Gene therapy may help reverse hereditary vision loss

Experimental gene therapy appears to improve eyesight in patients with a severe progressive form of Leber’s hereditary optic neuropathy (LHON) in an early access programme.

LHON is a mitochondrial genetic condition that causes rapid and progressive blindness in young adult males.  

In this analysis, 60 percent of patients treated with lenadogene nolparvovec intravitreal injection had improvement in the number of letters they could read on a visual acuity chart at the 2-year follow-up.

Study presenter Dr Chiara La Morgia from the IRCCS Istituto delle Scienze Neurologiche di Bologna in Bologna, Italy said this confirms the efficacy and safety of lenadogene nolparvovec in a real-life setting.

New kid on the block

Lenadogene nolparvovec uses an adeno-associated virus vector to deliver the wild-type ND4 gene directly to the mitochondrial membrane of the retinal ganglion cells. This compensates for the mutation and leads to protein synthesis and restoration of energy production.

According to La Morgia, five clinical studies have so far been conducted with gene therapy in patients in France, Italy, the UK, and the US.

In the current analysis, 63 patients with MT-ND4-LHON underwent unilateral or bilateral intravitreal injection at a dose of 9x10¹⁰ viral genomes per eye. Efficacy and safety data, as well as patient baseline characteristics, were analysed. [EAN 2023, abstract OPR-073]

Patients’ mean age at first injection was 33.7 years. The disease duration was about 11.3 years. Over 90 percent were 60 years of age or younger. Seventy-seven percent were male; 55 percent were from France and 28.6 percent were from the US.

Patient outcomes at 2 years

At 2 years, there was a marked improvement in best-corrected visual acuity (BCVA) scores. Of the 90 eyes treated in total, the mean change in BCVA from nadir at 1 year was -0.45 log of the minimum angle of resolution (LogMAR), or +22.5 Early Treatment Diabetic Retinopathy Study (ETDRS) letters on a chart.

Among 58 bilaterally treated eyes, the mean improvement was -0.49 LogMAR, or +24.5 ETDRS letters. In 32 unilaterally treated eyes, the mean improvement was -0.39 LogMAR, or +19.5 ETDRS letters.

Overall, 64.4 percent of treated eyes had an improvement from a nadir of ≥0.3 LogMAR. A clinically relevant response, defined as an improvement of ≥10 ETDRS letters, was achieved by 60 percent of patients.

“In terms of safety, 43 percent of eyes had one episode of intraocular inflammation, which was quite high, and lasted for 155.8 days,” said La Morgia. “But this was not severe and easily treatable.”

As for the regulatory approval, she shared that the application has been submitted to the European Medicines Agency early on but was later withdrawn. “The bilateral improvement in patients who received a unilateral injection was difficult to explain,” she added. Another question raised was the heterogeneity of patient data.

Currently, the short-chain benzoquinone, idebenone, is the only disease-specific drug approved to treat LHON.