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

Image courtesy of Allen C. Ho, MD

MCO-010 is a novel adeno-associated virus (AAV2)-delivered optogenetic gene therapy for treatment of 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 8,000-10,000 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

Image courtesy of Allen C. Ho, MD

A mutation-agnostic optogenetic gene therapy is 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 patients with a variety of retinal degenerative diseases where there is significant photoreceptor loss.

Principle of Optogenetic Vision Restoration

STARLIGHT (NCT05417126) is a phase-2 multicenter clinical trial 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 was 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.

Figure 2
Image courtesy of Allen C. Ho, MD

STARLIGHT Study Design

Allen C. Ho, MD, FACS, FASRS, reported the 24-week clinical study results at the American Society of Retina Specialists meeting in Seattle, Washington and the 2023 Retina Society conference in New York, New York. Six Stargardt disease patients (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. No endophthalmitis, retinitis, vasculitis, choroiditis, hypopyon or hypotony was reported. The intraocular inflammation grade at any time was lower than 2+. While all 6 patients in the STARLIGHT trial had ABCA4 mutations, 3 patients predominantly had macular atrophy. The other 3 patients exhibited a pan-retinal phenotype. There was approximately 5 ETDRS letter gain in mean BCVA and approximately 3 decibels (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). They 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 RESOTE randomized controlled study in RP.

The treated patients maintained an excellent performance in the MLYMT and MLSDT tests for the duration of the study. Furthermore, MCO-010—treated Stargardt patients reported improvements in key domain scores on reading, color, and contrast parameters measured by MRDQ. The testimonials from MCO-010—treated patients saw a positive impact on daily activities including using smartphones, watching TV, and distinguishing color and object details. These results support further clinical advancement of this gene therapy treatment to help restore vision in patients with Stargardt disease and severe vision loss from other retinal degenerative conditions.⁴

Allen C. Ho, MD, FACS, FASRS

E: achomd@gmail.com.

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.

Financial disclosures: consultant/grant funding (Adverum Biotechnologies, Apellis Pharmaceuticals, Asclepix Therapeutics, Clearside Biomedical, Genentech/Roche, Gyroscope Therapeutics, Iveric Bio, Kodiak Sciences, Lineage Healthcare, Regenxbio); consultant/scientific adviser (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.