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Gene and Cell Therapy Group

Developing gene and cell therapy for sight loss by translating basic research into new treatments


Research Highlights 

Research reveals new understanding into what happens when new photoreceptors are transplanted into an adult retina.

4 October 2016


Material Transfer Nat Comms Cover Art Small

Today in the journal Nature Communications, we and the group of Professor Marius Ader, Centre for Regenerative Therapies, Dresden, Germany, have published independent studies both showing that a new and previously unknown mechanism of interaction between transplanted photoreceptors (i.e. donor cells) and the photoreceptors of the recipient retina plays a major role in the rescue of visual function.

Previous Understanding

In some progressive retinal conditions, like retinitis pigmentosa or macular dystrophy, photoreceptors (the light-sensing cells in the eye) degenerate. Over time, a patient’s vision will decline as the photoreceptors lose the ability to respond to light. New, healthy photoreceptors transplanted into a degenerating retina might be used to replace lost cells and improve declining vision.

In previously published research, normal healthy photoreceptors carrying a genetic tag, which is fluorescent and can be used to trace donor cells, have been transplanted into the eyes of adult mice. Following transplantation, numerous fluorescent photoreceptor cells correctly positioned in the recipient retina have been observed. In addition to the fluorescent tag, these cells contain all of the proteins required to function, and that are normally present in the donor cells but are absent from the defective recipient photoreceptor cells. Tests of cell and retinal function, as well as mouse behaviour, suggest that these cells behave as you would expect a normal healthy photoreceptor to and can rescue some aspects of vision.

New Insights

Until now it has been understood that this rescue effect was the result of the donor cells migrating into and becoming integrated within the recipient retina, replacing the degenerating cells and functioning as a normal, healthy part of the retina. While we confirm that integration does happen, our new findings show that the rescue may largely be due to a previously undescribed process, which we have termed material transfer; whereby ‘packages' of genetic and cellular molecules, such as RNA and/or protein(s) from donor cells are released and then taken up by the degenerating photoreceptors. This process appears to provide degenerating photoreceptors with sufficient protein(s) (or instructions to produce these proteins) to drive a restoration of visual function.

There have been past reports of the transfer of material in other types of cells, particularly stem cells. Usually, this involves donor and recipient cells fusing together and sharing their genetic and cellular molecules, including their DNA. Photoreceptors show none of the typical characteristics associated with such donor-recipient cell fusions. Also, photoreceptors do not appear to uptake these genetic and cellular molecules if they are merely floating around the surrounding (extracellular) environment of the retina.

From these data, we conclude that we have identified an exciting, new and previously unreported physical method of communication between donor and recipient photoreceptors. So far material transfer has only been shown in mice, and further work will need to be carried out to determine if the same mechanism occurs between the photoreceptors of other species, including humans. However, these findings do highlight that cell transplantation into the retina is much more complex than previously thought and provides an important new understanding that will help inform the development of techniques to optimise integration of donor photoreceptors.

Future Implications

Should we be able to determine the underlying mechanism, then material transfer may represent an exciting new therapeutic approach. In earlier stages of degeneration, material transfer may offer a way to deliver functional biological molecules into degenerating photoreceptors, particularly for those where the underlying cause is unknown, to regenerate them and rescue visual function.

More immediately, however, cell transplantation is likely to be of benefit to those patients who have few or no photoreceptors left, commonly called end-stage disease. In this situation, material transfer cannot occur (as there are no photoreceptors left to receive donor material), but recent findings from our group and others, show that donor cells transplanted into these eyes appear to form new connections with the remaining retina and can drive visual function. With further development, transplantation of stem-cell derived photoreceptors offers a promising approach for the treatment of advanced retinal degeneration.

Latest News

Retina Day 2015 Wins UCL Award for Communications Excellence

30 June 2016

Retina Day Award

The Communication Excellence Awards were heldby the UCL Faculty of Brain Sciences on 29th June 2016. By demonstrating best practice and giving practical advice, the event aimed to empower faculty staff to use new and innovative communication methods to connect with audiences.

The event finished with an awards ceremony to recognise and celebrate the work of faculty staff who have demonstrated these new and innovative communication. 

Retina Day 2015, a free one-day event where patients with inherited retinal diseases could meet with clinicians, charities and researchers and learn more about ongoing research methods, won the prize for public engagement. 

Clinical Trial Updates

RPE65 Gene Therapy Trial Shows Benefit for up to Three Years After Treatment

5 May 2015

Potential benefit for people with Leber Congenital Amaurosis (LCA) Type 2 demonstrated


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.


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

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

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.


Video of trial participant with improved night vision as a result of gene therapy


Key Media Coverage

BBC

Link to article

New NH Voice

Link to article

MedPageToday

Link to article

Science aaas

Link to article


Data

  • 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


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