Gene and Cell Therapy Group
Developing gene and cell therapy for sight loss by translating basic research into new treatments
6 Million Euros Awarded For Batten Disease Research and Gene Therapy Development
9 February 2016
EU Horizon 2020 award to UCL
BATCure, a consortium of leading scientific research groups and companies, in which University College London is a key partner, has been awarded an EU Horizon 2020 grant of approximately 6 million Euros (Grant Agreement n. 666918). BATCure aims to investigate the natural history of Batten disease, elucidate the function of key proteins, and determine disease mechanisms, as well as develop new therapies for three forms of the disease.
Batten disease is one of approximately 50 lysosomal storage disorders (LSD), in which genetic mutations disrupt the cells ability to recycle waste. Children and young adults with Batten disease suffer progressive neurological impairment, which includes: seizures, visual impairment or blindness, personality and behaviour changes, dementia, loss of motor skills and loss of the ability to walk, talk and communicate. Until more strides are made in research, treatments and cures, Batten disease results in an early death.
Prof Robin Ali, Prof Rob Harvey, Dr Jason Rihel, Dr Ahad Rahim and Dr Sara Mole at UCL will support BATCure efforts through their expertise in developing gene therapy, the use of zebrafish for disease modelling, and the study of the underlying disease mechanism.
One of the aims of the BATCure project is the screening of thousands of compounds to identify those with therapeutic potential. Another aim is to develop a gene therapy that prevents the loss of vision that occurs with Batten disease, building on previous success at treating other types of visual failure.
The bringing together of diverse experts into this consortium is very important to the overall success of BATCure. To quote the Batten Disease Family Association, another partner in this project: "Together we WILL make a difference".
The BATCure consortium is coordinated by Dr Sara Mole, University College London, United Kingdom.
Further information: Sara Mole PhD at UCL E-mail: firstname.lastname@example.org
Clinical Trial Updates
Potential benefit for people with Leber Congenital Amaurosis (LCA) Type 2 demonstrated
5 May 2015
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.
Video of trial participant with improved night vision as a result of gene therapy
Key Media Coverage
- The full results from this study can be found in the NEJM:
- 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
- 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
Today a paper published in Nature Communication from the Gene and Cell Therapy Group at the UCL Institute of Ophthalmology has shed light on why, until now, it has not been possible to effectively restore vision in rd1 mice – the world’s major model for retinitis pigmentosa (RP).
The rd1 mouse is a model of retinitis pigmentosa caused by defects in the PDE6B gene. The model was first described back in 1924 and is the oldest and most widely used model of retinal degeneration in the world. When light enters the eye and hits the rod cells (a type of photoreceptor – the light sensing cells of the eye), PDE6B is required to help turn this stimulus into electrical signals that can be understood by the brain and translated into an image. In rd1 mice, the defect in PDE6B leads to a rapid degeneration of the retina within the first four weeks of life, which is characterised by the death of rod cells and a complete loss of vision.
Numerous attempts have been made to preserve and restore function to rod cells in rd1 mice in the hope that an approach towards developing a treatment for RP patients could be identified. Past attempts to restore vision in these mice using gene therapy (where the normal gene is put back into the effected cells by means of a harmless virus known as a vector) has had limited success. In this model retinal degeneration happens appears to happen so quickly that there aren’t enough, if any, healthy rod cells left to treat.
In other animal models (such as dogs) where progression of retinal degeneration caused by defects in PDE6B is somewhat slower, a restoration of vision has been possible and has led to the conclusion that in rd1 mice the degeneration happens too quickly to allow for a window of opportunity to treat. This has confused the issue around whether a gene therapy approach to treating this form of RP in people could be effective.
Recent work from our group in other more severe forms of retinal degeneration, specifically that of Leber Congenital Amaurosis Type 4 (LCA4 [caused by a defect in the gene AIPL1]), however, has cast doubts on this explanation of previous findings in rd1 mice. Using an AIPL1 gene therapy we have been able to rescue vision loss in an LCA4 mouse model, which experiences a complete loss of vision in the first three weeks of life; faster than in rd1 mice.
Seen at 13 weeks of age, PDE6B gene therapy given to rd1 mice in the first month of life preserves rod cells in the retina (Panel 1: ‘normal’ mouse retina – untreated; Panel 2: rd1 mouse retina – untreated; Panel 3: rd1 mouse retina – treated with PDE6B gene therapy)
Using the latest in gene therapy vector technology, the team has successfully created a more efficient and rapid acting PDE6B gene therapy then had previously been possible to address the short window of opportunity to treat. This approach was able to not only preserve the rod cells but restore their function as well (see picture above). However, despite this, the team found that these mice were still not responding to a light stimulus suggesting that somewhere in the pathway that carries signals from the rod cells to the brain there must be a second and currently unreported defect blocking the signal.
An analysis of the genetic code of rd1 mice has indeed identified a defect in a gene called GPR179 that had not previously been found in the rd1 mouse strain, but has been previously reported in other mouse strains. This defect affects the retinal bipolar cells – specialised cells that help transmit signals from the photoreceptors of the eye to the nerve cells that carry signals up to the brain. This defect is likely to be found in most of the rd1 mice around the world today and could have been present in this mouse strain for as long as 65 years. Through a process of selective breeding of different mouse models the team have successfully removed the GPR179 defect from rd1 mice and been able to demonstrate that PDE6B gene therapy does indeed lead to the preservation and restoration of rod cell function and that these mice can still sense and respond to light a year after treatment.
This study provides strong evidence to support the potential of gene therapy for RP caused by defects in the PDE6B gene and future studies will be required to assess further the potential. This study by no means suggests that previous work in rd1 mice is not valid but instead highlights the need, where appropriate, to reassess past findings and ensure that future work considers if the presence of a GPR179 defect may be a contributing factor to the results.
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