Researchers identify drug candidates for the treatment of spinal muscular atrophy

A chemical cousin of the common antibiotic tetracycline May in the treatment of spinal muscular atrophy (SMA), a disease currently incurable, the genetic cause of main causes of death among infants is useful. This is the result of a research collaboration with Adrian Krainer, Ph.D., of Cold Spring Harbor Laboratory (CSHL) and Paratek Pharmaceuticals Scientific, and Rosalind Franklin University of Medicine and Science. SMA is caused by mutations in a gene called survival motor neuron 1 (SMN1), decreased the amount of SMN protein in motor neurons of the spinal cord - muscle cells that control activity. Degenerate Without this protein, these neurons, and infants born with the mutation and gradually lose the ability to move, swallow, breathe, and. There are no approved treatments for the treatment of SMA, which affects about 1 baby in 6000 in the United States was born.

The new molecule, promotes the levels of SMN protein in cells that fixing a bug in a mechanism of cell transformation, such as RNA splicing. In a study published in the journal "Science" Translational Medicine November 4, reported the researchers, this update, both in mouse models of SMA, as well as in cells isolated from SMA patients.

Unlike previously identified molecules that stimulate the production of SMN, tetracycline-like compound has a unique therapeutic candidate is a small molecule that specifically altered splicing of spliced directly to the reaction.

Further collaborative research will focus on the clinical development of existing drugs, and is backed by a five-year, multimillion dollar agreement of cooperation of the National Institute of Neurological Disorders and Stroke (NINDS) and by families of SMA-support program.

Splicing correction

The drug candidates target the splicing of SMN2 gene, which is essentially a backup copy of the SMN1 gene is mutated in the repair SMA patients. SMN2 not compensate for the loss of SMN1, but because it is too little functional proteins produced. Most of the protein that is produced, it lacks one important piece, without which the protein is quickly degraded.

The removal of this part of the SMN protein is due to a flaw in how the cell processes the splicing machinery of RNA copied from DNA gene, SMN2. During splicing, a complex of patterns from the RNA of certain enzymes necessary pieces called introns. Typically, the remaining exons are called necessary parts back together, together, and the edited RNA molecule is then converted into a functional protein.

In the case of the SMN2 gene, however, jumping mechanism of splicing of exon. Thus Krainer and his team have sought ways to change, splice, so that missing piece to the 7th exon is located in the latest copy of RNA.

The researchers focused on finding a class of molecules, chemical variants of tetracycline, because this class of chemicals known as RNA on the bar and change are splicing, and is less toxic than others to do the same thing.

In tests of an experimental system that the effect of molecules exclusively on splicing, the researchers examined a series of tetracycline derivatives of the chemical Paratek said. The screen shows that the PTK-Sma1 molecule is very effective for a change in splicing, such that exon 7 is included in the quoted price.

PTK-Sma1 therapy

Researchers have confirmed that the effect of PTK on Sma1-splicing exon inclusion and, ultimately, a higher level of full length and functional SMN protein. The combination of increased levels of proteins in cells of SMA patients isolated and grown in lab dishes. Scientists have also demonstrated their ability to work from in vivo injection into mice with a human SMN2 gene. The mice showed more than 5-fold increase levels of human SMN protein in the week of treatment.

"PTK-Sma1 is the only small molecule known to affect specific splicing directly and exclusively to promote the splicing reaction, Krainer said. Other molecules based on splicing and other cellular processes and thus diluting their power, and possibly the risk of side effects. PTK-Sma1 has the advantage that a derivative of tetracycline, which are not toxic and safety demonstrated in humans.

The team is on the promising with so many candidates for the therapeutic treatment of SMA and plans next to focus on two main questions are: how to find exactly PTK Sma1 redirects splicing and a means to cross the blood-brain barrier and disrupted in affected neurons in the spinal cord.

Chemotherapy and radiotherapy for the removal of the prostate gland can prevent cancer recurrence

Researchers at Oregon Health & Science University Cancer Institute Knight and Portland Veterans Affairs Medical Center, found a combination of radiotherapy and chemotherapy given before removal of the prostate is safe and may have the potential to reduce cancer recurrence and survival of patients improve. Their results were this week at the 51st Annual Meeting of the American Society of Therapeutic Radiology and Oncology in Chicago.

"Occur men Achieved aggressive cancer of the prostate, such as white standard radiation treatment or surgery is often not enough to completely eliminate the cancer treatment site. In these tumors, again, they are often fatal, "said the report Mark Garzotto, MD, associate director INVESTIGATOR and professor of urology and radiation medicine OHSU Knight Cancer Institute and head of urologic oncology at Portland Veterans Affairs Medical Center.

Previous clinical trials evaluating the effect of two, or hormone therapy, chemotherapy before surgery showed little or no advantage over the prostate, only the kidnapping. New approaches are needed if we are to make progress in this disease, "one said Dr. Garzotto.

The use of multimodal therapy resulted - the association and radio-surgery Chemotherapy - Prostate In better results in a number of cancers, but has not yet been wrote in cancer.

This study sought to find out if radiotherapy and chemotherapy (docetaxel) Before the surgery is feasible, safe and could ultimately prevent, manage the recurrence of cancer. Responding to questions at CES Garzotto and his colleagues have developed a treatment regimen, administered in Which Radiation and docetaxel before prostatectomy Ensemble.

Twelve participants were eligible for the study between April 2006 and are trademarks of March 2008th The men were paid and the intensity of the radiation dose docetaxel Crescent Five weeks of pay, prostate Followed by surgical removal of the .

Participants tolerated the treatment well and had the surgery without major complications, with a potential interest in this study to be submitted. Especially when there were no lesions, rectal ureter, or the formation of blood clot in the legs. Examination of tumor tissue after surgery, the margins of cancer, suppression of evidence A comprehensive review of all cancers, one was found in 75 percent of patients is more than the pupil could clean s' wait. In addition, the prostate specific antigen or PSA, an indicator of recurrent prostate cancer, detected after treatment in all patients.

The combination of our study, since the first clinical trial for prostate cancer on radiation therapy, chemotherapy and surgery as treatment of the association before prostate surgery May require cure rates than traditional approaches with fewer side effects ", a declare Arthur Hung, MD, Co-Investigator and Assistant Professor of Nuclear Medicine OHSU Cancer Institute Knight.

The researchers found that the combination of chemotherapy and radiotherapy is feasible and safe, and potentially cancer recurrence in this population at high risk be reduced. In addition, they say, the development of this approach the door of the study, other drugs opens in combination with radiotherapy.

Gene therapy turns the spectacle of 12 born with a rare malformation

single injection into the eye of a patient brings "results" stunning. The results may offer hope for people with macular degeneration and retinitis pigmentosa.Pennsylvania researchers using gene therapy have made significant improvements in vision in 12 patients with rare hereditary problems of vision, finding suggests that it may be possible, similar improvements in the production of larger number of patients with retinitis pigmentosa and macular degeneration.

The team last year reported success with three adult patients, a feat that was celebrated as a great success for gene therapy. They now have a patient treated nine others, including five children, and find that the best results in younger patients who reached the defective cells of the retina have not had time to die.

The youngest patient, aged 9, Corey Haas, he was considered blind before treatment began. It was essentially confined to his house and came into play, had great difficulties in navigating an obstacle course and special equipment required for the expansion books, and help in the classroom.

Today, after a single injection of a gene in one eye, he rides his bike through the neighborhood, sailing no support in the classroom, the obstacle course quickly and has even played his first game softball.

The results are "astonishing," said Stephen Rose, scientific director of the Foundation Fighting Blindness, which supports the work, but not directly involved. "The big message is that each individual had improved in the group ... And there were no security problems at all."

The study holds "great promise for the future" and "is interesting because of its simplicity," wrote researchers at the Medical Center Nijmegen in the Netherlands in an editorial on the report, published online Thursday by the Lancet.

The 12 patients had liver congenital amaurosis, about 3,000 people in the United States and perhaps 130,000 worldwide concerns. The victims were born with a severe visual impairment, until they are completely blind, mostly deteriorated in childhood or adolescence. There is no treatment.

The liver is a good candidate for gene therapy because most of the visual system is intact, especially at birth and childhood. Errors in 13 different genes are known to cause this, but all 12 patients suffered from a defect in a gene, RPE65. This gene produces a derivative of vitamin A, detection of light is essential.

About five children are born each year in the United States with the defect, which was chosen because researchers at Children's Hospital of Philadelphia and the University of Pennsylvania School of Medicine, the gene has been cloned, making copies available.

The study conducted by Dr. Katherine A. Max, Dr. Albert M. Maguire, and Dr. Jean Bennett led by these two institutions, five people have registered in the United States, five from Italy and two from Belgium. Five children were, and the 44th oldest

The good copy of the RPE65 gene in a defanged version of a human adenovirus added. The virus was subsequently developed was added to the cells of the retina and the gene into the DNA of cells.

Maguire uses a long thin needle worst use to prepare in the retina of the eye in each patient. In two weeks, the treated eyes become sensitive to light has begun, and within a few weeks ago, the vision began to improve. The patients have been younger, he says. This was expected, Bennett said, because similar results were observed in dogs and rodents.

In both objective and subjective measures, the vision that all patients improved. They could navigate an obstacle course to read the eye charts for most tasks of daily life. The improvement has been written it as long as two years.

Children who have been treated, are "now able to go play like a child with normal vision," said Maguire.

Bennett believes that the oldest patients of study, a mother was not able to walk down the street to meet their children at school are. "Now they can. It also achieved its primary objective which was shown to her daughter in a hit run away from home. "

There are clear limitations of the study. The vision of patients was not normal, because the damage was inflicted, which was already fixed on the retina, and one eye.

"The big elephant in the room: Can we treat the other eye?" Rose said.

The foundation will put more resources into research to make sure that when you go back and treat the other eye, not the removal of positive results in the light first by an immune response or other thing. "

Researchers have not optimized the dose of adenovirus also used to transport the gene into the eye. These issues are in phase 2, a larger clinical trial that is expected to begin soon be studied.

Meanwhile, the team began to treat some patients at the University of Iowa.

Researchers hope that the situation reflected in the results in other congenital conditions with different genes.

The liver is a form of retinitis pigmentosa, an estimated 100,000 Americans are affected.

The results were for macular degeneration, which affects an estimated 1.25 million Americans and is the leading cause of visual impairment in the elderly.

A drug that increases the good cholesterol reduces clogging of the arteries

A drug that the level of "good" cholesterol increased when taken in addition to the standard treatment of statins to lower bad cholesterol, reduce calcification of arteries and in patients with established heart disease, a study Oxford University has shown.

The results are published in the current issue of the Journal of the American College of Cardiology.

"This is the first clear evidence that therapy levels of good cholesterol, where in addition to taking statins increase their beneficial effect is," explains Dr. Robin Choudhury Department of Cardiovascular Medicine at the University of Oxford, who led the study. "With MRI, we have reduced the size of the artery wall in patients after one year of treatment with nicotinic acid showed.

"Our study is to identify imaging appears as a very promising prospects for treatment, and if the results are confirmed in larger studies courses, this could benefit many people around the world."

Heart disease is still the leading cause of death in the Western world, and atherosclerosis - the scale "lime up" or hardening of the arteries - is closely linked to later heart attacks and strokes.

The standard treatment of patients with atherosclerosis, statins are prescribed. These drugs are in reducing the risk of heart attack and stroke more effectively and work by lowering levels of "bad" cholesterol or low density lipoprotein (LDL) which might otherwise be deposited in the arteries obtained.

"Good" cholesterol or high density lipoprotein (HDL) is believed to eliminate the "bad cholesterol from the arteries and high levels of good cholesterol, lower risk of heart disease. It was thought that patients could receive other treatments to lower cholesterol good to increase these values, but so far there has been little evidence to support is.

Nicotinic acid, sometimes also called niacin, is one of the oldest drugs used to treat atherosclerosis and only fallen from grace of statins increased. It is known to increase levels of good cholesterol in the blood. Researchers at the Oxford Center for Clinical Magnetic Resonance Research (CRMO) have one of the largest groups have developed methods to MRI study of vascular disease. Thus the Oxford team, with colleagues at the University of Manchester, undertook to see if a high dose of nicotinic acid, statins also have an impact on the progression of atherosclerosis with MRI on changes in wall thickness of Measure A. carotid artery (the blood to the head and neck), and in particular the increase and other measures of large arteries and blood vessels function.

71 patients, all suffering from existing cardiovascular disease were prescribed statins and lower good cholesterol as their primary care physicians were randomized to receive either 2 g of nicotinic acid or placebo for 1 year. The MRI examinations were performed before 6 months and 12 months of the study.

After a year, was the size of the wall of carotid arteries in patients receiving nicotinic acid has been reduced compared to placebo. The area of the arterial wall had fallen on average by 1.1 mm ², while receiving placebo, saw an average increase of the wall of the carotid artery of 1.2 mm ².

Patients receiving nicotinic acid for 12 months an average increase of 23% of the levels of good cholesterol in the blood and lowering the "bad" cholesterol by 19%.

"For years we were always taught that atherosclerosis is an inexorable progression of the disease," says Dr Choudhury. "It's exciting to see a decline, based in atherosclerosis.

While this is evidence of a change that could be beneficial for patients, it does not show a large study of clinical outcomes, also taking statins niacin actually leads to fewer heart attacks, stroke and reduce mortality. But two of these studies with thousands of patients results in the coming years (including one from a group of Oxford led report) that a clearer picture of whether treatment should increase good cholesterol, to give strategies against heart disease added.

"Our results are very encouraging results because they showed potential benefits specific and will certainly strengthen the interest of the test results are larger than in the years to come, a report," says Dr Choudhury.

Old-style CABG better than "off-pump"

It seemed a good idea - is a bypass while the heart still beats and spare patients the complications that can come and go on a heart-lung machine. Now, the first major test of this method produced a surprise: Bypass has fewer problems and has successfully done the old way.Most expected, there were no signs of mental deterioration in the machine for file. Avoid this problem has been considered one of the benefits of so-called "off-pump" surgery without a machine.

"For the vast majority are, there is no advantage to do so outside of the pump and there may be some inconveniences," said Dr. Frederick Grover, University of Colorado, Denver, a leading study.

CABG has been suggested that the most common operation in the world - an estimated 253.000 Americans have the operation each year. Traditionally, the operation is performed while the patient is connected to a heart-lung machine, whose task is to circulate the blood while the heart has stopped beating. The "on-pump" method makes it easier for the surgeon to create new arteries or veins attach to create detours around the clogged arteries.

But the heart-lung machine has a low risk of complications, including stroke. In the 1990s, surgeons have started doing surgery outside of the pump - without the machine, but with devices that would stabilize the beating heart.

Today, about one fifth to make deals outside of the pump, and it has been fiercely debated, which is better. Previous studies have suggested that small results were substantially the same, or gave a slight advantage to offset the pump. The debate was the attention during quadruple bypass former President Bill Clinton with a heart-lung machine in 2004. Patients are sometimes offered a choice of methods.

The research reported in Thursday's New England Journal of Medicine is the largest between the two techniques to rigorously compare. The study involved 2203 patients were enrolled in the Veterans Affairs medical centers 18.

Approximately half randomized to surgery with heart-lung machine, the side without the bypass. One month after surgery, there was no difference in the number of deaths and other complications in both groups.

But a year later, the group out of the pump had a poorer prognosis. About 10 percent had either died, had a heart attack or bypass or other procedures to open a blocked artery, cons about 7 percent of the on-pump group.

He also won the off-pump group than originally planned detours A. less of their offers were still open after a year, about 83 percent compared to 88 percent for in-line pump. Because the heart is full of blood during the off-pump surgery, it is more difficult to reach and repair the arteries behind the heart, "said Grover.

Some patients received a series of psychological tests before surgery and after one year, there was no mental deterioration in both groups.

"We still have the idea that less is more - less invasive or less nothing seems to be a better answer. This is not always the case, "said Dr. Eric Peterson, a heart doctor at Duke University Medical Center.

Peterson, who wrote an editorial in the newspaper, said he was "a particularly well done study, but not the end of the debate.

There may be certain types of patients, for whom off-pump bypass of the service, "said Grover and Peterson. Previous research has suggested that women, the elderly and people with other diseases not suck better. The VA-funded study, Peterson mostly men who were younger and healthier than the typical bypass patients found.

Based on the results, he said Grover become more conservative off-pump bypass on patients. But he agreed with surgeons, not much off pump bypass and firmly believe will probably stick with it.

"It is a good study: America must adopt? And the answer is probably not, "said Peterson