New Gene Discovery Provides Clue to Brain, Eye and Lymphatic Development


Posted on 9th February 2012 by Pacific ClearVision Institute in General

Researchers have found a new gene that, when mutated, can lead to lymphoedema (swollen limbs) as part of a rare disorder that can also cause problems with eye and brain development. This is the fourth lymphoedema-related gene found by the same researchers in three years, and the first linked to the eyes and brain. They say it could lead to better diagnosis and treatment for lymphoedema, an area that has been poorly understood previously.

The new study has linked mutations in the gene KIF11 to Microcephaly-Lymphoedema-Chorioretinal Dyplasia (MLCRD), a very rare condition. Patients with this condition have a small head (microcephaly), lymphoedema (swollen limbs caused by problems with the lymphatic system) and eye problems called chorioretinopathy, which frequently result in night blindness. The lymphatic system is a crucial part of the body which is important for draining fluid and preventing swelling.

The study was led by a group at St George’s, University of London and published online in The American Journal of Human Genetics (26 January). The St George’s team worked closely with the Biomedical Research Centre at Guy’s and St Thomas’ NHS Foundation Trust and King’s College London, Moorfields Eye Hospital, and a group at the Université catholique de Louvain in Belgium.

The team carried out next generation sequencing of the human genome, initially in five patients with MLCRD recruited from the UK’s only specialist primary lymphoedema clinic, based at St George’s Hospital. A candidate gene was identified using this new technology, which was then confirmed by traditional sequencing in 24 further patients and their families.

Lead researcher Dr Pia Ostergaard said: “The small head and eye problems associated with MLCRD are present at birth and there are no treatments as yet. These findings will increase our understanding of MLCRD’s genetic cause and may help find a way to prevent it. Microcephaly is rare, but is associated with learning difficulties in children.”

The range and severity of symptoms varies greatly within MLCRD even among people with the same mutation and within the same family. The researchers believe there may be other contributing genetic or environmental factors that determine how people are affected. Further understanding of KIF11 and the protein it encodes, EG5, may shed light on the varying symptoms. EG5 is known to be important for the normal division of cells, but its role in the development of the brain, retina and lymphatic systems is not yet understood.

Dr Ostergaard said: “The really exciting thing here is that, by very careful examination and grouping of the patients in our specialist lymphoedema clinic, we have successfully identified four genes associated with lymphatic development in a very short space of time. This has already led to extensive work looking at the development and function of the lymphatic system, an area that has been overlooked for years and which scientists still know little about.”

Dr Ostergaard said that, in addition to the previous genes identified, this new finding may lead the way to better treatment of lymphoedema. Currently, swelling can be relieved by compression garments, bandaging or massage, but the increasing understanding of the condition should lead to drug treatment in the future.

She added: “The lymphatic system is not just important for draining fluid and preventing swelling. It is vital for the maintenance of the immune system and is linked to the spread of cancer, so continued focus of our research in this area could provide other scientists with the key to understand these other problems.”

The Pupils Are the Windows to the Mind


Posted on 9th February 2012 by Pacific ClearVision Institute in General |Retina

The eyes are the window into the soul — or at least the mind, according to a new paper published in Perspectives on Psychological Science, a journal of the Association for Psychological Science. Measuring the diameter of the pupil, the part of the eye that changes size to let in more light, can show what a person is paying attention to. Pupillometry, as it’s called, has been used in social psychology, clinical psychology, humans, animals, children, infants — and it should be used even more, the authors say.

The pupil is best known for changing size in reaction to light. In a dark room, your pupils open wide to let in more light; as soon as you step outside into the sunlight, the pupils shrink to pinpricks. This keeps the retina at the back of the eye from being overwhelmed by bright light. Something similar happens in response to psychological stimuli, says Bruno Laeng of the University of Oslo, who cowrote the paper with Sylvain Sirois of Université du Québec à Trois-Rivières and Gustaf Gredebäck of Uppsala University in Sweden. When someone sees something they want to pay closer attention to, the pupil enlarges. It’s not clear why this happens, Laeng says. “One idea is that, by essentially enlarging the field of the visual input, it’s beneficial to visual exploration,” he says.

However it works, psychological scientists can use the fact that people’s pupils widen when they see something they’re interested in.

Laeng has used pupil size to study people who had damage to the hippocampus, which usually causes very severe amnesia. Normally, if you show one of these patients a series of pictures, then take a short break, then show them another series of pictures, they don’t know which ones they’ve seen before and which ones are new. But Laeng measured patients’ pupils while they did this test and found that the patients did actually respond differently to the pictures they had seen before. “In a way, this is good news, because it shows that some of the brains of these patients, unknown to themselves, is actually capable of making the distinction,” he says.

Pupil measurement might also be useful for studying babies. Tiny infants can’t tell you what they’re paying attention to. “Developmental psychologists have used all kinds of methods to get this information without using language,” Laeng says. Seeing what babies are interested in can give clues to what they’re able to recognize — different shapes or sounds, for example. A researcher might show a child two images side by side and see which one they look at for longer. Measuring the size of a baby’s pupils could do the same without needing a comparison.

The technology already exists for measuring pupils — many modern psychology studies use eye-tracking technology, for example, to see what a subject is looking at, and Laeng and his coauthors hope to convince other psychological scientists to use this method.

Gene Therapy for Inherited Blindness Succeeds in Patients’ Other Eye


Posted on 9th February 2012 by Pacific ClearVision Institute in General |Retina

Gene therapy for congenital blindness has taken another step forward, as researchers further improved vision in three adult patients previously treated in one eye. After receiving the same treatment in their other eye, the patients became better able to see in dim light, and two were able to navigate obstacles in low-light situations. No adverse effects occurred.

Neither the first treatment nor the readministered treatment triggered an immune reaction that cancelled the benefits of the inserted genes, as has occurred in human trials of gene therapy for other diseases. The current research targeted Leber congenital amaurosis (LCA), a retinal disease that progresses to total blindness by adulthood.

Scientists from The Children’s Hospital of Philadelphia and from the Perelman School of Medicine at the University of Pennsylvania led the study, recently published in Science Translational Medicine.

“Patients have told us how their lives have changed since receiving gene therapy,” said study co-leader Jean Bennett, M.D., Ph.D., F.M. Kirby professor of Ophthalmology at Penn. “They are able to walk around at night, go shopping for groceries and recognize people’s faces — all things they couldn’t do before. At the same time, we were able to objectively measure improvements in light sensitivity, side vision and other visual functions.”

Other objective results came from brain signals seen in neuroimaging. When a dimly flickering checkerboard pattern flashed in front of a patient’s recently treated eye, an area in the brain responsible for vision lit up during functional magnetic resonance imaging (fMRI).”This finding is telling us that the brain is responding to the eye’s sensitivity to dim light,” said radiology researcher Manzar Ashtari, Ph.D., of The Children’s Hospital of Philadelphia, the study’s co-leader.

LCA is a group of hereditary retinal diseases in which a gene mutation impairs production of an enzyme essential to light receptors in the retina. The study team injected patients with a vector, a genetically engineered adeno-associated virus, which carried a normal version of a gene called RPE65 that is mutated in one form of LCA.

The researchers in the current study previously carried out a clinical trial of this gene therapy in 12 patients with LCA, four of them children aged 11 and younger when they were treated. Exercising caution, the researchers treated only one eye — the one with worse vision. This trial, reported in October of 2009, achieved sustained and notable results, with six subjects improving enough to no longer be classified as legally blind.

The Center for Cellular and Molecular Therapeutics (CCMT) at The Children’s Hospital of Philadelphia sponsored both the initial clinical trial and the current study, and manufactured the vector used to carry the corrective gene. Katherine A. High, M.D., a co-author of both studies, is the director of the CCMT, and a pioneering gene therapy researcher.

The research team’s experiments in animals had showed that readministering treatment in a second eye was safe and effective. While these results were encouraging, the researchers were concerned that readministering the vector in the untreated eye of the patients might stimulate an inflammatory response that could reduce the initial benefits in the untreated eye.

“Our concern was that the first treatment might cause a vaccine-like immune response that could prime the individual’s immune system to react against a repeat exposure,” said Bennett. Because the eye is “immune-privileged” — relatively isolated from the body’s immune system — such a response was considered less likely than in other parts of the body, but the idea needed to be tested in practice.

As in the first study, retina specialist Albert M. Maguire, M.D., a study co-author, injected the vector into the untreated eyes of the three subjects at The Children’s Hospital of Philadelphia. The patients had been treated one and a half to three years previously.

The researchers continued to follow the three patients for six months after readministration. They found the most significant improvements were in light sensitivity, such as the pupil’s response to light over a range of intensities. Two of the three subjects were able to navigate an obstacle course in dim light, as captured in videos that accompanied the published study.

There were no safety problems and no significant immune responses. There was even an unexpected benefit — the fMRI results showed improved brain responses not just in the newly injected eye, but in the first one as well, possibly because the eyes were better able to coordinate with each other in fixating on objects.

The researchers caution that follow-up studies must be done over a longer period and with additional subjects before they can definitively state that readministering gene therapy for retinal disease is safe in humans. However, said Bennett, the findings bode well for treating the second eye in the remaining patients from the first trial — including children, who may have better results because their retinas have not degenerated as much as those of the adults.

Furthermore, Bennett added, the research holds promise for using a similar gene therapy approach for other retinal diseases. Ashtari said that fMRI may play a future role in helping to predict patients more likely to benefit from gene therapy for retinal disease.