Inherited retinal diseases (IRDs), such as retinitis pigmentosa (RP) or Stargardt disease, are progressive, degenerative conditions that often occur early in life and can result in permanent blindness.1 These conditions are caused by genetic mutations that damage or destroy retinal pigment epithelium (RPE) or photoreceptor cells, leading to visual deterioration and, eventually, complete vision loss. These diseases can be caused by mutations in any one of more than 250 different genes.2 Until recently, the progression of inherited retinal diseases could be slowed with treatment, but not reversed.
Gene Therapy
For more than a decade, gene therapy has been investigated as a potential therapy for IRDs. In 2017, the US Food and Drug Administration (FDA) approved Luxturna (voretigene neparvovec-rzyl; Spark Therapeutics) as the treatment for retinal dystrophy caused by a mutation on the RPE65 gene.2 When injected subretinally, Luxturna delivers normal copies of RPE65 to retinal cells, enabling them to regain their functionality and slowing disease progression.
However, therapies that focus on a specific gene, like Luxturna, only work when treatment is initiated early in the course of the disease, when the patient still has a large number of viable photoreceptor cells.
Optogenetics is an alternative gene therapy approach that is currently being explored in multiple clinical trials. This sort of therapy does not address specific genes or mutations; instead, transgenes are introduced into the retina that produce opsins, or light-sensitive proteins. These opsins can affect bipolar and retinal ganglion cells within the retina, sensitizing the bipolar cells to detect ambient light and transmit signals to the brain through residual neurons (Figure 1). This can preserve and even restore vision, even when many photoreceptors are no longer functioning.3
One promising multicharacteristic opsin currently being investigated is MCO-010 (Nanoscope Therapeutics), which is being studied in clinical trials as a treatment for both RP and Stargardt disease. MCO-010 is delivered by an adeno-associated virus (AAV2), introduced to the eye in a single intravitreal injection.
Top-line data from the recently completed phase 2b RESTORE trial of MCO-010 for patients with advanced RP showed clinically meaningful vision improvement in legally blind individuals who had progressive and permanent neurodegeneration of the retina.4 RESTORE was the first randomized, controlled trial of a mutation-agnostic gene therapy for a genetic disease.
“We observed significant vision restoration in many patients with severe vision loss, including those who were completely blind,” David Boyer, MD, an investigator in the trial and adjunct clinical professor of ophthalmology at the University of Southern California Keck School of Medicine, said in a press release. “Many patients treated with MCO-010 derived a clinically meaningful benefit measurable on the primary visual function test, and this effect was confirmed by a parallel improvement in functional vision assessments.”
ReSTORE Trial Results
RESTORE was a multicenter, randomized, double-masked, sham-controlled, dose-ranging study to evaluate 2 dose levels of MCO-010 in patients with advanced RP, based on clinical examination, dilated fundus examination, and genetic testing. Nine subjects received a single intravitreal injection containing a high dose (1.211 genomic copies [gc]/eye) of MCO-010, 9 received an injection with a low dose (0.911 gc/eye) of MCO-010, and 9 received a sham injection. All subjects were assessed for 100 weeks following treatment.
The trial met its primary endpoint of statistically significant best-corrected visual acuity (BCVA) improvement at week 52 in both the high-dose (0.337 LogMAR; P=.021) and low-dose (0.382 LogMAR; P=.029) treatment groups compared to the sham control group (0.050 LogMAR). Improvements in visual function persisted or increased following week 52 in the study, demonstrating the durable effect of MCO-010.
BCVA improvement at week 76, a key secondary endpoint, was statistically significant in the high-dose treatment group compared to the control group (0.539 LogMAR; P=.001). At week 76, the improvement in BCVA in the low-dose treatment group was not statistically significant compared to control (0.374 LogMAR; P=.065). These results are consistent with what had been previously observed in an earlier phase 1/2a open-label study.
In a press release, Nanoscope Therapeutics said RESTORE is the only randomized controlled trial in retinal degenerative disease to demonstrate improvement beyond the clinically important BCVA >0.3 LogMAR threshold in a statistically significant manner.4
Nanoscope expects to submit a biologics license application to the FDA in the second half of 2024. According to the company, the high-dose MCO-010 (1.211 gc/eye) is planned to be the commercial dose.
Starlight Trial Results
In the phase 2 STARLIGHT trial, which was completed last fall, a single dose of MCO-010 was evaluated for safety and effectiveness when delivered via intravitreal injection to patients with Stargardt disease. Key results were presented at last year’s American Academy of Ophthalmology annual meeting. Similar to the RESTORE trial results, patients demonstrated clinically meaningful improvements in BCVA.
Top-line results for STARLIGHT showed patients had a mean BCVA improvement of +5.5 ETDRS letters, with a 15-letter improvement with a wearable magnifier.5 Patients also showed a 2.6-decibel gain in mean sensitivity as measured by Octopus visual field perimetry, with no serious adverse effects (SAEs).6 A phase 3 trial is currently being planned.
Next Steps
MCO-010 has received both fast track and orphan drug designations from the FDA, as a treatment for both retinitis pigmentosa and Stargardt disease. Company officials are optimistic that the optogenetic approach can be used to successfully treat inherited retinal diseases.
“These results are the culmination of more than a decade of work by numerous dedicated individuals, underscoring the potential of our unique broadband, highly photosensitive, and rapid MCO-010 platform,” said Samarendra Mohanty, PhD, co-founder, president, and chief scientific officer of Nanoscope.4 “This achievement marks a significant milestone in the field of mutation-agnostic gene therapy, firmly establishing the promise of optogenetics as a therapeutic modality. We extend our sincere gratitude to the National Eye Institute-NIH and collaborators for their invaluable contributions in realizing the therapeutic potential of MCO therapy, offering hope for vision restoration to patients regardless of their underlying genetic mutation.” NRP
References
1. Schneider N, Sundaresan Y, Gopalakrishnan P, et al. Inherited retinal diseases: Linking genes, disease-causing variants, and relevant therapeutic modalities. Prog Retin Eye Res. 2022;89:101029. doi:10.1016/j.preteyeres.2021.101029
2. Aoun M, Passerini I, Chiurazzi P, et al. Inherited retinal diseases due to RPE65 variants: from genetic diagnostic management to therapy. Int J Mol Sci. 2021;22(13):7207. doi:10.3390/ijms22137207
3. Pan ZH, Lu Q, Bi A, Dizhoor AM, Abrams GW. Optogenetic approaches to restoring vision. Annu Rev Vis Sci. 2015;1:185-210.
4. Nanoscope Therapeutics announces positive top-line results from randomized controlled trial of MCO-010 for retinitis pigmentosa. News release. March 26, 2024. Accessed April 17, 2024. https://nanostherapeutics.com/2024/03/26/nanoscope-therapeutics-announces-top-line-results-from-ph2-trial-of-mco-010-for-retinitis-pigmentosa/
5. Nanoscope Therapeutics unveils clinical trial results for MCO-010 in treating Stargardt disease. News release. August 9, 2023. Accessed April 17, 2024. https://nanostherapeutics.com/2023/08/09/nanoscope-therapeutics-unveils-clinical-trial-results-for-mco-010-in-treating-stargardt-disease/
6. Tsang SH. MCO-010 optogenetic therapy for vision loss in Stargardt disease: topline data from the phase 2 STARLIGHT trial. Presented at: the 2023 American Academy of Ophthalmology Annual Meeting; November 3-6, 2023; San Francisco, CA.
