GENE THERAPY

Recent reports on the long-term follow-up of a small number of patients treated with RPE-65 replacement gene therapy suggest that the effects may be transient in nature.

The clinical trial research reports, published on 3 May 2015 by Jacobson et al (doi: 10.1056/NEJMoa1412965) at the Scheie Eye Institute, Department of Ophthalmology, University of Pennsylvania, US, and Bainbridge et al (doi:10.1056/NEJMoa1414221) at the Institute of Ophthalmology, University College London, had focused on the treatment of Leber’s congenital amaurosis (LCA), a group of early-onset inherited retinal dystrophies.

The formal publication of the long-term follow-up results should not come as a surprise, however, especially given the numerous reports at conferences and in blogs, including previous journal publications, on diminished retinal sensitivities in a number of the LCA-treated patients.

LCA is one of the most clinically severe retinal degenerations, on occasion causing near total blindness in infancy. While the disorder may result from mutations in any one of 19 different genes, a large proportion of the research to date has focused on the retinal pigment epithelium-65 gene (RPE-65), responsible for up to 10 per cent of recessive LCA cases.

INTENSE RESEARCH

The disorder has been the subject of intense medical research over the last 15 years, and in 2008 three independent clinical trials successfully delivered a gene encoding RPE-65 into the retina of patients with the disease.

In healthy individuals the RPE-65 gene makes a critically important protein involved in the biochemical visual transduction cascade. When RPE-65 is missing this key component of visual transduction is lost, causing photoreceptor cells in the retina to progressively degenerate over time. In each clinical trial, patients received a single subretinal administration of an AAV vector containing the RPE-65 gene followed by detailed and regular patient monitoring in follow-up clinical visits.

In the six-year follow-up from Jacobson and colleagues in the US, researchers reported on three patients. The first patient had a visual response at six months with enhanced visual sensitivity increasing until year three, where sensitivity reached its maximal peak and then diminished.

The second patient also had a visual response at six months, with sensitivity peaking between years one and three and diminishing thereafter. Finally, in patient number three, an increase of three log units was recorded in visual sensitivity, peaking one year after treatment, followed by a decline in visual sensitivity.

Similar data was presented by the UK-led study which reported results on 12 participants, four of whom received a lower dose of 1X1011 AAV vector genomes, while eight individuals received a higher dose of 1X1012. Improvements in retinal sensitivity were seen in six participants for a period of up to three years, peaking at six to 12 months after treatment and then, similar to the US data, declining visual sensitivity in subsequent years.

PERSPECTIVE REQUIRED

In summarising the long-term follow-up data, Bainbridge and colleagues described the efficacy outcomes as largely descriptive in nature, noting improvements in dark-adapted perimetry and micro-perimetry in approximately half the patients assessed.

Despite the disappointment, a healthy dose of perspective is required, most especially in recognising that:

1) The studies cover a very small number of patients

2) A suggestive dose response effect may be apparent from some of the UK data, which may be built upon in future studies

3) Considerable improvements have been made in manufacturing, vector biology, formulation, dosing and transgene expression since the original single injection administrations were made in 2008

4) Early results from other clinical studies support a continued level of visual sensitivity in LCA patients

5) A transient treatment effect over no effect is clearly desirable (and not unfamiliar for most other medical treatments).

While it is imperative that the field is guided by the science, it is equally critical that context and history are not absented from our assessment and that analysis of follow-up studies should clearly acknowledge that small incremental steps, in the long run, can readily match or exceed dramatic leaps. If gene therapy has taught us anything, it is patience.