Safety and efficacy data from the phase 2 STARLIGHT trial on MCO-010 (Nanoscope Therapeutics, Inc.) for Stargardt disease (SD) were presented at this weekend’s 2025 annual American Academy of Ophthalmology (AAO) meeting in Orlando.
Give me some background on optogenetics for SD.
SD is an inherited degenerative retinal disease that impacts rod and cone photoreceptors and retinal pigment epithelial (RPE) cells, resulting in severe and irreversible vision loss.
Optogenetics is a promising treatment approach for SD because it utilizes genetic bioengineering of light-sensitive opsin chromophores and light to achieve activation of the remaining retinal neurons, such as bipolar and retinal ganglion cells (RGCs).
- Note: By photosensitizing the higher-order neurons, optogenetic intervention bypasses the requirement for intact RPE and photoreceptors.
Since this optogenetic approach focuses broadly on an anatomic phenotype instead of a specific gene deficit, it is agnostic to gene mutations—meaning it can potentially treat a wide range of patients with inherited retinal diseases (IRDs).
Let’s move on to MCO-010.
MCO-010 (sonpiretigene isteparvovec) is a mutation-agnostic optogenetic gene therapy that uses adeno-associated viral vector serotype 2 (AAV2) to deliver a multicharacteristic opsin (MCO) transgene via a single, in-office intravitreal (IVT) injection.
- The result: Transduction of bipolar cells to express photosensitive opsin and enhance vision in spite of photoreceptor loss.
Tell me more about this.
Using the proprietary optogenetic technology from Nanoscope, “MCO-010 therapy does not require genetic testing, surgical intervention, or repeat dosing, enabling broad patient applicability within existing retina office workflows,” the company noted.
And most recently: The FDA granted Regenerative Medicine Advanced Therapy (RMAT) designation (in addition to prior Orphan Drug and Fast Track designations) for MCO-010 in SD patients.
Are there any other indications for MCO-010?
Indeed. Nanoscope recently initiated its submission of a Biologics License Application (BLA) to the FDA for MCO-010 in retinitis pigmentosa (RP) patients following successful completion of the phase 2b RESTORE trial (NCT04945772).
- A complete BLA submission is planned for early 2026.
Nanoscope also expects to initiate a phase 2 trial on MCO-010 for geographic atrophy (GA) in Q4 2025.
How did MCO-010 perform in previous clinical trials for SD?
A previous proof-of-concept, open-label, dose-escalation phase 1/2a study (NCT04919473) demonstrated that MCO-010 was well-tolerated and safe.
- Note: There is an ongoing 5-year long-term follow-up study of the phase 1/2a trial (EXTEND, NCT05921162).
Clinically meaningful vision improvement of >15 Early Treatment of Diabetic Retinopathy Study (ETDRS) letters was reported in patients with severe vision loss who could not read letters on a vision chart.
However: The trial did not assess if optogenetics could be used as a therapeutic agent to improve clinical outcomes in better-seeing patients who can read letters on the ETDRS chart.
Now talk about STARLIGHT.
STARLIGHT (NCT05417126) is a 48-week phase 2a, open-label, multicenter study that assessed the safety and efficacy of a single IVT injection of MCO-010 (1.2E11 genome copies [gc]/eye) in the worse-seeing eye of SD patients.
- The cohort: Six adults (mean age: 50 years, range 32-71 years, four males and two females)
What were the primary and secondary outcomes?
The primary outcome was the incidence, nature, and severity of the following factors:
- Treatment-emergent adverse events (TEAEs)
- Serious adverse events (SAEs)
- Intraocular inflammation
- Retinal thickness
- Best-corrected visual acuity (BCVA)
- Lesion size
Secondary endpoints included changes from baseline at weeks, 12, 24, and 48 in:
- BCVA
- Vision-guided mobility (measured via Multi-Luminance Mobility Test)
- Shape determination accuracy (assessed using Low Vision Multi-Parameter Test [LVMPT]
- Accuracy in determination of optical flow using the LVMPT
In addition: Visual field (VF) perimetry and Michigan Retinal Degeneration Questionnaire (MRDQ) were exploratory endpoints.
And those findings?
The mean ETDRS BCVA in the six treated eyes at baseline was 22.8±9.87 (range 9-35) letters and increased to 28.3±13.28 (range 4-42) letters at 48 weeks.
The research team reported mean ETDRS BCVA gains at the following time points:
- 12 weeks: 7.2±11.74 letters
- 24 weeks: 4.2±14.81 letters
- 48 weeks: 5.5±12.29 letters
With a wearable magnifier (low-vision glasses), the mean baseline ETDRS BCVA was 37.0 letters (Snellen equivalent ~20/125), and mean BCVA gains with a magnifier were observed as follows:
- 12 weeks: 17.8±13.35 letters
- 24 weeks: 15.7±17.37 letters
- 48 weeks: 13.3±21.37 letters
Plus: Three of six subjects gained > 15 ETDRS letters, and a case report of the first subject showed marked BCVA gains of > 25 ETDRS letters with and without a magnifier.
What about TEAEs?
All six participants had at least one ocular TEAE and non-ocular TEAEs occurred in three subjects.
The most common TEAEs were:
- Conjunctival hemorrhage
- Ocular hypertension
- Vitreous cells (two subjects)
Further: MCO-010 was well-tolerated, with no reported SAEs. One patient required long-term immunosuppression, potentially from cystoid macular edema that was present at baseline.
And the exploratory endpoints?
The improvement in mean defect in VF perimetry was as follows:
- 12 weeks: 1.02±3.54 dB
- 24 weeks: 2.47±5.00 dB
- 48 weeks: 2.63±5.26 dB
Specific improvements were noted in reading, color, and contrast domains of the MRDQ.
Expert opinion?
The study authors noted: “Additional testimonials from MCO-010-treated SD participants confirmed the positive impact on activities of their daily living while using a smartphone, watching television, and seeing brighter colors as well as finer details of various objects in their surroundings.”
Any limitations?
These included:
- Small sample size, which weakens the statistical significance of BCVA improvement
- STARLIGHT did not include active monitoring of the long-term effect of MCO-010 in SD patients, but is ongoing in a long-term follow-up study (NCT06048185)
- Future trials need to include a sham-injected control arm to elucidate a confounding factor related to contralateral gene transfer
Now the take home.
These findings support further investigation of MCO-010 optogenetic therapy for treatment of SD.
This is the first optogenetic trial in patients with on-chart vision at baseline, suggesting that optogenetic therapy is not limited to patients with profound vision loss.
Next steps?
Following the successful end-of-phase-2 meeting with the FDA, Nanoscope plans to initiate STARGAZE, a registration-enabling, randomized, double-masked, sham-controlled phase 3 trial, by the end of 2025.
Approximately 60 patients will be enrolled in STARGAZE, and top-line results are expected in 2027.