Medicine Man

In a clinical trial at The Children's Hospital of Philadelphia, researchers from The University of Pennsylvania have used gene therapy to safely restore vision in three young adults with a rare form of congenital blindness.

Although the patients have not achieved normal eyesight, the preliminary results set the stage for further studies of an innovative treatment for this and possibly other retinal diseases.

An international team led by The University of Pennsylvania, The Children's Hospital of Philadelphia, the Second University of Naples and the Telethon Institute of Genetics and Medicine (both in Italy), and several other American institutions reported their findings today in an online article in the New England Journal of Medicine.

"This is the first gene therapy trial for a nonlethal pediatric condition," said Albert M. Maguire, M.D., Associate Professor, Department of Ophthalmology, University of Pennsylvania School of Medicine and a physician at The Children's Hospital of Philadelphia. Maguire, together with his wife, Jean Bennett, M.D., Ph.D., Professor of Ophthalmology at Penn and Senior Investigator at the F.M. Kirby Center for Molecular Ophthalmology at Penn's Scheie Eye Institute, have been researching inherited retinal degenerations such as Leber congenital amaurosis (LCA), for 18 years. LCA is a group of inherited blinding diseases that damages light receptors in the retina. It usually begins stealing sight in early childhood and causes total blindness during a patient's twenties or thirties. Currently, there is no treatment for LCA.

"Patients' vision improved from detecting hand movements to reading lines on an eye chart," Maguire added. In 2001, Bennett and Maguire were part of a team which reported successfully reversing blindness using gene therapy on dogs affected by the same naturally occurring form of congenital blindness.

The current study is sponsored by the Center for Cellular and Molecular Therapeutics at The Children's Hospital of Philadelphia, directed by Katherine A. High, M.D. High, a study leader and an Investigator of the Howard Hughes Medical Institute, has been a pioneer in translational and clinical studies of gene therapy for genetic disease, and in 2005 initiated a collaboration with Bennett and her group to translate their exciting animal findings into a clinical study.

The scientists used a vector, a genetically engineered adeno-associated virus, to carry a normal version of the gene, called RPE65, that is mutated in one form of LCA. Three patients, ages 19, 26 and 26, received the gene therapy via a surgical procedure performed by Maguire between October 2007 and January 2008 at The Children's Hospital of Philadelphia, where the gene vector was manufactured at the hospital's Center for Cellular and Molecular Therapeutics (CCMT).

Starting two weeks after the injections, all three patients reported improved vision in the injected eye. "Standard vision tests showed significantly improved vision in the patients," said Alberto Auricchio, M.D., a study leader from the Telethon Institute of Genetics and Medicine and University of Naples Federico II. The researchers also reported that each injected eye became approximately three times more sensitive to light, and each was improved compared to the uninjected, previously better functioning eye.

The LCA gene therapy vector showed no signs of causing inflammation in the retina or other toxic side effects. One of the three patients had an adverse event, a hole in the retina that did not affect eyesight and may have been surgery-related, rather than related to biological effects of the therapeutic gene or the vector used to carry it.

The patients enrolled in the study to date were identified at the Department of Ophthalmology at the Second University of Naples, an institution with long-standing experience in collecting and studying patients with inherited retinal diseases, under the supervision of Francesca Simonelli, M.D.

Testing continued over a period of six months following the gene therapy vector administration. One patient was better able to navigate an obstacle course compared to before the injection. The patients also had less nystagmus, an involuntary movement of the eyes that is common in LCA. In the patient who experienced better vision even in the uninjected eye, the researchers suggest that the reduced nystagmus benefited both eyes.

"The current clinical trial will continue with more patients and with ongoing follow-up to monitor results," said Bennett. "We expect improvements to be more pronounced if treatment occurs in childhood, before the disease progresses."

"This result is important for the entire field of gene therapy," notes High, a past president of the American Society of Gene Therapy. "Gene transfer has been in clinical trials for over 15 years now, and although it has an excellent safety record, examples of therapeutic effect are still relatively few. The results in this study provide objective evidence of improvement in the ability to perceive light, and thus lay the groundwork for future studies in this and other retinal disorders," said High.

The pace of moving from pre-clinical discoveries into clinical trials has typically been slow in the field of gene therapy due to the breadth of expertise required, ranging from in-depth knowledge of the disorder to detailed understanding of vector design, manufacture, and pre-clinical evaluation. The complexities of regulatory oversight at both the federal and local levels also present challenges. Through the Center for Cellular and Molecular Therapeutics, The Children's Hospital of Philadelphia has developed concentrated expertise and substantial resources to facilitate the "bench to bedside" translation of gene therapy.

The scientists at the Clinical Vector Core at CCMT have over 30 years experience in the biopharmaceutical industry and in 2007 were awarded a National Institutes of Health contract for clinical grade vector production for trials throughout the United States, attesting to the quality of their vector manufacture. The CCMT's dedicated regulatory affairs support has specialized expertise in clinical gene therapy and coordinates trial approvals from multiple scientific and ethic review committees, manages the study activities at all clinical sites, and ensures compliance with international quality standards for conducting, monitoring, and reporting clinical trials.

The clinical trial was sponsored and primarily funded by the Center for Cellular and Molecular Therapeutics at The Children's Hospital of Philadelphia. Research support was received from The Department of Ophthalmology at the University of Pennsylvania, the F.M. Kirby Foundation, the Foundation Fighting Blindness, Research to Prevent Blindness, the Macula Vision Foundation, the Paul and Evanina Mackall Foundation Trust at the Scheie Eye Institute, the Rosanne H. Silbermann Foundation, the Italian Telethon Foundation, the Associazione Italiana Amaurosi Congenita di Leber, the National Center for Research Resources, the Howard Hughes Medical Institute, the National Eye Institute of the National Institutes of Health, private philanthropy, and an anonymous donor who is committed to advancing pediatric medicine through maximizing the potential of gene therapy.

http://www.chop.edu/ and http://www.uphs.upenn.edu/

Mothers born in India and Sri Lanka are three times more likely to suffer from extreme nausea and vomiting in pregnancy (hyperemesis gravidarum) than ethnic Norwegians.

This finding comes from the Norwegian Institute of Public Health's study of 900, 000 first-time pregnancies registered in the Medical Birth Registry of Norway over a forty year period.

Earlier studies reported that 90 percent of pregnant women experience some degree of nausea and vomiting, whereas 0.5 to 2 percent have hyperemesis gravidarum. Due to dehydration, loss of important electrolytes, malnutrition and weight loss, hyperemesis gravidarum could be life-threatening for mother and baby if left untreated. In the USA it is the commonest cause for hospitalisation during early pregnancy. The cause of hyperemesis gravidarum is unknown.

?e Vikanes, specialist in gynaecology and obstetrics at the institute's Division of Epidemiology, wanted to explore whether the mothers' country of birth affected the prevalence of hyperemesis gravidarum. Vikanes is primary author of the paper "Variations in prevalence of hyperemesis gravidarum by country of birth: A study of 900, 074 pregnancies in Norway, 1967-2005."

Vikanes and her colleagues collected data from the Medical Birth Registry of Norway, which since 1967 has recorded data on all pregnancies and pregnancy complications. 8, 300 cases of hyperemesis gravidarum were recorded out of 900, 000 pregnancies, giving an overall prevalence of 0.89 percent. Data on the mother's country of birth and education were recorded by Statistics Norway and linked to pregnancy information through the mother's unique personal identification number. Socio-demographic factors such as marital status, country of birth, education, age and number of foetuses in each pregnancy were also studied.

"This is one of the largest studies carried out on hyperemesis gravidarum. In contrast to earlier studies we tested the quality of the data and therefore have confidence in our findings" says Vikanes.

Mothers born in India and Sri Lanka had the highest prevalence of hyperemesis gravidarum, followed by those born in Africa (excluding North Africa) and Pakistan by 3.2 percent, 3.1 percent and 2.1 percent, respectively. Ethnic Norwegians, North Americans and Western Europeans had the lowest prevalence by 0.9 percent, 0.9 percent and 0.8 percent, respectively. A maternal age between 20-24 years old, being married, carrying a female foetus or more than one foetus were all socio-demographic characteristics associated with a higher prevalence of hyperemesis gravidarum.

"The difference in prevalence of hyperemesis gravidarum related to the mother's country of birth cannot be explained by differences in socio-demographic characteristics", says Vikanes. "We have to look for other explanations such as genetic factors, a change of diet or a history of infections. This topic needs further research to identify ways to prevent this life-threatening and distressing condition."

Vikanes A, Grjibovski AM, Vangen S and Magnus P. (2008) Variations in prevalence of hyperemesis gravidarum by country of birth: A study of 900, 074 pregnancies in Norway 1967-2005. Scandinavian Journal of Public Health 36: 135-142.

http://www.fhi.no/english

Minimally invasive heart bypass surgery using a DaVinci robot means a shorter hospital stay and faster recovery for patients, as well as fewer complications and a better chance that the new bypass vessels will stay open.

And, according to a University of Maryland study, robotic heart bypass surgery also makes good economic sense for hospitals. The study will be presented at the American Surgical Association on April 26, 2008.

Using a surgical robot increases the cost of each bypass case by about $8,000, according to Robert S. Poston, M.D., a cardiac surgeon formerly at the University of Maryland Medical Center who is the lead author of the study. He says those additional expenses, which are due to equipment and supplies, are offset by a shorter hospital stay, reduced need for transfusions and fewer post-surgical complications that would require a patient to be re-admitted to the hospital. Especially with high risk patients who have lung or kidney disease or other health problems, the researchers found that the minimally invasive, robotic approach saves costs.

"These findings are significant because payers are considering linking reimbursement for coronary artery bypass surgery to patient outcomes," says Stephen T. Bartlett, M.D., professor and chairman of the Department of Surgery at the University of Maryland School of Medicine and chief of surgery at the University of Maryland Medical Center.

"Our study shows that there are health benefits to patients from the minimally invasive approach, both in terms of a shorter recovery and also looking at the function of the bypass graft months after the surgery," adds Dr. Bartlett, who is one of the study's co-authors.

While the DaVinci surgical robot is in widespread use for prostate surgery, the University of Maryland Medical Center is among only a few hospitals nationwide, and was one of the first in the U.S., to use the robot to perform multiple vessel heart bypass surgery.

The researchers studied 100 consecutive patients who had minimally invasive coronary bypass surgery using a robot at the University of Maryland Medical Center. The technique requires no incisions except for a few small holes to insert instruments. These cases were compared to a matched group of 100 patients who had the traditional "open" bypass surgery with a sternotomy, a surgical incision through the sternum.

The average length of the hospital stay for the patients with the minimally invasive surgery was about four days compared to seven days for the traditional bypass operation; however the difference was even greater among patients considered to be at high risk. In that group, the average stay was five days with robotic surgery compared to 12 days with the traditional technique.

The complication rate for those who had the robotic bypass was also much lower, with 88 percent of patients free of complications after having the minimally invasive surgery compared to 66 percent of those with the "open" operation.

The patients in the study were followed up one year after their surgery. Using a CT angiography scan, the researchers found that those who had the robotic bypass were much less likely to have narrowing or clots in the bypass graft than those with the traditional bypass surgery from six months to a year after the operation.

"We saw a long term benefit to patients after their bypass in terms of the patency, or openness, of the bypass graft, according to Bartley Griffith, M.D., head of Cardiac Surgery at the University of Maryland Medical Center and professor of surgery at the University of Maryland School of Medicine. Dr. Griffith, also a co-author of the study, says the grafted vessels of more than 99 percent of the patients who had robotically-assisted bypass surgery were still open and functioning well compared to about 80 percent of those who had the "open" operation.

The reason for the difference is that for patients who need multiple bypasses, surgeons can easily access two internal mammary arteries to use as the new bypass vessels rather than taking a section of vein from another part of the body. In traditional bypass operations, only one internal mammary artery is used while other bypasses are performed using a vein. The long-term success of the bypass, or patency of the target vessel, is superior with an internal mammary artery versus a vein.

Dr. Poston says hospitals have been waiting for data on the costs and benefits of robotic-assisted heart bypass programs before investing in them. "Our conclusion from this study is that robotically-assisted coronary artery revascularization presents quality of life benefits for patients along with financial savings for those hospitals which care for large numbers of high risk patients," says Dr. Poston, who recently moved from the University of Maryland to be the chief of cardiac surgery at Boston Medical Center.

The study, "Superior Financial and Quality Metrics with Robotically-assisted (DaVinci) Coronary Artery Revascularization," will be presented at the 128th annual meeting of the American Surgical Association in New York on April 26, 2008.

http://www.umm.edu/

A Johns Hopkins University biologist, in research with implications for people suffering from seasonal affective disorder and insomnia, has determined that the eye uses light to reset the biological clock through a mechanism separate from the ability to see.

The findings suggest that patients with trouble sleeping or seasonal depression -- disorders that can be linked to lack of exposure to daylight -- could benefit from development of easier, more available tests to determine if they are able to detect light properly for functions distinct from normal sight, said Samer Hattar, assistant professor of biology in the university's Zanvyl Krieger School of Arts and Sciences.

"It seems that even if individuals have normal sight, they might be having a malfunction that is contributing to their inability to detect light, which can adversely affect their biological clocks," Hattar said.

Writing in the Advance Online issue of Nature and in the May 1 print issue, Hattar and colleagues reported that they genetically modified mice so that a particular set of retinal ganglion cells - cells that receive input from the rods and cones of the animals' eyes and send information to the brain - no longer functioned.

The mice were still able to use light to see normally, but had great difficulty synchronizing their circadian rhythms to light/dark cycles, the constant lengthening or shortening of daylight hours that occurs depending on the time of year.

Prior research in the field leads the researchers to believe that because the rodents' internal, biological "clocks" are out of sync with the solar day, the rodents would have difficulty learning and sleeping on a regular, 24-hour cycle. The team has not yet tested that hypothesis.

"This research illustrates that there are two distinct pathways for the two different aspects of light detection: image-forming and non-image-forming," Hattar said.

The team's next step will be working toward a broad understanding of the functions of light for animals and to differentiate between those which are associated with image formation and those which are associated with simple light detection.

Even without that additional research, however, Hattar and his team are convinced, on the basis of a long line of work by other researchers, that daily exposure to natural light enhances memory, mood and learning.

"Our tips are simple: Get out in the sun for at least a little while each day," Hattar said. "There's a reason why we seek the sun and the beach and we feel better when we can sit in the sun and bask.

"Also, avoid very bright lights during the night, as exposure to them can cause a malfunction in your biological clock," he said. "The idea is to keep your internal rhythm in sync with the cycle of the sun: exposure during the day when the sun is out, less exposure at night, when the sun is down, so to speak. I am convinced that this will help improve your memory and your learning."

http://www.jhu.edu/

Enzymes regulating genetic expression can be just as important as the genome itself, increasing evidence shows.

The expanding field of epigenetics focuses on the multiple influences on DNA and surrounding molecules that determine whether genes are turned on or off during development and disease processes.

A consortium of scientists, led by Albert Jeltsch at Jacobs University, Breman, Germany, Yoichi Shinkai at Kyoto University, Japan, and Xiaodong Cheng at Emory University, has now discovered new non-histone targets for one enzyme previously believed to modify only histones--the group of proteins that creates tightly bundled packages of DNA strands. The research is reported online in the journal Nature Chemical Biology.

These modification enzymes, called protein methyltransferases, add methyl groups to lysine amino acids within the histones and change their influence on gene expression. The newly identified non-histone targets add yet another influence on gene expression in addition to the already-known DNA methylation and histone modifications in the epigenome.

The international research team has found that a histone methyltransferase called G9a adds methyl groups to other proteins in addition to histones and changes the behavior of those proteins. The researchers used a peptide array technology called SPOT to identify the new enzyme targets.

"This discovery broadens our view of methyltransferases and tells us that epigenetic regulation in cells is even more complicated than we thought," says principal investigator Xiaodong Cheng, PhD, professor of biochemistry at Emory University School of Medicine and a Georgia Research Alliance Eminent Scholar.

"We have known for some time that we had a great deal more to discover about methyltransferases. This is an important piece of the puzzle, and additional research will continue to help us unwind the multiple mechanisms involved in epigenetic gene regulation."

http://www.emory.edu