MCO-010 optogenetic gene therapy for severe vision loss in Stargardt disease

(Image Credit: Adobestock/Kanisorn)

MCO-010 is a novel adeno-associated virus (AAV2)-delivered optogenetic gene therapy designed to treat severe vision loss in patients with Stargardt disease. This disease, also known as juvenile macular dystrophy, is an inherited retinal disorder that affects approximately 1 in 8000-10,000 people in the US.¹

Stargardt disease is caused by a variety of sequence variants, primarily in the ABCA4 gene that provides instructions for making a protein that plays a crucial role in the visual cycle. The protein helps to transport a substance called retinaldehyde, which is essential for the conversion of light into electrochemical signals in the retina.² The sequence variants result in a buildup of a toxic substance known as lipofuscin within the retinal cells, particularly the retinal pigment epithelial cells. This accumulation of lipofuscin contributes to the progressive degeneration of the macula, leading to vision loss.

Figure 1. Principle of Optogenetic Vision Restoration (Images courtesy of Allen C. Ho, MD, FACS, FASRS)

A mutation-agnostic optogenetic gene therapy is currently in development using multi-characteristic opsin (MCO) to sensitize the retinal bipolar cells to detect light (Nanoscope Therapeutics, Dallas, Texas) (Figure 1). MCO is a bioengineered fusion protein that is highly light-sensitive, with broadband spectral responsiveness and fast kinetics to activate MCO-expressing retinal cells in an ambient light environment.³ MCO therapy has the potential to restore vision in visually impaired patients with a variety of retinal degenerative diseases where there is significant photoreceptor loss (Figure 1).

STARLIGHT (NCT05417126) is a phase-2 multicenter clinical trial aimed to evaluate the safety and effectiveness of a single dose level of MCO-010 delivered intravitreally in patients with Stargardt disease. The study design is depicted in Figure 2.

The inclusion criteria included a clinical or genetic diagnosis of Stargardt disease with best-corrected visual acuity (BCVA) in the range of 1.3 to 1.9 logMAR. The patients were subjected to prophylactic treatment with an oral steroid that was tapered from day —3 to day 17, as well as to an overlapping tapered regimen of topical steroid eye drops from week 2 to week 36. Ocular and systemic safety, as well as multiple vision function tests, including BCVA using early treatment diabetic retinopathy study (ETDRS) charts at 50 cm with and without wearable magnifier, Octopus visual field perimetry, multi-luminance Y-mobility test (MLYMT), and multi-luminance shape discrimination test (MLSDT), were assessed. The Rasch-validated Michigan Retinal Degeneration Questionnaire (MRDQ) was used for evaluating patient-reported outcomes.

The 24-week clinical study results were reported by Allen C. Ho, MD, FACS, FASRS, at the American Society of Retina Specialists meeting (Seattle, Washington) and the 2023 Retina Society conference (New York, New York). Six Stargardt disease subjects (4 males and 2 females; mean age, 49 years) were treated with MCO-010 (1.2 E11 genome copies). The treatment was well-tolerated with no serious adverse events reported, consistent with the favorable profile observed in the phase 1/2a and phase 2b RESTORE studies in retinitis pigmentosa (RP) patients.

Figure 2. STARLIGHT Study Design

No endophthalmitis, retinitis, vasculitis, choroiditis, hypopyon or hypotony was reported. The intraocular inflammation grade at any time was lower than 2+. While all 6 Stargardt patients in the STARLIGHT trial had ABCA4 mutations, 3 patients predominantly had macular atrophy and the other 3 patients exhibited a pan-retinal phenotype. Regarding the effectiveness of the treatment, there was approximately 5 ETDRS letter gain in mean BCVA and approximately 3 dB gain in the visual field. When evaluated with the use of wearable magnifier at Baseline and longitudinally, the mean BCVA gain was enhanced to 15 ETDRS letters.

The 3 patients with predominantly macular atrophy experienced clinically meaningful improvements of more than 10 ETDRS letters in mean BCVA (and 30 ETDRS letters with wearable magnifier). These subjects also exhibited an approximate 5 dB gain in mean sensitivity measured by visual field perimetry. The improvement in BCVA is consistent with the previous MCO-010 phase 1/2 study and phase 2b randomized controlled study (RESTORE) in RP.

The treated patients also maintained excellent performance in the MLYMT and MLSDT tests throughout the duration of the study. Furthermore, MCO-010-treated Stargardt patients reported improvements in the key domain scores on reading, color, and contrast parameters, measured by MRDQ.

The testimonial from MCO-010-treated patients confirmed the positive impact in activities of daily living such as using smartphones, watching television, and distinguishing color as well as object details. These exciting clinical results support further clinical advancement of this novel gene therapy treatment to help restore vision in patients with not just Stargardt disease but severe vision loss due to other outer retinal degenerative conditions.⁴

Allen C. Ho, MD, FACS, FASRS

E: achomd@gmail.com

Ho serves as director of retina research at Wills Eye Hospital, Philadelphia, Pennsylvania, and professor of ophthalmology at Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, Pennsylvania. His financial disclosures include consultant/grant funding (Adverum Biotechnologies, Apellis Pharmaceuticals, Asclepix Therapeutics, Clearside Biomedical, Genentech/Roche, Gyroscope Therapeutics, Iveric Bio, Kodiak Sciences, Lineage Healthcare, Regenxbio); consultant/scientific advisor (Nanoscope Therapeutics).

References

1. Wang L, Shah SM, Mangwani-Mordani S, Gregori NZ. Updates on emerging interventions for autosomal recessive ABCA4-associated Stargardt disease. J Clin Med. 2023;12(19):6229. doi:10.3390/jcm12196229

2. Tanna P, Strauss RW, Fujinami K, Michaelides M. Stargardt disease: clinical features, molecular genetics, animal models and therapeutic options. Br J Ophthalmol. 2017;101(1):25-30. doi:10.1136/bjophthalmol-2016-308823

3. Batabyal S, Gajjeraman S, Pradhan S, Bhattachrya S, Wright W, Mohanty S. Sensitization of ON-bipolar cells with ambient light activatable multi-characteristic opsin rescues vision in mice. Gene Ther 28, 162–176 (2021). doi:10.1038/s41434-020-00200-2

4. Mohanty S, Idigo C, Ayyagari A, Narcisse D. Optogenetic approaches to gene therapy for vision restoration in retinal degenerative diseases. In: Ohia SE, Sharif NA, eds. Handbook of Basic and Clinical Ocular Pharmacology and Therapeutics. Academic Press, Oxford (UK); 2022: 581-606.