LCA gene therapy unable to stop long-term sight loss

Leber’s congenital amaurosis (LCA) is an inherited retinal condition in which the photoreceptors degenerate. The condition typically affects young children, and can cause severe vision loss and blindness.

While a number of genes are implicated in the condition, around 10% of cases are linked to the loss of function of a single gene, called RPE65.

Gene therapy treatments have been trialled as an approach to treating RPE65-related LCA, where a virus is used as a vector to introduce a new working copy of the gene to remaining photoreceptors in those with the condition. 

While the process has shown success in the initial months and years following the treatment, the latest findings show that in the longer term, gene therapy is unable to stave off the decline of the retinal cells.   

In the first of two studies, a US team followed up three patients with the condition for up to six years following treatment. Following a single injection in one eye, with the fellow eye serving as the control, patients reported improvements in visual acuity – with the improvement peaking between one and three years, post-treatment.

However, long-term follow up showed that despite the increase in visual sensitivity shown by all three patients, they continued to lose photoreceptors. The team concluded that while the gene therapy treatment improved vision, it couldn’t delay the degeneration of the photoreceptors. 

“Our earlier results and these new measurements showed that photoreceptors continued to die at the same rate as they do in the natural course of the disease, regardless of the treatment,” said Dr Samuel G. Jacobson, professor of ophthalmology at Scheie Eye Institute at Penn Medicine, and lead author of the study.

Temporary improvement

In a second key trial, conducted by researchers at the University College (UCL) Institute of Ophthalmology, 12 UK patients with RPE65-related LCA were given a single gene therapy treatment and followed up for three years. Six of the participants in the study showed a modest improvement in retinal sensitivity for up to three years, peaking between 6–12 months. But again, the effect lessened or was lost by the three-year mark. But again, the effect lessened or was lost by the three-year mark.

The UK team also ran a parallel study in dogs, which showed that the treatment was effective and persisted much longer than in humans – a detail which, say the group, is due to the human visual system requiring more of the RPE65 protein.

Lead researcher and Professor of Human Molecular Genetics at UCL, Professor Robin Ali, said: “We have concluded that the demand for RPE65 is not fully met with the current generation of vector, expressing higher levels of RPE65 is likely to provide greater benefit and protection against progressive degeneration.”

In an accompanying editorial piece in the same edition of the NEJM, Professor Alan Wright of the University of Edinburgh comments that “human disease may necessitate more efficient RPE65 delivery”.

The UCL group has confirmed that it is working to this end and has since developed a more powerful viral vector for delivery of the gene. The group aims to test the efficacy of the new vector in a second clinical trial, funded by the Medical Research Council.

Image credit: Häggström, Mikael