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A New Glaucoma Gene Therapy Is Entering Human Trials — Could It Protect Vision Without Lowering Eye Pressure? · Glaucoma, Vision & Longevity: Supplements & Science

• 0:00
  SPEAKER_00: A new glaucoma gene therapy is entering human trials.
• 0:03
  SPEAKER_00: Could it protect vision without lowering eye pressure?
• 0:07
  SPEAKER_00: For more than a century, glaucoma treatment has focused on one central strategy: lower the pressure inside the eye.
• 0:14
  SPEAKER_00: Pressure-lowering eye drops, laser treatment, and surgery can slow damage, but they do not directly make retinal ganglion cells more resistant to injury.
• 0:23
  SPEAKER_00: Some patients continue to lose vision even when their eye pressure appears to be well controlled.
• 0:29
  SPEAKER_00: ASP 2767, an experimental gene therapy from Estellus, is designed around a different idea.
• 0:36
  SPEAKER_00: Deliver protective genes directly to retinal ganglion cells so that the cells may better survive glaucoma-related stress.
• 0:42
  SPEAKER_00: The treatment is now entering its first human study, registered as NCT-0777085, a combined phase 1 and phase 2 trial.
• 0:52
  SPEAKER_00: The trial is important because it is specifically designed to test a neuroprotective treatment for progressive open-angle glaucoma, not simply another pressure-lowering drug.
• 1:03
  SPEAKER_00: The most likely interpretation of the available evidence is that ASP2767 is intended primarily to preserve surviving retinal ganglion cells and their function.
• 1:13
  SPEAKER_00: It is not yet demonstrated to regenerate a damaged optic nerve, replace dead neurons, or restore established visual field loss.
• 1:22
  SPEAKER_00: The bottom line, ASP-2767, is an investigational intravitreal gene therapy.
• 1:28
  SPEAKER_00: The first human trial plans to enroll approximately 156 adults with progressive open-angle glaucoma.
• 1:35
  SPEAKER_00: The public trial record does not disclose the clinical vector, gene sequence, dose levels, or names of the anti-inflammatory preventive treatments.
• 1:43
  SPEAKER_00: The strongest scientific trail connects AS Puny767 to work from Quithera, a company acquired by Estellus in 2018.
• 1:51
  SPEAKER_00: The best matching preclinical program uses an adenoassociated virus type II vector to express both tropomyosin receptor kinase B, a receptor that supports retinal ganglion cell survival, mature brain-derived neurotrophic factor, a protein that activates that receptor.
• 2:08
  SPEAKER_00: In mice and rats, the related construct preserved retinal ganglion cells and electrical measures of retinal ganglion cell function after optic nerve injury or experimentally elevated eye pressure.
• 2:20
  SPEAKER_00: There is no public evidence yet that the treatment regenerates long-distance optic nerve axons or restores permanent visual field loss.
• 2:29
  SPEAKER_00: If it works, ASP2767 would most likely be an add-on treatment used together with eye pressure control, not a replacement for it.
• 2:38
  SPEAKER_00: What is ASP767?
• 2:40
  SPEAKER_00: Established facts, ASP2767 is developed by Estellus Pharma, intended for optic neuropathy caused by glaucoma, administered by a single intravitreal injection into one eye, being tested in adults with progressive open-angle glaucoma, entering humans for the first time in the registered phase 1-phase 2 study, listed in Estellus's ophthalmology pipeline as a gene therapy for glaucoma.
• 3:05
  SPEAKER_00: The public-facing trial materials describe ASP 2767 as a harmless virus-based gene therapy.
• 3:12
  SPEAKER_00: The delivered genes are expected to cause retinal nerve cells to produce proteins intended to protect them and slow further vision loss.
• 3:19
  SPEAKER_00: What has not been officially disclosed, the publicly available clinical trial listing does not identify the exact adeno-associated virus type or engineered capsid used clinically, the promoter controlling gene expression, the exact genes or protein sequences in the clinical product, the vector dose levels, the number of patients in each phase one dose cohort, the precise primary and secondary endpoint definitions, the identity and schedule of prophylactic regimen A and prophylactic regimen B, the clinical trial sites.
• 3:54
  SPEAKER_00: Those emissions are normal for a newly registered first-in-human gene therapy study.
• 3:59
  SPEAKER_00: Some details may be available in the investigator brochure, regulatory submissions, or later registry updates, but are not currently visible in the public record.
• 4:08
  SPEAKER_00: I could verify, the strongest reconstruction of ASP2767's mechanism.
• 4:14
  SPEAKER_00: Strongly supported inference, a dual tropomyosin receptor kinase B and mature brain-derived neurotrophic factor therapy.
• 4:22
  SPEAKER_00: The most important clue is the history of Quethera, a British gene therapy company acquired by Estellus in 2018.
• 4:28
  SPEAKER_00: Quethera's glaucoma program used recombinant adenassociated virus vectors to deliver protective genes to retinal cells.
• 4:36
  SPEAKER_00: Estellus stated that the lead preclinical candidate significantly improved retinal ganglion cell survival in experimental glaucoma models.
• 4:44
  SPEAKER_00: A later paper provides an unusually close match to that description.
• 4:49
  SPEAKER_00: It was authored by researchers from the University of Cambridge, Quithera, Estellus, other institutions involved in glaucoma gene therapy research.
• 4:58
  SPEAKER_00: The paper describes a bisystronic adeno-associated virus vector that expresses two fully humanized components.
• 5:05
  SPEAKER_00: Tropomyosin receptor kinase B, also called the TERC B receptor, mature brain-derived neurotrophic factor.
• 5:13
  SPEAKER_00: A short self-cleaving 2A peptide allows both proteins to be produced from a single genetic cassette.
• 5:19
  SPEAKER_00: The paper does not explicitly state that this published construct is identical to clinical ASP2767.
• 5:25
  SPEAKER_00: Astellus may have modified the vector, promoter, capsid, protein sequences, or manufacturing process before entering human trials.
• 5:33
  SPEAKER_00: Therefore, best supported conclusion ASP2767 is probably an optimized clinical version of the Quethera Astellus dual tropomyosin receptor kinase B mature brain-derived neurotrophic factor program.
• 5:47
  SPEAKER_00: What remains unproven, the exact identity of the clinical vector and genetic cassette.
• 5:52
  SPEAKER_00: How the proposed pathway works.
• 5:54
  SPEAKER_00: Brain-derived neurotrophic factor is a natural support signal used by neurons.
• 5:58
  SPEAKER_00: It binds to the tropomyosin receptor kinase B receptor on retinal ganglion cells and activates intracellular survival pathways, including the protein kinase B pathway, the extracellular signal-regulated kinase pathway, other pathways involved in cellular metabolism, synaptic maintenance, and resistance to programmed cell death.
• 6:18
  SPEAKER_00: In glaucoma, injury near the optic nerve head can interfere with the normal transport of growth and survival signals between the brain and retinal ganglion cells.
• 6:28
  SPEAKER_00: The cells may then become metabolically stressed and more vulnerable to pressure, mechanical strain, reduced blood supply, oxidative stress, and inflammation.
• 6:38
  SPEAKER_00: The proposed treatment attempts to bypass part of that problem by making retinal ganglion cells produce both, more of the survival receptor, more of the receptors activating ligand.
• 6:50
  SPEAKER_00: This dual approach is scientifically important because delivering brain-derived neurotrophic factor alone can lead to reduced receptor availability over time.
• 7:00
  SPEAKER_00: The related research was designed to avoid that limitation by increasing both sides of the signaling system.
• 7:07
  SPEAKER_00: Why an intravitrial adenoassociated virus vector?
• 7:10
  SPEAKER_00: An intravitre injection places the vector into the gel-filled cavity inside the eye.
• 7:16
  SPEAKER_00: From there, the vector can contact the inner retina, including retinal ganglion cells.
• 7:21
  SPEAKER_00: Adeno-associated virus type 2 has been widely studied for retinal ganglion cell delivery because it can transduce inner retinal neurons after intravitreal injection.
• 7:31
  SPEAKER_00: However, it is not perfectly specific.
• 7:33
  SPEAKER_00: Depending on the vector design and promoter, other retinal cells may also receive the genetic material.
• 7:40
  SPEAKER_00: The likely advantages are a single injection rather than daily treatment.
• 7:45
  SPEAKER_00: Local production of the protective proteins inside the eye, long-lasting expression in non-dividing retinal neurons, theoretical activity even when eye pressure is already controlled.
• 7:56
  SPEAKER_00: The likely disadvantages are the vector cannot be easily removed after injection.
• 8:01
  SPEAKER_00: Not every retinal ganglion cell may be transduced.
• 8:04
  SPEAKER_00: Existing antibodies against the viral capsid may reduce delivery.
• 8:09
  SPEAKER_00: Inflammation can damage the retina or optic nerve.
• 8:12
  SPEAKER_00: Excessive or poorly controlled growth factor signaling could have unintended effects.
• 8:17
  SPEAKER_00: The newly registered human trial trial identity.
• 8:20
  SPEAKER_00: The study is trial number NCT0770685.
• 8:28
  SPEAKER_00: Sponsor, Estellus Pharma Global Development.
• 8:31
  SPEAKER_00: Design, Phase 1, Open Label, Dose Escalation Followed by Phase 2, Randomized, Sham Controlled, and Masked.
• 8:38
  SPEAKER_00: Planned Enrollment, 156 Participants.
• 8:41
  SPEAKER_00: Treatment, 1 intervitrial injection in 1 study eye.
• 8:44
  SPEAKER_00: Follow-up, approximately 52 weeks after treatment.
• 8:48
  SPEAKER_00: As of August 25, 2026, public registry mirrors described the study as not yet recruiting, with a planned start in August 2026 and a primary completion date in July 2030.
• 9:01
  SPEAKER_00: The patient-facing listing says enrollment is expected to begin during August 2026.
• 9:06
  SPEAKER_00: No trial locations were publicly posted in the record available at that time.
• 9:11
  SPEAKER_00: Phase 1.
• 9:12
  SPEAKER_00: Phase 1 is intended to test safety, assess tolerability, escalate through increasing doses, identify the highest dose that can be given safely.
• 9:22
  SPEAKER_00: Observe preliminary effects on visual function and retinal structure.
• 9:26
  SPEAKER_00: Phase 1 is open label, meaning the participants and investigators know that ASP 2767 is being given.
• 9:33
  SPEAKER_00: Participants in the dose escalation portion must have relatively severe but not completely end stage disease.
• 9:40
  SPEAKER_00: Mean deviation between 9-12 and minus 20 decibels.
• 9:44
  SPEAKER_00: Evidence of glaucomatous visual field loss, corresponding optic nerve damage, at least one quadrant with remaining visual field function.
• 9:53
  SPEAKER_00: Best corrected visual acuity of at least 2200.
• 9:56
  SPEAKER_00: Controlled eye pressure or no anticipated need for additional pressure lowering treatment during the study.
• 10:02
  SPEAKER_00: Phase 2.
• 10:04
  SPEAKER_00: Phase 2 is expected to include adults with moderate to advanced disease.
• 10:08
  SPEAKER_00: Mean deviation between minus 6 and minus 20 decibels.
• 10:12
  SPEAKER_00: Documented progression of at least approximately 0.5 decibels per year.
• 10:16
  SPEAKER_00: At least three reliable previous visual field tests, at least three consecutive usable optical coherence tomography scans, open drainage angles, remaining visual function in at least one quadrant.
• 10:29
  SPEAKER_00: Participants will be assigned to one of three groups: a higher dose of AS-2767, a lower dose of AS-2767, a sham injection.
• 10:38
  SPEAKER_00: The phase two portion is described as double masked in the official title, while the public listing describes a quadruple mask design because the treatment and preventive treatment assignments are also concealed.
• 10:53
  SPEAKER_00: Why the trial requires stable eye pressure?
• 10:56
  SPEAKER_00: This is one of the most revealing features of the study.
• 10:59
  SPEAKER_00: Participants must have eye pressure of 21 mm of mercury or lower while receiving current treatment or be considered stable enough that no pressure treatment change is expected during the next year.
• 11:12
  SPEAKER_00: That requirement serves two purposes.
• 11:14
  SPEAKER_00: It protects participants from uncontrolled pressure-related damage.
• 11:18
  SPEAKER_00: It helps investigators determine whether ASP 2767 provides benefit beyond pressure lowering.
• 11:25
  SPEAKER_00: If a treated eye performs better than a sham-treated eye despite similar eye pressure, that would support a pressure-independent neuroprotective effect.
• 11:34
  SPEAKER_00: Why the trial excludes many patients?
• 11:36
  SPEAKER_00: The study excludes people with narrow angle, uveatic, congenital, or pigmentary glaucoma, other optic nerve diseases, significant cataract, previous vitrectomy, active eye inflammation, previous gene therapy, or certain intravitreal treatments, retinal degeneration or macular disease, a history of steroid response, severe uncontrolled systemic disease, conditions that could make visual field testing unreliable.
• 12:02
  SPEAKER_00: These exclusions are designed to reduce safety risks and make it easier to distinguish glaucoma-related effects from other causes of visual loss.
• 12:11
  SPEAKER_00: The preclinical evidence behind AS-27 Early Quitera research.
• 12:16
  SPEAKER_00: Quitera was established to develop gene therapies that could make retinal ganglion cells more resistant to glaucoma-related damage.
• 12:25
  SPEAKER_00: The proposed treatment was designed as a one-time injection, providing long-term local production of protective proteins.
• 12:32
  SPEAKER_00: The University of Cambridge describes the lead candidate as having significantly improved retinal ganglion cell survival in experimental glaucoma models.
• 12:42
  SPEAKER_00: Estellus acquired Quethera in August 2018, bringing the program into its ophthalmology portfolio.
• 12:49
  SPEAKER_00: The original dual growth factor strategy.
• 12:52
  SPEAKER_00: The original research used a dual construct designed to enhance brain-derived neurotrophic factor signaling through the tropomyosin receptor kinase B receptor.
• 13:01
  SPEAKER_00: The rationale was stronger than simply giving brain-derived neurotrophic factor alone.
• 13:07
  SPEAKER_00: Brain-derived neurotrophic factor could be produced locally.
• 13:11
  SPEAKER_00: The receptor could be increased at the same time.
• 13:14
  SPEAKER_00: The combined system could activate survival signals more consistently.
• 13:19
  SPEAKER_00: The vector could continue producing the proteins after one injection.
• 13:22
  SPEAKER_00: A review of adeno-associated virus glaucoma studies reports that the earlier dual construct maintained expression of both proteins for up to 24 weeks, or approximately six months, in experimental animals.
• 13:35
  SPEAKER_00: It also summarizes retinal ganglion cell survival and functional benefits in both optic nerve crush mice and laser-induced eye pressure elevation rats.
• 13:45
  SPEAKER_00: The 2025 Humanized Preclinical Study, the most informative publicly available paper, published in 2025, tested a more clinically oriented version containing fully human tropomyosin receptor kinase B and mature brain-derived neurotrophic factor.
• 14:02
  SPEAKER_00: Cell Studies.
• 14:03
  SPEAKER_00: In cultured cells, the construct produced tropomyosin receptor kinase B, mature brain-derived neurotrophic factor, increased phosphorylated tropomyosin receptor kinase B, increased activation of extracellular signal-regulated kinase, increased activation of protein kinase B, secreted brain-derived neurotrophic factor.
• 14:23
  SPEAKER_00: The 2A peptide allowed the two functional proteins to be made from one genetic cassette.
• 14:28
  SPEAKER_00: Mouse optic nerve crush model.
• 14:30
  SPEAKER_00: In mice, intravitreal doses ranged from 1.5210T genome copies per eye, 7.6 eurtimes 10 genome copies per eye.
• 14:40
  SPEAKER_00: Both the middle and high doses significantly reduced retinal ganglion cell loss after optic nerve crush compared with control treatment.
• 14:48
  SPEAKER_00: The study used approximately 8 to 11 animals per comparison group in the retinal ganglion cell analyses.
• 14:55
  SPEAKER_00: Rat elevated eye pressure model.
• 14:58
  SPEAKER_00: In rats, the dose range included 9.501010 CRT genome copies per eye, 3.8010C genome copies per eye, 1.901010C genome copies per eye.
• 15:10
  SPEAKER_00: The middle and high doses preserved nylganglion cell numbers, positive scotopic threshold response, an electrical measure that reflects inner retinal and retinal ganglion cell function.
• 15:21
  SPEAKER_00: The relevant post-injury retinal ganglion cell analyses included approximately 11 to 14 eyes per group.
• 15:28
  SPEAKER_00: Safety observations in animals.
• 15:30
  SPEAKER_00: At the tested doses, the study reported no meaningful reduction in retinal ganglion cell numbers in uninjured eyes.
• 15:38
  SPEAKER_00: No major retinal structural abnormality on routine examination.
• 15:42
  SPEAKER_00: No major deterioration in the measured electrical retinal responses in uninjured eyes.
• 15:47
  SPEAKER_00: Persistent expression of the delivered proteins for at least nine weeks in rats.
• 15:52
  SPEAKER_00: Earlier work suggesting expression for approximately six months in experimental animals.
• 15:58
  SPEAKER_00: What the preclinical studies did not show.
• 16:01
  SPEAKER_00: The public evidence does not demonstrate that the ASP2767-related program regenerated a fully severed optic nerve over a long distance, reconnected retinal ganglion cell axons to the correct brain targets, reversed established visual field loss, restored normal visual acuity, produced a durable behavioral vision benefit carable to reading or driving vision in humans, worked when most retinal ganglion cells had already died.
• 16:29
  SPEAKER_00: The strongest evidence is for cell survival and electrical retinal function, not optic nerve regeneration.
• 16:35
  SPEAKER_00: Is ASP 2767 intended to protect, restore, or regenerate?
• 16:40
  SPEAKER_00: The most realistic classification is.
• 16:42
  SPEAKER_00: For the full table, please open this article on VisualFieldTest.com.
• 16:46
  SPEAKER_00: The treatment is best viewed as a neuroprotective therapy.
• 16:50
  SPEAKER_00: That means it would aim to slow or prevent additional damage.
• 16:53
  SPEAKER_00: It would not be expected to recreate retinal ganglion cells that have already disappeared.
• 16:59
  SPEAKER_00: Could it work without lowering eye pressure?
• 17:02
  SPEAKER_00: In theory, yes.
• 17:04
  SPEAKER_00: ASP2767 could work independently of eye pressure because its proposed action occurs inside retinal ganglion cells.
• 17:12
  SPEAKER_00: It does not need to improve drainage of eye fluid or reduce fluid production.
• 17:16
  SPEAKER_00: That is important because glaucoma damage can continue despite apparently acceptable eye pressure.
• 17:21
  SPEAKER_00: Possible contributors include individual sensitivity to pressure, fluctuations in eye pressure, reduced blood supply, mechanical strain at the optic nerve head, mitochondrial dysfunction, oxidative stress, neuroinflammation, abnormal immune responses, age-related loss of cellular resilience.
• 17:40
  SPEAKER_00: Gene therapy reviews identify pressure-independent retinal ganglion cell protection as one of the major goals of glaucoma gene therapy.
• 17:48
  SPEAKER_00: In practice, it would probably be an add-on treatment.
• 17:52
  SPEAKER_00: Even if ASP-2767 protects retinal ganglion cells, it would not remove the physical stress caused by high eye pressure.
• 17:59
  SPEAKER_00: A patient receiving it would probably still need eye drops, laser treatment, glaucoma surgery, regular eye pressure monitoring.
• 18:08
  SPEAKER_00: The most plausible future use would be pressure lowering to reduce the damaging stress, plus ASP2767 to increase the surviving retinal ganglion cells' resistance to that stress.
• 18:20
  SPEAKER_00: Could severely damaged retinal ganglion cells recover?
• 18:23
  SPEAKER_00: There are two different situations stressed but living cells.
• 18:27
  SPEAKER_00: Some retinal ganglion cells may be metabolically impaired without being permanently dead.
• 18:32
  SPEAKER_00: They may have reduced electrical activity, damaged axonal transport, swollen or abnormal dendrites, poor energy production, reduced neurotrophic signaling.
• 18:44
  SPEAKER_00: Those cells might regain some function if their survival pathways are restored.
• 18:48
  SPEAKER_00: This is the most plausible explanation for any early improvement in electrical retinal tests or visual field performance.
• 18:55
  SPEAKER_00: Dead cells or disconnected axons.
• 18:58
  SPEAKER_00: A retinal ganglion cell that has died cannot be rescued by ASP-2767.
• 19:03
  SPEAKER_00: Similarly, an optic nerve axon that has degenerated cannot simply be repaired by increasing brain-derived neurotrophic factor.
• 19:10
  SPEAKER_00: Regeneration would require several additional steps.
• 19:14
  SPEAKER_00: New axon growth, guidance through the optic nerve, passage through the optic chiasm, connection to the correct brain targets, restoration of accurate visual signaling.
• 19:25
  SPEAKER_00: That is a much more difficult biological problem than keeping a threatened cell alive.
• 19:30
  SPEAKER_00: For this reason, patients with moderate or advanced glaucoma but remaining visual field islands are more logical candidates than patients with nearly complete loss of useful vision.
• 19:41
  SPEAKER_00: How long could one injection last?
• 19:43
  SPEAKER_00: The honest answer is unknown.
• 19:46
  SPEAKER_00: The rationale for using an adenoassociated virus is that retinal ganglion cells are long-lived and do not normally divide.
• 19:53
  SPEAKER_00: Genetic material can therefore remain active for a prolonged period.
• 19:58
  SPEAKER_00: In the related preclinical work, expression was demonstrated at nine weeks.
• 20:03
  SPEAKER_00: Earlier studies reported expression for up to approximately six months.
• 20:07
  SPEAKER_00: Protective effects were observed during the experimental follow-up periods.
• 20:11
  SPEAKER_00: Human duration could be several years, potentially much longer, shorter than expected if the immune system suppresses expression.
• 20:20
  SPEAKER_00: Different in older or severely diseased retinas.
• 20:23
  SPEAKER_00: A one-year phase one-phase two study can establish early safety and possible biological activity, but it cannot prove that one injection will protect vision for decades.
• 20:34
  SPEAKER_00: Could patients be retreated?
• 20:36
  SPEAKER_00: Retreatment is theoretically possible, but technically difficult.
• 20:40
  SPEAKER_00: After the first injection, a patient may develop antibodies against the viral capsid.
• 20:45
  SPEAKER_00: Those antibodies could neutralize a second dose before it reaches retinal ganglion cells.
• 20:51
  SPEAKER_00: Possible future approaches could include a different viral capsid, a different serotype, temporary immune suppression, a second vector that is less visible to the immune system, a non-viral delivery method.
• 21:04
  SPEAKER_00: However, none of these strategies is established for ASP 2767.
• 21:09
  SPEAKER_00: A patient should not assume that an unsuccessful or waning treatment could simply be repeated.
• 21:14
  SPEAKER_00: Major risks of intraocular gene therapy, risks from the injection itself, intravitreal injection can cause infection inside the eye, retinal tear or retinal detachment, bleeding, temporary or sustained eye pressure elevation, inflammation, cataract progression, damage to the lens or retina.
• 21:33
  SPEAKER_00: These risks are shared with other intravitreal treatments, although the exact rates depend on the procedure and product.
• 21:41
  SPEAKER_00: Inflammation and immune reactions, adenassociated virus vectors are often considered relatively low in immunogenicity, but they can still cause inflammation.
• 21:50
  SPEAKER_00: Ocular immune privilege reduces immune reactions, but does not eliminate them.
• 21:55
  SPEAKER_00: Gene therapy studies have reported concerns, including inflammatory infiltrates.
• 22:00
  SPEAKER_00: Uveitis, retinal inflammation, and immune responses against either the vector or the protein being produced.
• 22:08
  SPEAKER_00: The ASP 2767 trial includes two preventive treatment regimens specifically to reduce the risk of inflammation.
• 22:16
  SPEAKER_00: The fact that these regimens are built into the study indicates that inflammation is a recognized development concern, even though the exact medicines have not been publicly identified.
• 22:26
  SPEAKER_00: Retinal toxicity.
• 22:28
  SPEAKER_00: Too much or poorly controlled expression of a growth factor could potentially disturb retinal signaling, alter synaptic function, increase excitatory stress, affect non-target retinal cells, cause retinal swelling or structural abnormalities.
• 22:44
  SPEAKER_00: The published preclinical studies did not show major short-term retinal toxicity at their tested doses, but human eyes may respond differently and rare effects may only appear after broader exposure.
• 22:55
  SPEAKER_00: Irreversibility.
• 22:57
  SPEAKER_00: The most important practical difference from an eye drop is that a gene therapy is not easily stopped.
• 23:03
  SPEAKER_00: If a patient develops an adverse reaction to a pressure-lowering eye drop, the medicine can usually be discontinued.
• 23:09
  SPEAKER_00: With an adenoassociated virus gene therapy, the vector may remain in the eye, the delivered genes may continue producing proteins.
• 23:18
  SPEAKER_00: A late immune reaction may be difficult to reverse.
• 23:21
  SPEAKER_00: There may be no simple antidote.
• 23:23
  SPEAKER_00: Adeno-associated virus generally does not integrate efficiently into the genome, which reduces, but does not completely eliminate theoretical long-term genomic risks.
• 23:34
  SPEAKER_00: How ASP 2067 compares with other neuroprotection programs.
• 23:39
  SPEAKER_00: Conventional pressure lowering treatment.
• 23:42
  SPEAKER_00: Pressure lowering treatment remains the only established approach proven to reduce the risk of glaucoma progression.
• 23:49
  SPEAKER_00: Its limitations are that it does not directly strengthen retinal ganglion cells, does not restore lost vision, requires long-term adherence when eye drops are used, may not completely stop progression, can become less effective or more burdensome as disease advances.
• 24:05
  SPEAKER_00: AS-2767 would be complementary rather than a replacement.
• 24:10
  SPEAKER_00: ER-100.
• 24:11
  SPEAKER_00: ER-100 is an early clinical program from life biosciences being studied in open-angle glaucoma and non-arteritic anterior ischemic optic neuropathy.
• 24:21
  SPEAKER_00: Its reported strategy is fundamentally different from ASP-2767.
• 24:25
  SPEAKER_00: Rather than mainly supplying a survival signal, it aims to use partial epigenetic reprogramming to make aged or damaged cells behave more like younger cells.
• 24:35
  SPEAKER_00: Public descriptions refer to factors associated with the Yamanaka reprogramming system, including OCT4, SOX2, and KLF-4.
• 24:45
  SPEAKER_00: Potential advantage.
• 24:46
  SPEAKER_00: It could theoretically address several age-related cellular defects at once.
• 24:51
  SPEAKER_00: Potential concern: reprogramming is biologically broader and less predictable than activating a defined survival pathway.
• 24:57
  SPEAKER_00: Excessive reprogramming could cause loss of cell identity or unwanted cell growth.
• 25:02
  SPEAKER_00: It remains completely unproven in glaucoma patients.
• 25:05
  SPEAKER_00: ASP2767 is the more conservative strategy.
• 25:09
  SPEAKER_00: Reinforce an existing retinal ganglion cell survival pathway rather than attempt to reset the cell's biological age.
• 25:16
  SPEAKER_00: NT501 and ciliary neurotrophic factor NT501 is not a gene therapy.
• 25:22
  SPEAKER_00: It is a small implant containing encapsulated cells that continuously release ciliary neurotrophic factor into the eye.
• 25:30
  SPEAKER_00: In a small phase 1 glaucoma study, only six treated eyes and eight fellow eyes contributed usable visual field data.
• 25:37
  SPEAKER_00: Treated eyes showed a median mean deviation improvement of approximately 1.2 decibels.
• 25:42
  SPEAKER_00: Fellow eyes worsened by approximately 3.9 decibels.
• 25:46
  SPEAKER_00: Retinal nerve fiber layer thickness increased by approximately 10.16 micrometers in treated eyes compared with 2.66 micrometers in fellow eyes.
• 25:56
  SPEAKER_00: The implant was reported to be safe and well tolerated.
• 26:00
  SPEAKER_00: The findings are encouraging but limited by the small sample and non-randomized early design.
• 26:05
  SPEAKER_00: A later randomized study has been used to further evaluate the approach.
• 26:10
  SPEAKER_00: Compared with NT501, ASP2767 could be delivered as a single injection.
• 26:16
  SPEAKER_00: AS-2767 would not require an implanted device.
• 26:20
  SPEAKER_00: NT501 may be more controllable because the implant can potentially be removed.
• 26:25
  SPEAKER_00: AS2767 may provide more targeted retinal ganglion cell signal if the vector transduces the intended cells effectively.
• 26:33
  SPEAKER_00: Nicotinamide and pyruvate.
• 26:36
  SPEAKER_00: Nicotinamide is a form of vitamin B3 that can help support production of nicotinamide adenine dinucleotide, a molecule important for cellular energy metabolism.
• 26:46
  SPEAKER_00: A phase 2 randomized trial tested oral nicotinamide and pyruvate in people with treated glaucoma.
• 26:52
  SPEAKER_00: Over a short period, more visual field test locations improved in the treatment group than in the placebo group.
• 26:59
  SPEAKER_00: The study suggested possible short-term improvement in retinal ganglion cell function, but it was not proof of long-term prevention of visual field loss.
• 27:08
  SPEAKER_00: A larger phase 3 study, called the nicotinamide and glaucoma trial, has been registered to test whether nicotinamide can slow visual field loss over a longer period.
• 27:17
  SPEAKER_00: Compared with nicotinamide, ASP767 is local rather than systemic.
• 27:24
  SPEAKER_00: ASP2767 could theoretically provide continuous protein production.
• 27:29
  SPEAKER_00: Nicotinamide is easier to stop and does not involve a permanent viral vector.
• 27:33
  SPEAKER_00: Nicotinamide targets cellular energy broadly, while von Sin67 targets a defined survival signaling pathway.
• 27:40
  SPEAKER_00: Mitochondrial therapies.
• 27:42
  SPEAKER_00: Mitochondrial approaches attempt to improve the energy systems that keep retinal ganglion cells alive.
• 27:48
  SPEAKER_00: These include nicotinamide, antioxidant strategies, mitochondrial gene delivery, agents intended to reduce oxidative stress, experimental mitochondrial transfer or replacement approaches, preclinical adeno-associated virus delivery of superoxide dismutase 2 improved antioxidant defenses and mitochondrial measures in an experimental glaucoma model, but the benefit did not completely eliminate oxidative stress and was not fully durable.
• 28:16
  SPEAKER_00: ASP2767 does not directly repair mitochondria.
• 28:20
  SPEAKER_00: Its proposed benefit is more downstream.
• 28:22
  SPEAKER_00: A retinal ganglion cell with stronger survival signaling may better tolerate mitochondrial stress.
• 28:28
  SPEAKER_00: Rhoe-associated protein kinase inhibitors.
• 28:31
  SPEAKER_00: Rhoe-associated protein kinase inhibitors such as riposudal and netarseudal are primarily used to lower eye pressure by improving fluid outflow.
• 28:40
  SPEAKER_00: Experimental work also suggests that they may reduce retinal ganglion cell death, suppress cell death signaling, promote axon growth after optic nerve injury.
• 28:50
  SPEAKER_00: Riposudal protected retinal ganglion cells in a mouse model of normal tension glaucoma while also lowering eye pressure.
• 28:58
  SPEAKER_00: Other animal work found that a row associated protein kinase and norepinephrine transporter inhibitor promoted retinal ganglion cell survival and axon regeneration after optic nerve injury.
• 29:09
  SPEAKER_00: The difference is practical.
• 29:11
  SPEAKER_00: Rhoe-associated protein kinase inhibitors require regular dosing.
• 29:15
  SPEAKER_00: They have a pressure-lowering effect.
• 29:18
  SPEAKER_00: Their independent long-term neuroprotective benefit in human glaucoma remains unsettled.
• 29:23
  SPEAKER_00: ASPUD767 is designed as a one-time pressure-independent gene therapy.
• 29:28
  SPEAKER_00: Other retinal ganglion cell gene therapies.
• 29:31
  SPEAKER_00: Animal studies have explored brain-derived neurotrophic factor alone, brain-specific homeobox protein 3B, B cell lymphoma extra-large, nuclear factor erythroid II-related factor 2, superoxide dysmutase 2, MIC-associated protein X, C3 exoenzyme transferase, nicotinamide mononucleotide adenyl L transferase 2, neuroserpin, nerve growth factor.
• 29:55
  SPEAKER_00: These programs generally show one or more of the following in animals greater retinal ganglion cell survival, less optic nerve damage, better electrical retinal responses, reduced oxidative stress, partial axon regrowth after acute injury.
• 30:09
  SPEAKER_00: But the field has a major translational problem.
• 30:12
  SPEAKER_00: Many animal studies treat the animals before injury or soon afterward, while patients usually receive treatment after years of chronic glaucoma damage.
• 30:20
  SPEAKER_00: Reviews emphasize that chronic, multifactorial glaucoma is difficult to reproduce accurately in experimental models.
• 30:28
  SPEAKER_00: Probability estimates.
• 30:30
  SPEAKER_00: These are informed forecasts, not clinical trial results.
• 30:34
  SPEAKER_00: Probability ASP 2767 shows a measurable biological effect in humans, approximately 50 to 60%.
• 30:42
  SPEAKER_00: My central estimate is about 55%.
• 30:45
  SPEAKER_00: Reasons supporting that estimate?
• 30:47
  SPEAKER_00: The target pathway has a strong neurobiological rationale.
• 30:51
  SPEAKER_00: Related constructs worked in two different injury models.
• 30:54
  SPEAKER_00: The treatment produced dose-dependent effects.
• 30:57
  SPEAKER_00: The treatment preserved both retinal ganglion cell numbers and an electrical function measure.
• 31:02
  SPEAKER_00: The clinical trial enriches for patients with documented progression and remaining visual field function.
• 31:08
  SPEAKER_00: Estellus and the original Quethera team have had several years to optimize the program.
• 31:13
  SPEAKER_00: Reasons lowering the estimate?
• 31:16
  SPEAKER_00: No human exposure or safety data exist.
• 31:18
  SPEAKER_00: Human retinal ganglion cell transduction may be incomplete.
• 31:22
  SPEAKER_00: Animal models are shorter and simpler than human glaucoma.
• 31:26
  SPEAKER_00: A one-year trial may not reliably distinguish true preservation from visual field variability.
• 31:32
  SPEAKER_00: Excessive neurotrophic signaling could cause toxicity or loss of biological control.
• 31:38
  SPEAKER_00: Probability of eventually demonstrating clinically meaningful visual field preservation, approximately 20% to 30%.
• 31:45
  SPEAKER_00: My central estimate is about 25%.
• 31:48
  SPEAKER_00: This is substantially lower than the probability of showing a measurable biological effect.
• 31:53
  SPEAKER_00: A treatment might produce more protein in the retina, a modest optical coherence tomography difference, better electrical retinal responses, a small short-term visual field signal, yet still fail to demonstrate meaningful long-term preservation of vision.
• 32:10
  SPEAKER_00: The key challenge is that regulators and patients need evidence that treated people retain useful vision for longer, not merely that a laboratory marker changes.
• 32:20
  SPEAKER_00: Probability of eventual approval from the current stage, approximately 10% to 20%.
• 32:26
  SPEAKER_00: This estimate includes the possibility of phase one safety problems, failure to show a meaningful randomized effect, manufacturing difficulties, retreatment limitations, commercial or strategic discontinuation, a larger phase three trial failing after an encouraging phase two result.
• 32:43
  SPEAKER_00: These estimates are not specific to ASP 2767 alone.
• 32:47
  SPEAKER_00: Historically, most experimental therapies entering first-in-human trials do not become approved treatments.
• 32:54
  SPEAKER_00: When could ASP 767 become available?
• 32:58
  SPEAKER_00: The current trial's planned primary completion is approximately July 2030, with one year of follow-up after treatment.
• 33:05
  SPEAKER_00: If the program succeeds, the likely sequence would be 2026-2030, phase 1-phase 2 study.
• 33:12
  SPEAKER_00: 2030-2031, data analysis and regulatory planning.
• 33:17
  SPEAKER_00: 2031-2034 or later, larger pivotal phase 3 trial.
• 33:22
  SPEAKER_00: 2034-2036, regulatory review and possible approval.
• 33:27
  SPEAKER_00: Earliest plausible availability, approximately 2034, assuming no major safety problem, clear biological and clinical benefit, a relatively rapid pivotal trial.
• 33:38
  SPEAKER_00: Regulators accept the development plan without requiring extensive additional studies.
• 33:43
  SPEAKER_00: More realistic estimate mid to late 2030s.
• 33:46
  SPEAKER_00: An approval before 2033 would be unusually fast for a first-in-class gene therapy for a slowly progressive disease.
• 33:54
  SPEAKER_00: Which patients would be the most logical candidates?
• 33:57
  SPEAKER_00: If ASP 2767 eventually works, the most logical initial candidates would probably be people with progressive primary open-angle glaucoma, documented worsening despite well-controlled eye pressure, moderate to advanced disease, remaining visual field function, a measurable rate of progression, enough surviving retinal ganglion cells to protect, no major retinal, macular, inflammatory, or non-glaucomatous optic nerve disease.
• 34:25
  SPEAKER_00: The current phase 2 eligibility range, mean deviation from minus 6 to minus 20 decibels, provides a reasonable clue about the intended population.
• 34:36
  SPEAKER_00: The treatment would probably be less suitable for newly diagnosed patients with stable disease, patients whose eye pressure remains uncontrolled, patients with almost no remaining visual field function, patients with optic nerve damage from another cause, patients with active uveitis or a history of severe steroid response, patients whose visual loss is mainly caused by cataract or macular disease.
• 35:00
  SPEAKER_00: The ideal candidate is not necessarily the person with the worst glaucoma.
• 35:05
  SPEAKER_00: It is more likely the person with rapidly progressing disease and enough viable retinal ganglion cells left to save.
• 35:12
  SPEAKER_00: What this could mean for patients.
• 35:14
  SPEAKER_00: Best case scenario: ASP2767 safely transduces a useful percentage of retinal ganglion cells and produces sustained tropomyosin receptor kinase B and mature brain-derived neurotrophic factor signaling.
• 35:28
  SPEAKER_00: Patients experience slower retinal nerve fiber layer loss, slower visual field decline, better preservation of contrast sensitivity, and daily visual function, fewer emergency pressure lowering procedures, a meaningful delay before disability from glaucoma.
• 35:43
  SPEAKER_00: In this scenario, AS-2767 becomes an add-on treatment for patients progressing despite well-controlled eye pressure.
• 35:51
  SPEAKER_00: Realistic case scenario ASP767 demonstrates biological activity, but the benefit is modest.
• 35:58
  SPEAKER_00: Possible results, a measurable structural or electrical retinal benefit, a small slowing of visual field decline, greater benefit in a selected subgroup, no meaningful restoration of already lost vision, continued need for eye drops, laser treatment, or surgery.
• 36:15
  SPEAKER_00: Possible need for another treatment years later, although retreatment may be difficult.
• 36:20
  SPEAKER_00: This would still be clinically valuable if it delayed functional disability, but it would not be a cure.
• 36:26
  SPEAKER_00: Failure case scenario.
• 36:28
  SPEAKER_00: The treatment may fail because too few retinal ganglion cells are transduced, the proteins do not remain active long enough.
• 36:35
  SPEAKER_00: The survival benefit in animals does not translate to human glaucoma.
• 36:40
  SPEAKER_00: Inflammation offsets the neuroprotective effect.
• 36:43
  SPEAKER_00: Visual field testing is too variable to show a reliable benefit.
• 36:47
  SPEAKER_00: The treatment protects retinal structure but not useful vision.
• 36:50
  SPEAKER_00: The therapy is safe but biologically inactive.
• 36:53
  SPEAKER_00: A rare retinal or inflammatory complication makes the risk unacceptable.
• 36:58
  SPEAKER_00: In that situation, ASP2767 would join a long list of scientifically promising glaucoma neuroprotection programs that did not produce a practical treatment.
• 37:09
  SPEAKER_00: Conclusion: ASP2767 represents a meaningful change in the direction of glaucoma research.
• 37:17
  SPEAKER_00: Instead of treating only the pressure environment around the optic nerve, it attempts to make retinal ganglion cells more resistant to injury from inside the retina.
• 37:26
  SPEAKER_00: The scientific strategy is credible.
• 37:28
  SPEAKER_00: The preclinical evidence is stronger than a simple company announcement.
• 37:33
  SPEAKER_00: Related dual gene constructs have activated known survival pathways, preserved retinal ganglion cells, maintained electrical retinal function, and worked in more than one animal model.
• 37:45
  SPEAKER_00: But the most important claims remain unproven.
• 37:47
  SPEAKER_00: There is no human evidence yet that AS-2767 will preserve visual fields, restore dysfunctional retinal ganglion cells, regenerate optic nerve axons, or provide decades of benefit from one injection.
• 38:01
  SPEAKER_00: For patients, the most realistic hope is not that A767 will restore severely damaged vision.
• 38:07
  SPEAKER_00: It is that, when combined with good eye pressure control, it may help protect the retinal ganglion cells that are still alive and slow the progression of otherwise relentless glaucoma.
• 38:18
  SPEAKER_00: All links to sources are available in the text version of this article.
• 38:22
  SPEAKER_00: You can find the full article at VisualFieldTest.com.
• 38:26
  SPEAKER_00: Thanks for listening.
• 38:28
  SPEAKER_00: To check your visual field, click the link at the bottom of this article or visit visualfieldtest.com.