Leber congenital amaurosis: Gene therapy sparks foveal morphological changes

Reviewed by Dr Friederike C. Kortuem.

Treatment with voretigene neparvovec-rzyl (Luxturna, Spark Therapeutics) resulted in a short-term change in foveal morphology in one young visually impaired patient, according to Dr Friederike C. Kortuem of the Eye Clinic Tübingen, Eberhard Karls University of Tübingen in Baden-Württemberg, Germany. The patient was a 15-year-old girl whose visual impairment included nyctalopia and decreased visual acuity (VA) in early childhood.

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 fourth decade of life, patients are usually legally blind.

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Sub-retinal administration of voretigene neparvovec-rzyl in an adeno-associated viral vector was approved in the United States by the Food and Drug Administration 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 aforementioned 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. Dr 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. Dr 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.

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

“The overall disrupted appearance improved,” Dr Kortuem commented. After 5 weeks, the layering of the central fovea further improved out to 3 months.

Disrupted photoreceptor cells are characteristic of inherited retinal diseases. (Image courtesy of Dr Friederike C. Kortuem)

The adaptive optics images obtained at baseline showed a mosaic of disrupted photoreceptor cells that, according to Dr Kortuem, is characteristic of inherited retinal diseases. Following treatment, the superior nasal area appeared partly clear and the cones were identifiable.

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In the first 5 weeks following treatment, the initially patchy areas seemed to be decreasing over time. These morphological rescue parameters changed gradually 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 one 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,” Dr Kortuem concluded.

Friederike C. Kortuem, MD, MSc

e: friederike.kortuem@med.uni-tuebingen.de

This article was adapted from Dr 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.

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