomyelinase activation.
• 6:15
  SPEAKER_00: Acid sphingomyelinase is encoded by the SMPD1 gene.
• 6:19
  SPEAKER_00: Its main form is located inside lysosomes, where it works best in an acidic environment.
• 6:24
  SPEAKER_00: A separate form can be processed and secreted outside the cell.
• 6:28
  SPEAKER_00: The lysosomal form is often described as the zinc-independent pool, whereas secreted acid sphingomyelinase is more dependent on zinc at neutral extracellular pH.
• 6:39
  SPEAKER_00: The new human study found increased retinal ganglion cell acid sphingomyelinase expression and increased zinc-independent activity, while the secretory pool did not significantly change.
• 6:50
  SPEAKER_00: That pattern points toward an intracellular lysosomal abnormality rather than a generalized rise in circulating or extracellular enzyme.
• 6:58
  SPEAKER_00: Step 2.
• 6:59
  SPEAKER_00: Sphingomyelin breakdown.
• 7:00
  SPEAKER_00: Acid sphingomyelinase converts sphingomyelin into ceramide, phosphorylcholine.
• 7:05
  SPEAKER_00: Sphingomyelin is not merely structural fat, it contributes to plasma membrane stability, membrane thickness and order, lipid raft organization, receptor signaling, lysosomal membrane properties, vesicle trafficking.
• 7:18
  SPEAKER_00: The 2022 retinal and optic nerve head study found that sphingomyelin species were concentrated in the retinal ganglion cell layer, optic nerve, and choroidal regions.
• 7:28
  SPEAKER_00: In experimental ocular hypertension, retinal acid sphingomyelinase activity increased from approximately 54.98 mg protein at baseline to 121.6 mg protein, about a 2.2 fold increase.
• 7:43
  SPEAKER_00: In the optic nerve head, activity increased from approximately 95.6 to 267.0 meter moles per milligrams protein, about a 2.8 fold increase.
• 7:53
  SPEAKER_00: Sphingomyelinases in retinas and optic nerve heads.
• 7:56
  SPEAKER_00: Step 3, ceramide accumulation and clustering.
• 7:59
  SPEAKER_00: Ceramide is a signaling lipid, not simply a waste product.
• 8:02
  SPEAKER_00: Depending on its chain length, location, and concentration, ceramide can promote membrane domain formation, cluster death receptors, alter calcium handling, impair vesicle trafficking, affect lysosomal stability, stimulate inflammatory signaling, disrupt mitochondrial membranes, activate caspases and apoptosis.
• 8:23
  SPEAKER_00: The new human glaucoma study suggests that ceramide aggregation in selected retinal ganglion cells may be more important than total retinal ceramide.
• 8:31
  SPEAKER_00: This would explain why whole tissue lipidomics may fail to detect a large increase, the damaging signal may be concentrated in a small number of vulnerable cells.
• 8:41
  SPEAKER_00: Step 4.
• 8:42
  SPEAKER_00: Lysosomal and autophagy dysfunction.
• 8:45
  SPEAKER_00: Lysosomes must maintain a precise lipid composition.
• 8:48
  SPEAKER_00: Too much sphingomyelin can impair lysosomal function, but too little acid sphingomyelinase can also be harmful.
• 8:54
  SPEAKER_00: This is demonstrated by acid sphingomyelinase deficient mice.
• 8:58
  SPEAKER_00: Complete deletion caused progressive photoreceptor degeneration, reduced electroretinogram responses, retinal pigment epithelium dysfunction, lipofusin accumulation, abnormal sphingomyelin and sphingazine accumulation, increased autophagosome-associated protein.
• 9:16
  SPEAKER_00: Lack of acid sphingomyelinase induces age-related retinal degeneration.
• 9:20
  SPEAKER_00: This is a critical warning.
• 9:22
  SPEAKER_00: Complete acid sphingomyanase blockade is not a safe therapeutic goal.
• 9:26
  SPEAKER_00: The likely goal would be partial, localized, and disease stage-specific reduction.
• 9:31
  SPEAKER_00: Step 5.
• 9:32
  SPEAKER_00: Mitochondrial stress.
• 9:34
  SPEAKER_00: Retinal ganglion cells are highly energy-dependent neurons with long axons.
• 9:39
  SPEAKER_00: Mitochondrial dysfunction is an established early feature of glaucoma.
• 9:43
  SPEAKER_00: Ceramide may worsen mitochondrial stress by altering mitochondrial membrane permeability, impairing electron transport, increasing reactive oxygen species, changing mitochondrial fission and fusion, reducing energy production, increasing susceptibility to calcium overload.
• 9:59
  SPEAKER_00: However, the new human glaucoma study did not directly demonstrate that acid sphingomyelinase caused mitochondrial damage.
• 10:06
  SPEAKER_00: The mitochondrial step remains a plausible bridge between lipid dysfunction and neuronal death, not a proven part of the human glaucoma sequence.
• 10:15
  SPEAKER_00: Step 6.
• 10:16
  SPEAKER_00: apoptosis and axon degeneration.
• 10:19
  SPEAKER_00: In human-induced pluripotent stem cell-derived retinal ganglion cells, adding cell permeable ceramide reduced cell survival in a concentration and time-dependent manner.
• 10:29
  SPEAKER_00: Tumor necrosis factor alpha caused a larger reduction in cell number, and conditioned medium from ceramide-treated optic nerve head astrocytes was also toxic.
• 10:39
  SPEAKER_00: Evidence for ceramide-induced cytotoxicity in retinal ganglion cells.
• 10:44
  SPEAKER_00: In an ocular hypertension mouse model, reducing acid sphingomyelinase expression preserved retinal ganglion cell structure and pattern electroretinogram function.
• 10:54
  SPEAKER_00: This is stronger evidence for causality than the human donor study, although it remains an animal model.
• 10:59
  SPEAKER_00: Evidence for ceramide-induced cytotoxicity in retinal ganglion cells.
• 11:04
  SPEAKER_00: Has this pathway been implicated in other diseases?
• 11:08
  SPEAKER_00: Glaucoma.
• 11:09
  SPEAKER_00: Evidence now comes from several levels human donor retina, less sphingomyelin, more retinal ganglion cell acid sphingomyelinase, higher lysosomal acid sphingomyelinase activity, and more ceramide aggregates.
• 11:22
  SPEAKER_00: Experimental ocular hypertension, increased retinal and optic nerve head acid sphingomyelinase activity.
• 11:29
  SPEAKER_00: Genetic reduction, acid sphingomyelase heterozygosity protects retinal ganglion cells in mice with ocular hypertension.
• 11:36
  SPEAKER_00: Ceramide exposure, toxic to human retinal ganglion cell-like neurons in culture.
• 11:41
  SPEAKER_00: Downstream lipid targeting, reducing selected ceramide species through ceramide synthase 5 deletion, protects retinal ganglion cells.
• 11:49
  SPEAKER_00: The evidence is therefore convergent but incomplete.
• 11:52
  SPEAKER_00: Optic nerve injury.
• 11:54
  SPEAKER_00: Direct evidence specifically implicating acid sphingomyelinase in traumatic optic neuropathy is limited.
• 12:01
  SPEAKER_00: A mouse study of indirect traumatic optic neuropathy found time-dependent alterations in sphingolipids, including increases in sphingomyelin and hexosalceramide species.
• 12:11
  SPEAKER_00: The authors did not show that acid sphingomyelinase inhibition improved optic nerve survival or vision.
• 12:18
  SPEAKER_00: Temporal alterations of sphingolipids in optic nerves after indirect traumatic optic neuropathy.
• 12:24
  SPEAKER_00: This suggests that lipid remodeling occurs after optic nerve injury, but it does not establish that acid sphingomyelinase is the initiating enzyme.
• 12:33
  SPEAKER_00: Retinal ischemia.
• 12:35
  SPEAKER_00: The evidence is stronger for ischemic retinal injury.
• 12:38
  SPEAKER_00: In mice, retinal ischemia increased acid sphingomyelinase activity and ceramide levels.
• 12:44
  SPEAKER_00: Mice with only one functional copy of the acid sphingomyelinase gene had smaller ceramide increases and less structural and functional retinal damage.
• 12:52
  SPEAKER_00: Desipramine, a functional acid sphingomyelinase inhibitor, was administered at 10 mg per gram intraperitoneally before ischemic injury in one experiment.
• 13:03
  SPEAKER_00: Suppression of acid sphingomyelinase protects the retina from ischemic injury.
• 13:08
  SPEAKER_00: This supports a model in which acid sphingomyelinase is an early stress response enzyme during retinal ischemia.
• 13:14
  SPEAKER_00: Alzheimer disease.
• 13:16
  SPEAKER_00: Acid sphingomyelinase has been studied more extensively in Alzheimer disease than in glaucoma.
• 13:22
  SPEAKER_00: Research has reported increased acid sphingomyelinase in patient-derived cells, brain tissue, and Alzheimer mouse models.
• 13:29
  SPEAKER_00: Increased enzyme activity was associated with lysosomal depletion, abnormal autophagy, and impaired clearance of amyloid-related material.
• 13:38
  SPEAKER_00: Partial genetic reduction of acid sphingomyelinase in an amyloid mouse model improved some pathological and behavioral outcomes.
• 13:46
  SPEAKER_00: Acid sphingomyelinase modulates autophagy in Alzheimer disease.
• 13:51
  SPEAKER_00: The relationship is not simple, however.
• 13:53
  SPEAKER_00: Acid sphingomyelinase is necessary for normal lysosomal lipid turnover, so both excessive and insufficient activity can be harmful.
• 14:01
  SPEAKER_00: Parkinson disease.
• 14:03
  SPEAKER_00: Parkinson disease has a biologically plausible connection to sphingolipid metabolism and SMPD1 variation, but the direct treatment evidence is weaker than an Alzheimer disease or ischemic injury.
• 14:15
  SPEAKER_00: The important distinction is there is evidence linking sphingomyelin metabolism and some SMPD1 variants to Parkinson disease susceptibility.
• 14:24
  SPEAKER_00: There is not yet comparable evidence that acid sphingomyelinase inhibition preserves dopaminergic neurons or improves motor function in a Parkinson disease model.
• 14:34
  SPEAKER_00: Therefore, Parkinson disease currently supports the broader idea that sphingolipid imbalance matters in neurodegeneration, but it does not yet validate acid sphingomyelinase inhibition as a treatment.
• 14:46
  SPEAKER_00: Ischemic brain injury.
• 14:48
  SPEAKER_00: The pathway is also implicated in stroke recovery.
• 14:52
  SPEAKER_00: After cerebral ischemia and reperfusion, brain acid sphingomyelinase activity and ceramide levels increase.
• 14:58
  SPEAKER_00: Ametryptaline, fluoxetine, and dizipromine reduced acid sphingomyelinase-dependent ceramide signaling in experimental systems.
• 15:06
  SPEAKER_00: In mice, acid sphingomyelinase inhibition was associated with increased microvascular growth, improved blood-brain barrier integrity, reduced leukocyte infiltration, increased neuronal survival, improved post-stroke remodeling.
• 15:20
  SPEAKER_00: Acid sphingomyelinase deactivation after ischemia promotes brain remodeling.
• 15:25
  SPEAKER_00: A later study linked amatryptaline's angiogenic effect to changes in mitochondrial reactive oxygen species.
• 15:32
  SPEAKER_00: Acid sphingomyelinase inhibition induces cerebral angiogenesis.
• 15:36
  SPEAKER_00: What happens when acid sphingomyelinase is manipulated?
• 15:40
  SPEAKER_00: For the full table, please open this article on visualfieldtest.com.
• 15:44
  SPEAKER_00: A particularly important recent study found that deleting ceramide synthase 5 reduced retinal C16NO and C181 ceramide species and protected retinal ganglion cells during ocular hypertensive injury.
• 15:58
  SPEAKER_00: Lack of ceramide synthase 5 protects retinal ganglion cells.
• 16:02
  SPEAKER_00: This does not prove that those ceramides were generated by acid sphingomyelinase.
• 16:07
  SPEAKER_00: Ceramide synthases regulate de novo and salvage pathways, while acid sphingomyelinase generates ceramide by breaking down sphingomyelin.
• 16:16
  SPEAKER_00: Nevertheless, it suggests that the exact ceramide species may matter more than total ceramide.
• 16:21
  SPEAKER_00: Functional inhibitors of acid sphingomyelinase.
• 16:25
  SPEAKER_00: Functional inhibitors of acid sphingomyelinase are often called phyasmas.
• 16:30
  SPEAKER_00: They are usually weak bases, lepophilic, able to cross-cell membranes concentrated inside acide acidic lysosomes.
• 16:37
  SPEAKER_00: The drugs do not usually block the catalytic site directly.
• 16:41
  SPEAKER_00: Instead, they accumulate in lysosomes, disturb the electrostatic interaction between acid sphingomyelinase and the lysosomal membrane, and promote enzyme detachment and degradation.
• 16:51
  SPEAKER_00: The original phiasma screening work generally classified a compound as active when it reduced residual acid sphingomyelinase activity below approximately 50% at 10 micromolar.
• 17:03
  SPEAKER_00: This is a useful screening definition, but it is not the same as a standard half-maximal inhibitory concentration.
• 17:10
  SPEAKER_00: Identification of novel functional inhibitors of acid sphingomyelinase.
• 17:15
  SPEAKER_00: At least 64 marketed or clinically used drugs have been classified as phiasmas using this type of screening approach.
• 17:21
  SPEAKER_00: They include some tricyclic antidepressants, selective serotonin reuptake inhibitors, antipsychotic drugs, antihistamines, calcium channel blockers, anti-Parkinsonian drugs.
• 17:32
  SPEAKER_00: Update on phiasmas.
• 17:34
  SPEAKER_00: Why the screening number can mislead.
• 17:36
  SPEAKER_00: A drug that inhibits acid sphingomyelinase at 10 micromolar in a cell assay may not reach that concentration in retinal ganglion cell lysosomes.
• 17:46
  SPEAKER_00: There are three separate concentrations to consider.
• 17:49
  SPEAKER_00: Plasma concentration, unbound concentration near the retina, free concentration inside retinal lysosomes.
• 17:57
  SPEAKER_00: The third is the one that matters and it is rarely measured.
• 18:00
  SPEAKER_00: A simple illustrative calculation shows the problem.
• 18:03
  SPEAKER_00: If a drug leaves 10% residual enzyme activity at 10 micromolar, a basic one-site model would imply an approximate half maximal inhibitory concentration near 1.1 micromolar.
• 18:15
  SPEAKER_00: If the free retinal concentration were only 0.05 micromolar, expected inhibition would be roughly 4%.
• 18:22
  SPEAKER_00: If lysosomal accumulation raised the effective concentration to 5 micromolar, inhibition could approach 80%.
• 18:30
  SPEAKER_00: But this calculation is only illustrative because phiasma action is time-dependent and involves enzyme degradation, not simple reversible binding.
• 18:38
  SPEAKER_00: Existing drugs, how plausible are they?
• 18:41
  SPEAKER_00: Fluoxetine.
• 18:43
  SPEAKER_00: Why it is biologically attractive, it is a recognized phiasma.
• 18:47
  SPEAKER_00: It crosses the blood-brain barrier.
• 18:49
  SPEAKER_00: Parent fluoxetine plus norfluoxetine has been estimated at approximately 1 to 2 micromolar in plasma and 15 to 25 micromolar in brain in treated patients, although these values vary with dose, timing, and tissue measurement.
• 19:03
  SPEAKER_00: Fluxetine concentration discussion.
• 19:05
  SPEAKER_00: It has shown acid sphingomyelinase dependent effects in neuronal and ischemic brain models.
• 19:11
  SPEAKER_00: Problems.
• 19:11
  SPEAKER_00: Brain concentration does not prove retinal ganglion cell lysosomal concentration.
• 19:17
  SPEAKER_00: Fluoxetine has many targets unrelated to acid sphingomyelinase.
• 19:21
  SPEAKER_00: Human glaucoma benefit has not been demonstrated.
• 19:24
  SPEAKER_00: Long half-life and drug interactions complicate dose experimentation.
• 19:28
  SPEAKER_00: Assessment.
• 19:29
  SPEAKER_00: Probably the best existing drug for a carefully designed mechanistic study because it combines central nervous system penetration, long exposure, and an established safety record.
• 19:39
  SPEAKER_00: It is not, however, a proven glaucoma treatment.
• 19:42
  SPEAKER_00: Ametryptaline.
• 19:44
  SPEAKER_00: Amitriptyline is among the stronger phiasmas.
• 19:47
  SPEAKER_00: In one commonly cited residual activity table, it left approximately 11% residual acid sphingomyelinase activity at 10 micromolar.
• 19:56
  SPEAKER_00: Phiasma antidepressant activity table.
• 19:59
  SPEAKER_00: Advantages, strong functional acids phenomyelinase activity in cell studies, good tissue and central nervous system penetration.
• 20:06
  SPEAKER_00: Demonstrated benefit in ischemic brain models, long clinical experience.
• 20:11
  SPEAKER_00: Problems, anticholinergic effects, cardiac conduction risk, sedation, weight gain, possible angle closure risk in susceptible eyes.
• 20:19
  SPEAKER_00: No evidence that oral amatryptaline reaches a therapeutic acid sphingomyelinase inhibiting concentration in human retinal ganglion cells.
• 20:28
  SPEAKER_00: Assessment, strong mechanistic candidate, poor repurposing candidate for routine glaucoma treatment.
• 20:35
  SPEAKER_00: Desipromine has a particularly relevant retinal evidence base.
• 20:39
  SPEAKER_00: It protected the retina in an ischemic model and is frequently used experimentally as a functional acid sphingomyelinase inhibitor.
• 20:46
  SPEAKER_00: A reported residual activity value is approximately 15% at 10 micromolar.
• 20:51
  SPEAKER_00: Phiasma activity table, advantages, direct preclinical retinal experience, central nervous system penetration, strong functional inhibition in cell-based assays, problems, cardiac toxicity, and arrhythmia risk, not commonly used for long-term treatment, no human retinal pharmacokinetic data, experimental doses cannot be translated directly to safe chronic glaucoma doses.
• 21:15
  SPEAKER_00: Assessment.
• 21:16
  SPEAKER_00: The most relevant existing compound for a preclinical glaucoma study, but not an attractive unmodified clinical drug.
• 21:23
  SPEAKER_00: Nortriptyline, immipromine, and clomipramine.
• 21:26
  SPEAKER_00: Reported residual activity at 10 micromolars approximately, nortriptyline, 13%, clomipramine, 21%, emipromine, 32%.
• 21:36
  SPEAKER_00: Phiasma antidepressant activity table.
• 21:39
  SPEAKER_00: They are central nervous system penetrant, but their anticholinergic, cardiac, and psychiatric effects make them unattractive as broad glaucoma therapies.
• 21:47
  SPEAKER_00: Tricyclic antidepressants can be problematic in people with narrow drainage angles because anticholinergic effects may precipitate angle closure.
• 21:56
  SPEAKER_00: This is different from the usual mechanism of primary open angle glaucoma.
• 22:00
  SPEAKER_00: Certrale and fluvoxamine.
• 22:03
  SPEAKER_00: These drugs have been classified as phiasmas in several screening programs, but their activity is less consistently reported in standardized quantitative tables.
• 22:12
  SPEAKER_00: They may be more tolerable than tricyclic antidepressants.
• 22:16
  SPEAKER_00: A meta-analysis of antidepressant use found that selective serotonin reuptake inhibitors were not associated with increased glaucoma risk and were associated with slightly lower intraocular pressure.
• 22:28
  SPEAKER_00: Although the studies were heterogeneous and observational, risk of glaucoma and serotinergic antidepressants, assessment, better clinical tolerability than tricyclic antidepressants, but uncertain retinal acid sphingomyelinase target engagement.
• 22:43
  SPEAKER_00: Amlodopine.
• 22:44
  SPEAKER_00: Amlodopine is an important cautionary example.
• 22:47
  SPEAKER_00: It has been classified as a phiasma, but human epidemiological findings do not support assuming it is beneficial for glaucoma.
• 22:55
  SPEAKER_00: Several studies have associated calcium channel blocker use with a modestly higher risk of primary open angle glaucoma.
• 23:02
  SPEAKER_00: A recent study specifically linked amlotopine with increased primary open angle glaucoma prevalence or risk, although it did not show increased intraocular pressure.
• 23:12
  SPEAKER_00: Amlotipine and primary open angle glaucoma.
• 23:16
  SPEAKER_00: Long-term calcium channel blocker use and primary open angle glaucoma.
• 23:20
  SPEAKER_00: Assessment.
• 23:21
  SPEAKER_00: Mechanistically interesting but clinically unattractive.
• 23:25
  SPEAKER_00: It illustrates why phiasma classification alone should not drive treatment decisions.
• 23:30
  SPEAKER_00: Is systemic treatment realistic?
• 23:33
  SPEAKER_00: Systemic phyasma treatment faces three major problems.
• 23:36
  SPEAKER_00: The required retinal concentration is unknown.
• 23:38
  SPEAKER_00: No study has convincingly measured acid sphingomyelinase inhibition inside human retinal ganglion cells after standard oral dosing.
• 23:47
  SPEAKER_00: Systemic toxicity may occur before ocular target engagement.
• 23:50
  SPEAKER_00: The doses needed to produce substantial lysosomal inhibition may cause sedation, cardiac conduction abnormalities, anticholinergic effects, psychiatric effects, liver or metabolic effects, drug interactions.
• 24:03
  SPEAKER_00: Broad acid sphingomyelinase inhibition may damage healthy retinal cells.
• 24:08
  SPEAKER_00: Complete acid sphingomyelinase deficiency causes retinal degeneration in mice.
• 24:13
  SPEAKER_00: Any successful therapy would likely need to reduce pathological activation without eliminating normal lysosomal activity.
• 24:20
  SPEAKER_00: For these reasons, systemic repurposing is more plausible as a short mechanistic trial or biomarker study than as long-term routine glaucoma therapy.
• 24:30
  SPEAKER_00: Could topical or intravitreal treatment work better?
• 24:34
  SPEAKER_00: Topical eye drops?
• 24:35
  SPEAKER_00: A topical eyedrop is attractive because it is easy to administer, but the posterior retina is difficult to reach from the ocular surface.
• 24:43
  SPEAKER_00: A drug must pass through the cornea, aqueous humor, lens or around the lens, the vitreous, the internal limiting membrane, the blood retinal barrier.
• 24:53
  SPEAKER_00: Many topically delivered drugs produce high anterior segment concentrations but low retinal concentrations.
• 25:00
  SPEAKER_00: A specially designed, highly lipophilic sustained release molecule might improve posterior penetration, but ordinary antidepressants are not optimized for this purpose.
• 25:10
  SPEAKER_00: Intravitrial injection.
• 25:11
  SPEAKER_00: Intravitrial delivery could expose the inner retina and retinal ganglion cell layer more directly.
• 25:17
  SPEAKER_00: Potential advantages include lower systemic exposure, higher retinal concentration, ability to use a more selective molecule, potential for sustained release delivery.
• 25:27
  SPEAKER_00: Potential risks include retinal toxicity, inflammation, pressure spikes, cataract, endophthalmitis, excessive lysosomal lipid disruption, repeated injection burden.
• 25:38
  SPEAKER_00: The complete acid sphingomyelinase knockout phenotype argues strongly against delivering a high potency inhibitor throughout the entire retina without a carefully defined therapeutic window.
• 25:50
  SPEAKER_00: A better development strategy, a more rational drug development program would aim for partial inhibition, not complete inhibition, selectivity for pathologically activated acid sphingomyelinase, limited systemic and brain exposure, delivery to the inner retina or optic nerve head, measurable target engagement through sphingomyelin and ceramide biomarkers, preservation of normal lysosomal activity, a sustained release ocular formulation or retinally targeted nanoparticle may ultimately be more realistic than repurposing an oral antidepressant.
• 26:24
  SPEAKER_00: Would directly targeting ceramide be better?
• 26:27
  SPEAKER_00: Possibly.
• 26:28
  SPEAKER_00: The human donor study did not show a broad increase in total ceramide.
• 26:32
  SPEAKER_00: It showed more ceramide aggregates in selected retinal ganglion cells.
• 26:37
  SPEAKER_00: That raises the possibility that the true treatment target is a specific ceramide species, a specific membrane compartment, ceramide trafficking, ceramide clustering, or conversion of ceramide into toxic downstream signals.
• 26:51
  SPEAKER_00: The ceramide synthase 5 study supports this direction because reducing selected C16 and C18 ceramide species protected retinal ganglion cells during ocular hypertension.
• 27:02
  SPEAKER_00: Ceramide synthase 5 and glaucoma.
• 27:05
  SPEAKER_00: Possible downstream strategies include selective inhibition of C16 or C18 ceramide generation, enhancing ceramide clearance, redirecting ceramide toward less toxic sphingolipid products, blocking ceramide-rich membrane domain formation, preventing ceramide-induced mitochondrial injury, inhibiting ceramide-driven inflammatory signaling.
• 27:27
  SPEAKER_00: The main risk is that ceramide is not universally harmful.
• 27:30
  SPEAKER_00: It is also involved in normal cell signaling, membrane repair, immune responses, and differentiation.
• 27:37
  SPEAKER_00: Broad suppression could therefore be as problematic as broad acid sphingomyelinase blockade.
• 27:42
  SPEAKER_00: Does acid sphingomyelinase sit upstream of other glaucoma mechanisms?
• 27:47
  SPEAKER_00: It could, but probably as one branch of a network rather than a single master switch.
• 27:51
  SPEAKER_00: For the full table, please open this article on VisualFieldTest.com.
• 27:57
  SPEAKER_00: The most plausible model is a feedback loop.
• 27:59
  SPEAKER_00: Elevated eye pressure, impaired perfusion, oxidative stress, and mitochondrial weakness activate acid sphingomyelinase.
• 28:07
  SPEAKER_00: Ceramide then worsens lysosomal function, inflammation, and mitochondrial stress, making retinal ganglion cells more vulnerable to the original insult.
• 28:17
  SPEAKER_00: This would explain why acid sphingomyelinase inhibition might preserve some neurons without eliminating the mechanical cause of glaucoma.
• 28:25
  SPEAKER_00: It also explains why acid sphingomyelinase treatment would probably need to be combined with pressure reduction.
• 28:32
  SPEAKER_00: My biological interpretation probability that the human acid sphingomyelinase abnormality is causal rather than merely secondary.
• 28:40
  SPEAKER_00: Estimated probability, approximately 60 to 70% that it contributes causally in at least a subset of glaucoma.
• 28:48
  SPEAKER_00: Reason supporting causality, the abnormality is localized to retinal ganglion cells.
• 28:53
  SPEAKER_00: Acid sphingomyelinase activity rises in experimental ocular hypertension.
• 28:58
  SPEAKER_00: Partial genetic reduction protects retinal ganglion cells.
• 29:02
  SPEAKER_00: Ceramide directly injures human retinal ganglion cell-like neurons.
• 29:06
  SPEAKER_00: The pathway is biologically connected to lysosomes, inflammation, mitochondria, and apoptosis.
• 29:12
  SPEAKER_00: Reasons against a stronger conclusion.
• 29:14
  SPEAKER_00: The new human study is cross-sectional and post-mortem.
• 29:18
  SPEAKER_00: Total ceramide did not significantly increase.
• 29:20
  SPEAKER_00: Exact human effect sizes and clinical staging are not yet clear from the accessible report.
• 29:27
  SPEAKER_00: Acid sphingomyelinase may be activated by several upstream injuries.
• 29:31
  SPEAKER_00: Complete enzyme loss damages the retina.
• 29:34
  SPEAKER_00: The probability that acid sphingomyelinase is the sole initiating cause of most glaucoma is probably below 15%.
• 29:41
  SPEAKER_00: Probability that acid sphingomyelinase inhibition protects retinal ganglion cells in glaucoma animal models.
• 29:47
  SPEAKER_00: Estimated probability, approximately 70 to 80%.
• 29:51
  SPEAKER_00: The evidence is reasonably strong for partial genetic suppression, ceramide reduction, and related sphingomyelinase interventions.
• 29:59
  SPEAKER_00: However, direct pharmacological acid sphingomyelinase inhibition has been studied more extensively in retinal ischemia than in chronic glaucoma.
• 30:08
  SPEAKER_00: Probability that this pathway reaches a human glaucoma clinical trial mom.
• 30:12
  SPEAKER_00: My estimate, any exploratory human glaucoma trial involving an acid sphingomyelinase modulating drug by 2036, approximately 25 to 35%.
• 30:22
  SPEAKER_00: A trial of a selective ocular acid sphingomyelinase inhibitor, approximately 15 to 25%.
• 30:29
  SPEAKER_00: A trial using an existing antidepressant solely as a glaucoma neuroprotective treatment, approximately 10 to 20%.
• 30:36
  SPEAKER_00: The main barriers are uncertain ocular exposure, lack of validated biomarkers, concern about complete or excessive lysosomal inhibition, availability of safer neuroprotective targets, need to prove benefit beyond pressure lowering, plausible timeline.
• 30:52
  SPEAKER_00: If the target is validated quickly, 2026 to 2029, replication in additional human donor cohorts and glaucoma models, 2028 to 2032, development of selective inhibitors or ocular delivery systems, 2030 to 2034, toxicology, retinal pharmacokinetics, and regulatory preparation, 2033-2038, possible first in human ocular trial.
• 31:17
  SPEAKER_00: A repurposed drug biomarker study could happen sooner, but a true neuroprotection trial would require evidence that the drug reaches retinal ganglion cells at a safe concentration.
• 31:28
  SPEAKER_00: Maximum plausible therapeutic effect.
• 31:31
  SPEAKER_00: If acid sphingomyelinase is genuinely causal in only a subset of retinal ganglion cell death, the realistic goal would be slowing progression, not restoring lost vision.
• 31:42
  SPEAKER_00: A plausible upper range might be 10 to 20% slowing of overall retinal ganglion cell or visual field decline in an unselected glaucoma population.
• 31:52
  SPEAKER_00: Perhaps 20 to 30% slowing in a biomarker-selected group with high acid sphingomyelinase activity or ceramide clustering, unlikely to exceed 50% benefit across all glaucoma patients, because mechanical, vascular, genetic, mitochondrial, and inflammatory mechanisms would remain active.
• 32:09
  SPEAKER_00: These are biological estimates, not clinical trial results.
• 32:13
  SPEAKER_00: Conclusion.
• 32:14
  SPEAKER_00: The new human donor study adds an important piece to the glaucoma puzzle.
• 32:18
  SPEAKER_00: Retinal ganglion cells in glaucoma appear to have depleted sphingomyelin, increased lysosomal acid sphingomyelinase, and more localized ceramide abnormalities.
• 32:28
  SPEAKER_00: The result is more compelling than a nonspecific whole retina lipid change because it points toward a particular neuronal population and a particular enzyme compartment.
• 32:39
  SPEAKER_00: Still, the evidence does not yet justify taking an antidepressant or another phasma to treat glaucoma.
• 32:45
  SPEAKER_00: Existing drugs are pharmacologically messy, their retinal concentrations are unknown, and complete acid sphingomyelinase inhibition can damage healthy retinal tissue.
• 32:55
  SPEAKER_00: The most promising future strategy may be a moderate, retinally targeted intervention that reduces pathological acid sphingomyelinase activity or selected ceramide species while preserving normal lysosomal function.
• 33:08
  SPEAKER_00: Could an existing drug already affect this pathway?
• 33:11
  SPEAKER_00: Ranked by biological plausibility, not proven clinical benefit.
• 33:15
  SPEAKER_00: For the full table, please open this article on visualfieldtest.com.
• 33:20
  SPEAKER_00: The most rational next experiment would not be a large clinical trial of an antidepressant.
• 33:25
  SPEAKER_00: It would be a target engagement study asking, does a selected compound reduce acid sphingomyelinase activity in the retina?
• 33:33
  SPEAKER_00: Does it restore sphingomyelin without causing lysosomal storage?
• 33:37
  SPEAKER_00: Does it reduce ceramide clustering in retinal ganglion cells?
• 33:41
  SPEAKER_00: Does it preserve axons and pattern electroretinogram function?
• 33:45
  SPEAKER_00: Can this be achieved at a dose that does not produce unacceptable systemic or ocular toxicity?
• 33:51
  SPEAKER_00: Until those questions are answered, acid sphingomyelinase should be viewed as a promising neurodegeneration target, not an established glaucoma treatment.
• 34:01
  SPEAKER_00: All links to sources are available in the text version of this article.
• 34:05
  SPEAKER_00: You can find the full article at visualfieldtest.com.
• 34:09
  SPEAKER_00: Thanks for listening.
• 34:10
  SPEAKER_00: To check your visual field, click the link at the bottom of this article or visit visualfieldtest.com.