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UCL RPE65 Gene Therapy Trial Shows Benefit in People with Leber Congenital Amaurosis Type 2 for up to Three Years After Treatment

Andi MSkilton5 May 2015

NEJM 2015 Cover

We are delighted to be able to announce that yesterday, Monday 4th May, the long-term results of our RPE65 gene therapy trial for Leber Congenital Amaurosis Type 2 (LCA2) were published in the prestigious New England Journal of Medicine.

Begun in 2007, this was the world’s first-in-human trial of gene therapy to treat an inherited form of blindness. Twelve patients were enrolled in the trial over the course of six years and followed up over a three year period to assess the long-term safety and benefit of treatment with gene therapy in this Phase I/II clinical trial.

A number of patients enrolled in the trial experienced gains in night vision for a period of two to three years with greatest improvements seen in the first 6 to 12 months after treatment. This is consistent with the published results and interim findings of other studies of RPE65 gene therapy.

This study confirms our preliminary findings (published in NEJM, 2008) that gene therapy can improve night vision, providing further evidence of benefit in inherited blindness.
Professor James Bainbridge, lead clinician for the trial

Our latest results provide confirmation of efficacy but the data, together with results of a parallel study in dogs, indicate that the demand for RPE65 is not fully met with the current generation of vectors. We have concluded that early intervention using a more potent vector, expressing higher levels of RPE65 is likely to provide greater benefit and protection against progressive degeneration.
Professor Robin Ali, lead for the research group

The group has now developed a new, more powerful gene therapy vector and is aiming to test this in a second clinical trial funded by The UK Medical Research Council.


Links to further information:

  • The full results from this study can be found in the NEJM:
  1. Bainbridge, JWB, Mehat MS, Sundaram V, et al. Long-term Effect of Gene Therapy on Leber Congenital Amaurosis. New England Journal of Medicine. 2015;10.1056/NEJMoa1414221
  2. Bainbridge, JWB, Smith AJ, Barker SS, et al. Effect of Gene Therapy on Visual Function in Leber’s Congenital Amaurosis. New England Journal of Medicine. 2008; 358: 2231-9

A New Viral Vector with the Potential to Improve Eye Gene Therapy

PrateekBuch28 June 2013


 

A new type of viral vector has been developed using an innovative research technique, by researchers at the University of California, Berkeley. The new virus shows great promise as a tool for delivering genes to the eye, because it has the potential to deliver genes to the retina when injected into the gel of the eye (called the vitreous), whereas current eye gene therapy vectors have to be injected under the retina using a more invasive approach in order to reach the target cells. The new vector was reported in the media as a ‘wonder jab’ that could ‘cure blindness in 15 minutes,’ but a closer examination of its effectiveness shows there is a long way to go before such a vector could be effective in the clinic.

While the new vector was shown to deliver genes very efficiently to the light sensitive photoreceptor cells and supporting RPE cells in the mouse eye when injected into the vitreous gel, experiments in non-human primates suggest that there might be further barriers to overcome before the new vector can be considered for use in clinical trials.

The new virus is based on the same adeno-associated virus (AAV) that we are using in our clinical trial of gene therapy for Leber congenital amaurosis (LCA) – in this study David Schaffer and colleagues took the most commonly-used type of AAV and altered it in a number of ways. They were looking to develop a virus that would deliver genes to the light sensitive photoreceptor cells at the back of the eye after an injection into the vitreous jelly at the front of the eye.

The approach they took was to introduce variation into the protein coat of AAV – which is what determines the type of cell the virus delivers genes to, and how efficiently it does so. They did this by introducing a random protein sequence into the virus coat, or by shuffling protein sequences with other types of AAV. The investigators injected these randomly-altered AAV particles, and a week later harvested cells that the vector had successfully delivered DNA to (which Dr. Schaffer’s team could identify as the gene being delivered was for green fluorescent protein, GFP). This allowed the team to see which of the new variants could deliver genes to cells in the eye – by repeating the process, the team identified the most efficient AAV variant. This process of directed evolution – selecting randomly-altered viruses for their ability to deliver genes to cells in the retina – produced dozens of new AAVs capable of targeting photoreceptor cells. Dr. Schaffer’s team used one variant for further testing in models of sight loss.

The new AAV – called 7m8 –efficiently delivered DNA to all cell types in the mouse retina when injected into the vitreous gel. When engineered to deliver therapeutic genes, it also restored vision in mouse models of retinoschisis and of LCA – inherited conditions caused by mutations in the Rsh1 and RPE65 genes respectively.

Dr. Schaffer’s team then used the new 7m8 vector in monkey eyes, to test how well it could deliver genes to a non-human primate retina following an injection into the front of the eye. Here, they saw that whilst the new virus could deliver the GFP gene to some photoreceptor cells, the vector was not nearly as efficient in monkey as in mouse. There was patchy gene delivery, suggesting that photoreceptor cells in the monkey eye, which has many features in common with the human eye, are harder to reach following injection into the vitreous gel – even when using the new type of vector.

The aim of this research was to develop a new type of AAV – using directed evolution to generate lots of variations and selecting the best one – that could deliver genes to the retina using a less invasive approach that would be faster and less risky than the sub-retinal surgery that is currently used. Dr Schaffer’s vector appears to be the most efficient way of delivering genes to the mouse retina when injected into the vitreous, an approach that has been tried with less efficiency by other labs in previous studies. If this new vector can be further modified to be efficient in larger eyes that resemble the human eye, then it has promise for clinical application – but it is far from the ‘wonder jab’ that it was reported to be by some in the media. It is an improved tool to deliver genes, but in itself the new vector can’t be considered a treatment. We’ll need to watch this space, as further research is required to see if this tool can lead to more effective treatments.

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