World’s first gene therapy for inherited blindness

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 27 April 2008 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 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.

The team conducting the trial is led by Professor Robin Ali and includes eye surgeon 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.

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 those 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.

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 team have already begun to trial the technique in younger patients, where they hope to achieve even better results.

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.”

US, Japan set up alliance for pharmacogenomics

United States and Japanese scientists have established a partnership creating a Global Alliance for Pharmacogenomics. The initiative aims to identify genetic factors that contribute to individual responses to medicines, including rare and dangerous side effects. The results of such work will eventually help doctors optimise the safety and effectiveness of drugs for each patient. The agreement was signed by the US National Institutes of Health (NIH) and the Center for Genomic Medicine in Japan.

US scientists joining the alliance are members of the NIH Pharmacogenetics Research Network, a consortium of research groups that study how genetic factors influence the way drugs work in and are handled by the body.

Japanese scientists in the alliance represent the newly created Center for Genomic Medicine, a component of the RIKEN Yokohama Institute that conducts high-throughput analyses of human genes involved in diseases and drug responses.

“By bringing together our resources, we will advance the understanding of how changes in DNA affect our responses to medicines. Thus we can begin to realise the promise of personalised medicine,” said Yusuke Nakamura, MD, PhD, director of the Center for Genomic Medicine at RIKEN.

“We expect this international agreement to speed scientific discovery and the translation of results into improved treatments for cancer, heart disease and other serious conditions,” said NIH Director Elias A. Zerhouni, MD. “Ultimately, physicians worldwide will be able to tailor the treatment of each patient - - one of the great frontiers of health care today.”

Some people withstand stress better than others

Inherited variations in the amount of an innate anxiety-reducing molecule help explain why some people can withstand stress better than others, according to a new study led by researchers at the US National Institute on Alcohol Abuse and Alcoholism (NIAAA).

Scientists led by David Goldman, MD, chief of the NIAAA Laboratory of Neurogenetics, identified gene variants that affect the expression of a signaling molecule called neuropeptide Y (NPY). Found in brain and many other tissues, NPY regulates diverse functions, including appetite, weight, and emotional responses.

"NPY is induced by stress and its release reduces anxiety," said Dr. Goldman. "Previous studies have shown that genetic factors play an important role in mood and anxiety disorders. In this study, we sought to determine if genetic variants of NPY might contribute to the maladaptive stress responses that often underlie these disorders."

The report was published recently online in Nature.

The researchers evaluated the NPY gene variants' effects on brain responses to stress and emotion. Using functional brain imaging, they found that individuals with the variant that yielded the lowest level of NPY reacted with heightened emotionality to images of threatening facial expressions. "Metabolic activity in brain regions involved in emotional processing increased when these individuals were presented with the threatening images," explained Dr Goldman.

The researchers conclude that this and other converging findings are consistent with NPY’s role as an anxietyreducing peptide and help explain inter-individual variation in resiliency to stress.

Six new clues to type 2 diabetes

An international team of scientists has identified six more genetic variants involved in type 2 diabetes, boosting to 16 the total number of genetic risk factors associated with increased risk of the disease. None of the genetic variants uncovered by the new study had previously been suspected of playing a role in type 2 diabetes.

Intriguingly, the new variant most strongly associated with type 2 diabetes also was recently implicated in a very different condition: prostate cancer.

The analysis published recently in Nature Genetics combined genetic data from more than 70,000 people. The work was carried out through the collaborative efforts of more than 90 researchers at more than 40 centers in Europe and North America.

“None of the genes we have found was previously on the radar screen of diabetes researchers,” said Mark McCarthy, MD, of the University of Oxford, one of the paper's senior authors, in England. “Each of these genes, therefore, provides new clues to the processes that go wrong when diabetes develops, and each provides an opportunity for the generation of new approaches for treating or preventing this condition.”

David Altshuler, MD, PhD, of Massachusetts General Hospital in Boston and the Broad Institute of Massachusetts Institute of Technology and Harvard in Cambridge, Massachusetts said: “By combining information from the large number of genes now implicated in diabetes risk, it may be possible to use genetic tools to identify people at unusually high or low risk of diabetes. However, until we know how to use this information to prompt beneficial changes in people's treatment or lifestyle, widespread genetic testing would be premature.”

Type 2 diabetes affects more than 200 million people worldwide.

The director of the US National Human Genome Research Institute, Francis S. Collins, MD, PhD, who is a coauthor of the study, said: “These new variants, along with other recent genetic findings, provide a window into disease causation that may be our best hope for the next generation of therapeutics. By pinpointing particular pathways involved in diabetes risk, these discoveries can empower new approaches to understanding environmental influences and to the development of new, more precisely targeted drugs.”

Patent controversy end in sight

In Europe, an end to the long running controversy over patenting genes for genetic tests appears in sight following the launch in April of new guidelines drafted by leading European experts. Over the past 4 years, geneticists from the European Society of Human Genetics (ESHG) and EuroGentest have consulted with key authorities on patenting and key stakeholders in the field of genetic testing. Published in the European Journal of Human Genetics, the working party's main conclusion is that patents should not be granted for genes or DNA sequences, but only for technological inventions that facilitate genetic testing . These recommendations will now be taken forward to the European Patent Office, European Parliament and the European Commission, to stimulate their incorporation into existing patent legislation.

Professor Gert Matthijs of the Catholic University of Leuven chaired the group and believes a major breakthrough has been made: “ESHG has a well respected history of researching and issuing recommendations on different aspects of genetic testing. As soon as the first monopolies on genetic tests started appearing, we realised patenting had become a major issue. This new proposal aims to reconcile what until now have appeared to be conflicting interests of patent owners, commercial companies, health authorities, policy makers, and geneticists with the ultimate goal of ensuring that patients retain access to the latest technological advances.”

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