Changes in Photoreceptor Morphology Quantifiable Following Gene Therapy


Short-term morphological rescue was seen after voretigene neparvovec-rzyl treatment.

Reviewed by Friederike C. Kortuem, MD, MSc. This content originally appeared on our sister site, Ophthalmology Times.

Voretigene neparvovec-rzyl (Luxturna, Spark Therapeutics) led to a short-term change in the foveal morphology in a 15-year-old girl with visual impairment, including nyctalopia and decreased visual acuity (VA) in early childhood. This case study was presented by Friederike C. Kortuem, MD, MSc, Eye Clinic Tübingen, Eberhard Karls University of Tübingen, Baden-Württemberg, Germany, at the Association for Research in Vision and Ophthalmology 2021 virtual annual meeting.

Visual deterioration generally occurs early in Leber congenital amaurosis type 2 (LCA2) and early-onset severe retinal dystrophy (EOSRD), from as soon as birth to 5 years of age.

Characteristically, rapid degeneration of the rods and cones, visual field reduction, sluggish or near-absent pupillary responses, photophobia, nystagmus, and nyctalopia can occur. By the 4th decade of life, patients usually are legally blind.

Subretinal administration of voretigene neparvovec-rzyl in an adeno-associated viral vector was approved in the US by the FDA in 2017 and in Germany in 2019 to treat retinal dystrophies caused by bi-allelic RPE65 mutations; RPE65 is involved in the vitamin A restoration cycle in the eye.

Case report

The current patient had an RPE65 homozygous mutation. The VA in the right eye at examination was 20/63, and the anterior segment was unremarkable. The retinal examination in that eye showed central macular atrophy, narrowed vessels, and diffuse peripheral atrophy.

Kortuem demonstrated the overall decreased retinal thickness in the right eye. The clinical examinations included measurement of the best-corrected VA (BCVA), spectral-domain optical coherence tomography (OCT), and adaptive optics retinal imaging.

At baseline, the patient was injected with the gene therapy vector, which was successfully positioned between the neural retina and the retinal pigment epithelium. She was evaluated at baseline and then at 2 and 5 weeks and 3 months following treatment. At baseline, compared with healthy individuals of the same age, this patient’s retina was thinner.

Kortuem showed that the central fovea had alterations in its layers and the retinal structures were not well demarcated, in contrast to the parafoveal layer with a preserved outer retina and photoreceptors.

As soon as 2 weeks after treatment, the foveal layer started to change. The external limiting membrane was visualized in the fovea.

“The overall disrupted appearance improved,” Kortuem commented.

After 5 weeks, the layering of the central fovea further improved out to 3 months.

The adaptive optics images obtained at baseline showed a mosaic of disrupted photoreceptor cells that, according to Kortuem, is characteristic of inherited retinal diseases.

Following treatment, the superior nasal area appeared partly clear, and the cones were identifiable. In the first 5 weeks following treatment, the initially patchy areas seemed to be decreasing over time.

These morphologic rescue parameters changed gradually over time and were correlated partly with the improvement in the foveal-mediated vision after the treatment.

Regarding the safety of the treatment, no signs of inflammation were observed.

Cone functionality improved slightly and the patient reported “brighter” vision, which she also reported 5 weeks after surgery. At 3 months after surgery, the objective changes persisted.

The VA remained stable from baseline to week 5 and then improved by 1 line to 20/50. The contrast sensitivity also remained stable over time. Chromatic pupil campimetry showed a dramatic increase in the central 10 degrees of the pupil from week 2 to week 5 and this improvement persisted to month 3.

“Rapid changes in the photoreceptor morphology seen on OCT and adaptive optics imaging after successful gene therapy in patients with LCA and EORD can be quantifiable at the individual level,” Kortuem concluded.


Friederike C. Kortuem, MD, MSc
e:[email protected]
This article is adapted from Kortuem’s presentation at the Association for Research in Vision and Ophthalmology 2021 virtual annual meeting. She has no financial interest in this subject matter.

Korteum FC, Kempf M, Jung R, et al. Short term morphological rescue of the fovea after gene therapy with voretigene neparvovec. Acta Ophthalmol. Published online July 21, 2021. doi: 10.1111/aos.14990
Related Videos
Jacques Galipeau, MD, on Highlights from ISCT 2024’s Presidential Plenary
Zheng-Yi Chen, DPhil, on International Collaboration on Clinical Trials
Shankar Ramaswamy, MD, the cofounder, chairman, and CEO of Kriya Therapeutics
Zheng-Yi Chen, DPhil, on Looking Deeper Into Effects of Gene Therapy on OTOF Deafness
Arshad Khanani, MD
Alfonso Sabater, MD, PhD
Shankar Musunuri, PhD
Ula V. Jurkunas, MD
Alfonso Sabater, MD, PhD, on Bringing Gene Therapy to Ophthalmology
Shankar Musunuri, PhD
© 2024 MJH Life Sciences

All rights reserved.