A gene therapy treatment for adults with Stargardt dystrophy (SD) due to mutations in ABCA4 found the investigational product is safe and well-tolerated across 3 dose levels, according to a study published in the American Journal of Ophthalmology

The nonrandomized multicenter phase I/IIa clinical trial looked at the first cohorts in the gene therapy trial, with 22 patients first undergoing standard three port vitrectomy and EIAV-ABCA given as a subretinal injection of approximately 300 microliters in a hydraulically created retinotomy. The injection was given in patients’ worse-seeing eye at 3 dose levels. They were followed for 3 years after treatment. The primary endpoints were ocular and systemic adverse events and the secondary endpoints included best-corrected visual acuity (BCVA), static perimetry (SP), kinetic perimetry (KP), total field hill of vision (VTOT), full field electroretinogram (ffERG), multifocal ERG (mfERG), color fundus photography (CFP), short-wavelength fundus autofluorescence (FAF), and spectral domain optical coherence tomography (SD-OCT).

Researchers found the subretinal injections were well-tolerated with only a single case of a treatment-related ophthalmic serious adverse event (chronic ocular hypertension), and most common adverse events were associated with the surgical procedure. 


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A patient who received the highest dose had a significant decline in the number of macular flecks when compared to the untreated eye. Another 6 patients had hypoautofluorescent changes that were worse in the treated eye than the untreated eye, and 1 patient had retinal pigment epithelium (RPE) atrophy “that was characteristic of tissue damage likely associated with bleb induction.” No “clinically significant changes in visual function tests were found to be attributable to the treatment,” investigators report.

They found that none of the patients studied had clinically significant changes in BCVA, SP, KP, VTOT, ffERG, or mfERG attributable to the treatment.

“Similar to a previous study [published in Proceedings of the National Academy of Sciences of the United States of America] utilizing the same vector, this study has demonstrated that lentiviral vectors may be a potential platform for delivery of large genes that are beyond the capacity of AAV vectors,” according to the researchers. “We show that the subretinal injection of EIAV in SD is generally safe, and continued development of EIAV and dedicated subretinal injection tools will likely improve the safety of these procedures. Further studies in patients with milder disease and more viable retinal tissue will be needed to fully determine the safety and efficacy profile of this treatment.”

The study’s limitations include the fact that early cohorts of patients had advanced disease and poor visual acuity/fixation (which was the design for safety reasons) but that could have assisted in decreasing poor visual acuity/fixation and making imaging more difficult. “In addition, patients with severe retinal degeneration likely benefit less from gene therapy due to lower levels of viable tissue for transduction. However, this was an early phase clinical trial, and safety was the primary endpoint,” investigators explain. Lack of fixation data was another study limitation. 

The study was also nonrandomized and had a small patient population. “But SD is a rare disease and thus the size of the cohorts and open label study design were commensurate with an early phase clinical trial,” according to the researchers.

Reference


Parker MA, Erker LR, Audo I, et al. Three-year safety results of SAR422459 (EIAV-ABCA4) gene therapy in patients with ABCA4-associated Stargardt disease: An open-label dose-escalation phase I/IIa clinical trial, cohorts 1-5. Am J Ophthalmol. 2022:S0002-9394(22)00069-1. doi:10.1016/j.ajo.2022.02.013