Gene therapy sparks foveal morphologic changes in LCA

Reviewed by Friederike C. Kortuem, MD, MSc

Treatment with voretigene neparvovec-rzyl (Luxturna, Spark Therapeutics) resulted in a short-term change in the foveal morphology in a 15-year-old girl with visual impairment, according to Friederike C. Kortuem, MD, MSc, from the Eye Clinic Tübingen, Eberhard Karls University of Tübingen in Baden-Württemberg, Germany.

The 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.

Related: First patient dosed in optogenetic gene therapy trial

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.

Related: Investigators start pivotal subretinal gene therapy trial

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.

Related: Expansion study examines safety, efficacy of subretinal gene therapy for X-linked RP

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.

Related: Retinal therapeutic clinical trials address disease at core

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