Author: Srinivas Sadda
Co-authors: Santosh Mahapatra, Subrata Batabyal, Gayatri Kanungo, Michael Carlson, Brenden Truman, Ananta Ayyagari, Kissaou Tchedre, Samuel Barone, Sai Chavala, Samarendra Mohanty
AbstractPurpose: Retinitis Pigmentosa, caused by different genetic mutations, leads to severe photoreceptor degeneration throughout the retina as the disease advances. Optogenetic therapy offers the potential for vision restoration in these patients by transforming bipolar or ganglion cells to become photosensitive. Since this approach focuses on disease phenotype versus a specific genetic defect, it is applicable to a wide patient population. Existing optogenetic tools utilize opsins that do not generate adequate electrical current in ambient light requiring an external device for stimulation. Multi-Characteristic Opsin (MCO) is an engineered fast opsin that is activated at ambient light levels, with broadband sensitivity. The objective of this study was to evaluate the safety and efficacy of intravitreal Multi-Characteristic Opsin Optogenetic Therapy for vision restoration in advanced retinitis pigmentosa patients.
Setting/Venue: Phase 1/2a Clinical Trial
Methods: Patients were screened based on a clinical diagnosis of RP, irrespective of gene mutation. To be enrolled, the worse (study) eye was required to be no better than Light Perception and the Fellow eye no better than Count Fingers. Baseline examinations include multiple exploratory efficacy measures such as Freiburg Visual Acuity, mobility assays at multiple light luminance, perimetry, shape discrimination ability, and a patient reported outcome (NEI VFQ-25). A single intravitreal injection was used to deliver AAV2-MCO (vMCO) in 11 advanced RP subjects (3 in a low-dose cohort and 8 in a high dose cohort). Subjects received prophylactic oral steroids prior to injection, and the safety of different doses was assessed by slit lamp biomicroscopy, indirect ophthalmoscopy, and OCT. The primary endpoint was at 16 weeks, though patients were examined at regular intervals through 52 weeks.
Results: vMCO was well-tolerated with no reported serious adverse events up to 52 weeks following injection. Ocular adverse events were limited to inflammation and intraocular pressure rise, both of which could be controlled with topical therapy. Furthermore, dose-dependent improvement in visual acuity was observed with >0.6 logMAR improvement at 16 weeks as compared to baseline in 6 out of 8 high dose subjects. Significant improvement in light-guided mobility score and shape discrimination was observed after vMCO injection. These improvements appeared to be durable through end of study (at 52 weeks). The improvement in measured functional vision also correlated with improvements in activities of daily living.
Conclusions: In this Phase 1 study, vMCO was well tolerated with no serious adverse events. Higher dose vMCO appeared to improve visual acuity and visual function, showing a promise for visual restoration in patients with advanced RP.
Financial Disclosure: S Sadda is a consultant for Nanoscope Inc, Iveric, Amgen, Apellis, Allergan, Gyroscope, 4DMT, Roche, Novartis, Regeneron, Pfizer, Optos, Centervue, and Heidelberg; S. Batabayal, M. Carlson, A. Ayyagari, K. Tchedre, S. Barone, and S. Monanty are employees and have equity interest in Nanoscope; S. Chavala is a consultant and equity holder in Nanoscope. S. Mahapatra, G. Kanungo, and B. Truman report no financial interest.