Clinical trial of gene therapy Leber’s congenital amaurosis: new phase includes higher dose and inclusion of children.
1 st July 2009
Researchers at UCL Institute of Ophthalmology and Moorfields Eye Hospital have begun the next step in its Phase 1 / 2 dose escalation clinical trial to treat a form of Leber’s Congenital Amaurosis caused by defects in the gene encoding the RPE65 protein. Leber’s Congenital Amaurosis, or LCA, is an inherited disease that typically results in blindness.
Researchers have received approval of the regulatory bodies to include younger LCA patients and to treat patients with higher doses of an adeno-associated virus (AAV) vector containing the RPE65 gene.
“We are very pleased to be able to include younger children, who have more viable retina, and to use a higher dose, which increases the probability of a durable response,” stated Professor Robin Ali, University College of London Institute of Ophthalmology and Moorfields Eye Hospital, who is leading the study. “We believe this protocol optimizes risk/benefit for subjects and will further improve the quality of data acquired.”
The higher dose of vector has been administered by subretinal injection at Moorfields Eye Hospital to a patient referred for inclusion in the trial by Dr Ingeborgh van den Born of The Rotterdam Eye Hospital in The Netherlands.
The deterioration in visual function experienced by individuals with LCA results from a progressive retinal degeneration compounded by amblyopia caused by stimulus deprivation during early childhood. For these reasons the benefit of gene delivery therapy is expected to be greatest when applied at an early stage in the condition.
The revised protocol was reviewed and approved by the Gene Therapy Advisory Committee, the Medicines and Healthcare Products Regulatory Agency, and local ethics committees. Targeted Genetics’ LCA program was initiated in 2005 when Targeted Genetics entered into a collaboration agreement to develop, manufacture and commercialize an AAV-RPE65 product candidate with University College London.
Results from the first stage of this open label, single center, Phase 1/2 clinical study were reported in April 2008 in three young adults between the ages of 23 and 17 years of age with early-onset severe retinal dystrophy. Data demonstrated that administration improved visual function as measured by visual field tests and improvement in subjective tests of visual mobility in one patient. The study resulted in no serious adverse events and findings supported further clinical studies. The study results were also published in the May 2008 issue of the New England Journal of Medicine. Completion of the current phase of the trial is anticipated in the second half of 2010.
The primary endpoint of this study is to determine whether AAV vector- mediated gene delivery to the retina is safe, and the secondary endpoint is to determine whether efficacy can be demonstrated in humans. Targeted Genetics, a leader in the development and manufacture of AAV-based product candidates, manufactured the vector that is being used in this trial.
About Leber’s Congenital Amaurosis
Mutations in a number of genes, one of which is RPE65, disrupt the retinoid cycle that underlies human vision and cause a congenital retinopathy known as Leber’s Congenital Amaurosis (LCA). LCA is a complex retinal disease in which visual loss is caused by a combination of dysfunction and degeneration of retinal photoreceptors. LCA is an inherited retinal degenerative disease characterized by severe impairment of vision from birth and total blindness by the third decade of life. There is no treatment currently available for LCA.
About UCL Institute of Ophthalmology and Moorfields Eye Hospital NIHR Biomedical Research Centre
The Centre was established in April 2007, funded by the Department of Health through the National Institute for Health Research (NIHR). It is one of 12 NHS-university partnerships that have been awarded Biomedical Research Centre status, following an international peer reviewed competition based on an outstanding international reputation for medical research and expertise, and experience of translating that research into the clinical setting.
About UCL Institute of Ophthalmology
UCL Institute of Ophthalmology is one of a number of specialized research centers linked to UCL (University College London) and is, together with Moorfields Eye Hospital, one of the leading centers for eye research. The Institute scored 5*A (the highest possible rating) in the last Research Assessment Exercise and is committed to a multi-disciplinary research portfolio that furthers an understanding of the eye and visual system, linked with clinical investigations targeted to specific problems in the prevention and treatment of eye disease. The combination of the Institute’s research resource with the resources of Moorfields Eye Hospital, which has the largest ophthalmic patient population in the Western World, opens the way for advances at the forefront of vision research.
About The Rotterdam Eye Hospital
The Rotterdam Eye Hospital opened in 1874 and is the only hospital in the Netherlands specialized in eye health care. It receives tertiary referral cases from throughout the rest of The Netherlands.
About Targeted Genetics Corporation
Targeted Genetics Corporation is a biotechnology company committed to the development of innovative therapies for the prevention and treatment of diseases with significant unmet medical need. A key area of focus for Targeted Genetics is applying its proprietary Adeno-Associated Virus (AAV) technology platform to deliver genetic constructs to increase gene function or silence gene function. Targeted Genetics' lead product development efforts target ocular and neurological indications, two therapeutic areas where AAV delivery may have competitive advantages over other therapeutic modalities. To learn more about Targeted Genetics, visit its website at www.targetedgenetics.com.
Results of World's first Gene Therapy for inherited blindness show sight improvement
27th April 2008
UK researchers from the UCL Institute of Ophthalmology and Moorfields Eye Hospital NIHR Biomedical Research Centre have announced results from the world’s first clinical trial to test a revolutionary gene therapy treatment for a type of inherited blindness. The results, published today in the New England Journal of Medicine, show that the experimental treatment is safe and can improve sight. The findings are a landmark for gene therapy technology and could have a significant impact on future treatments for eye disease.
The trial, conducted in the NIHR Biomedical Research Centre which received additional funding from the Department of Health, represented a world first when it began in February 2007. It involves young patients with a condition called Leber’s congenital amaurosis (LCA), a rare inherited eye disease caused by an abnormality in a gene called RPE65. The condition appears at birth or in the first few months of life and causes progressive deterioration and loss of vision. There are currently no effective treatments available. The trial’s purpose was firstly to find out whether gene therapy for retinal disease is safe, and secondly to find out if it can benefit vision in young adults who already have advanced retinal disease.
Crucially, the experimental treatment was found to cause no side effects in this trial. Following the treatment, the three patients involved underwent a series of tests designed to establish the effects of the therapy on vision. They all achieved levels of vision at least equivalent to before the operation, but one patient (Steven Howarth, 18) benefited from significantly improved night vision. This was demonstrated by his ability to negotiate a specially constructed simulation of a night-time street scene. Before the operation he completed the task slowly and made several mistakes, but following the surgery he was able to navigate quickly and without mistakes. (Video available for media release – please see Notes to Editors.)
The researchers believe the operation’s success for this particular patient could be because his disease had not progressed to the same extent as the others. The other two patients may also still benefit from the new treatment in the future, but it will be some time before this becomes apparent. The team have already begun to trial the technique in younger patients, where they hope to achieve even better results.
The team conducting the trial is led by Professor Robin Ali and includes eye surgeon Mr James Bainbridge and retinal specialist Professor Tony Moore. The technique used in the trial involved inserting healthy copies of the missing RPE65 gene into the cells of the retina to help them to function normally. This involved an operation which delivered the normal genes to the retina, using a harmless virus or ‘vector’ to carry the gene into the cells – the vector was manufactured by US company Targeted Genetics.
Commenting on the findings, Professor Ali said: “Showing for the first time that gene therapy can work in patients with eye disease is a very significant milestone. This trial establishes proof of principle of gene therapy for inherited retinal disease and paves the way for the development of gene therapy approaches for a broad range of eye disorders.”
Explaining the technique, Mr James Bainbridge, who leads the surgical team, said: "We developed surgical techniques to enable access to the cells beneath the retinas of patients, using a very fine needle to deliver the modified virus in a controlled retinal detachment that resolves as the vector is absorbed. It is tremendously exciting to see that this technique is safe in an extremely fragile tissue and can improve vision in a condition previously considered wholly untreatable."
Professor Moore said: “It is very encouraging to see that this treatment can work, even in young adults who have severely advanced disease. We anticipate an even better outcome in the younger patients we are now beginning to involve as the trial proceeds, as we will be treating the disease in the early stages of its development.”
Professor Ali added: “These results give us great confidence that this technique is safe and can bring real benefit to patients with impaired vision. While we’re very excited about the improvement in Steven’s vision, it’s important to emphasise that gene therapy is still an experimental treatment not yet generally available to patients. The technique will be tested in other patients with LCA and we also hope to begin trials for other forms of retinal disease in the future.”
Further information for patients, including FAQs can be found here.
A special Moorfields Eye Hospital Helpline number has also been set up for patients seeking further information. This is +44 (0)20 7566 2645.
Moorfields Eye Hospital
British Retinitis Pigmentosa Society
This page last modified
18 December, 2012