Posts tagged medicine
Articles and news from the latest research reports.
UAB researchers cure type 1 diabetes in dogs
Researchers from the Universitat Autònoma de Barcelona (UAB), led by Fàtima Bosch, have shown for the first time that it is possible to cure diabetes in large animals with a single session of gene therapy. As published this week in Diabetes, the principal journal for research on the disease, after a single gene therapy session, the dogs recover their health and no longer show symptoms of the disease. In some cases, monitoring continued for over four years, with no recurrence of symptoms.
The therapy is minimally invasive. It consists of a single session of various injections in the animal’s rear legs using simple needles that are commonly used in cosmetic treatments. These injections introduce gene therapy vectors, with a dual objective: to express the insulin gene, on the one hand, and that of glucokinase, on the other. Glucokinase is an enzyme that regulates the uptake of glucose from the blood. When both genes act simultaneously they function as a “glucose sensor”, which automatically regulates the uptake of glucose from the blood, thus reducing diabetic hyperglycemia (the excess of blood sugar associated with the disease).
As Fàtima Bosch, the head researcher, points out, “this study is the first to demonstrate a long-term cure for diabetes in a large animal model using gene therapy.”
This same research group had already tested this type of therapy on mice, but the excellent results obtained for the first time with large animals lays the foundations for the clinical translation of this gene therapy approach to veterinary medicine and eventually to diabetic patients.
The study was led by the head of the UAB’s Centre for Animal Biotechnology and Gene Therapy (CBATEG) Fàtima Bosch, and involved the Department of Biochemistry and Molecular Biology of the UAB, the Department of Medicine and Animal Surgery of the UAB, the Faculty of Veterinary Science of the UAB, the Department of Animal Health and Anatomy of the UAB, the Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), the Children’s Hospital of Philadelphia (USA) and the Howard Hughes Medical Institute of Philadelphia (USA).
Scientists prevent development of deafness in animals engineered to have Usher syndrome
Hearing impairment is the most common sensory disorder, with congenital hearing impairment present in approximately 1 in 1,000 newborns, and yet there is no physiological cure for children who are born deaf. Most cases of congenital deafness are due to a mutation in a gene that is required for normal development of the sensory hair cells in the inner ear that are responsible for detecting sound. To cure deafness caused by such mutations, the expression of the gene must be corrected, a feat that has been elusive until recently.
Rosalind Franklin University of Medicine and Science (RFUMS) Assistant Professor Michelle Hastings and her team, along with investigators at Louisiana State University Health Sciences Center in New Orleans, Louisiana and Isis Pharmaceuticals in Carlsbad, CA, have now found a way to target gene expression in the ear and rescue hearing and balance in mice that have a mutation that causes deafness in humans. The results of the study are reported in the paper, Rescue of hearing and vestibular function in a mouse model of human deafness, which was published February 4, 2013 in the journal Nature Medicine.
Dr. Hastings collaborated with research leaders across the country, including RFUMS colleagues Francine Jodelka and Anthony Hinrich, who were co-first authors on the study, as well as Dr. Dominik Duelli and Kate McCaffrey; co-first author Dr. Jennifer Lentz at Louisiana State University Health Sciences Center New Orleans, and Dr. Lentz’s research team, including Drs. Hamilton Farris and Nicolas Bazan and Matthew Spalitta; and Dr. Frank Rigo at Isis Pharmaceuticals. The collaboration led to the development of a novel therapeutic approach to treat deafness and balance impairment by injecting mice with a single dose of a small, synthetic RNA-like molecule, called an antisense oligonucleotide (ASO). The ASO was designed to specifically recognize and fix a mutation in a gene called USH1C, that causes Usher syndrome in humans. The ASO blocks the effect of the mutation, allowing the gene product to function properly, thereby preventing deafness.
Usher syndrome is the leading genetic cause of combined deafness and blindness in humans. Treatment of these Usher mice with the ASO early in life rescues hearing and cures all balance problems. “The effectiveness of the ASO is striking,” states Hastings. “A single dose of the drug to newborn mice corrects balance problems and allows these otherwise deaf mice to hear at levels similar to non-Usher mice for a large portion of their life,” she says.
Validating ASO efficacy in the Usher mice is an important step in the process of developing the strategy for human therapy. Dr. Lentz, who has been studying Usher syndrome for almost 10 years and engineered the mice to model the human disease, states, “Successfully treating a human genetic disease in this animal model brings the possibility of treating patients much closer.”
The results of the study demonstrate the therapeutic potential of this type of ASO in the treatment of deafness and provide evidence that congenital deafness can be effectively overcome by treatment early in development to correct gene expression.
"The discovery of an ASO-type drug that can effectively rescue hearing opens the door to developing similar approaches to target and cure other causes of hearing loss," says Dr. Hastings who has been awarded a grant from the National Institute of Health to further develop the ASOs for the treatment of deafness with Drs. Lentz, Rigo and Duelli.
(Source: eurekalert.org)
Cells forged from human skin show promise in treating MS, myelin disorders
A study out today in the journal Cell Stem Cell shows that human brain cells created by reprogramming skin cells are highly effective in treating myelin disorders, a family of diseases that includes multiple sclerosis and rare childhood disorders called pediatric leukodystrophies.
The study is the first successful attempt to employ human induced pluripotent stem cells (hiPSC) to produce a population of cells that are critical to neural signaling in the brain. In this instance, the researchers utilized cells crafted from human skin and transplanted them into animal models of myelin disease.
"This study strongly supports the utility of hiPSCs as a feasible and effective source of cells to treat myelin disorders," said University of Rochester Medical Center (URMC) neurologist Steven Goldman, M.D., Ph.D., lead author of the study. "In fact, it appears that cells derived from this source are at least as effective as those created using embryonic or tissue-specific stem cells."
The discovery opens the door to potential new treatments using hiPSC-derived cells for a range of neurological diseases characterized by the loss of a specific cell population in the central nervous system called myelin. Like the insulation found on electrical wires, myelin is a fatty tissue that ensheathes the connections between nerve cells and ensures the crisp transmission of signals from one cell to another. When myelin tissue is damaged, communication between cells can be disrupted or even lost.
The most common myelin disorder is multiple sclerosis, a condition in which the body’s own immune system attacks and destroys myelin. The loss of myelin is also the hallmark of a family of serious and often fatal diseases known as pediatric leukodystrophies. While individually very rare, collectively several thousand children are born in the U.S. with some form of leukodystrophy every year.
The source of the myelin cells in the brain and spinal cord is cell type called the oligodendrocyte. Oligodendrocytes are, in turn, the offspring of another cell called the oligodendrocyte progenitor cell, or OPC. Myelin disorders have long been considered a potential target for cell-based therapies. Scientists have theorized that if healthy OPCs could be successfully transplanted into the diseased or injured brain, then these cells might be able to produce new oligodendrocytes capable of restoring lost myelin, thereby reversing the damage caused by these diseases.
However, several obstacles have thwarted scientists. One of the key challenges is that OPCs are a mature cell in the central nervous system and appear late in development.
"Compared to neurons, which are among the first cells formed in human development, there are more stages and many more steps required to create glial cells such as OPCs," said Goldman. "This process requires that we understand the basic biology and the normal development of these cells and then reproduce this precise sequence in the lab."
Another challenge has been identifying the ideal source of these cells. Much of the research in the field has focused on cells derived from tissue-specific and embryonic stem cells. While research using these cells has yielded critical insight into the biology of stem cells, these sources are not considered ideal to meet demand once stem cell-based therapies become more common.
The discovery in 2007 that human skin cells could be “reprogrammed” to the point where they returned to a biological state equivalent of an embryonic stem cell, called induced pluripotent stem cells, represented a new path forward for scientists. Because these cells – created by using the recipient’s own skin – would be a genetic match, the likelihood of rejection upon transplantation is significantly diminished. These cells also promised an abundant source of material from which to fashion the cells necessary for therapies.
Goldman’s team was the first to successfully master the complex process of using hiPSCs to create OPCs. This process proved time consuming. It took Goldman’s lab four years to establish the exact chemical signaling required to reprogram, produce, and ultimately purify OPCs in sufficient quantities for transplantation and each preparation required almost six months to go from skin cell to a transplantable population of myelin-producing cells.
Once they succeeded in identifying and purifying OPCs from hiPSCs, they then assessed the ability of the cells to make new myelin when transplanted into mice with a hereditary leukodystrophy that rendered them genetically incapable of producing myelin.
They found that the OPCs spread throughout the brain and began to produce myelin. They observed that hiPSC-derived cells did this even more quickly, efficiently, and effectively than cells created using tissue-derived OPCs. The animals were also free of any tumors, a dangerous potential side effect of some stem cell therapies, and survived significantly longer than untreated mice.
"The new population of OPCs and oligodendrocytes was dense, abundant, and complete," said Goldman. "In fact, the re-myelination process appeared more rapid and efficient than with other cell sources."
The next stage in evaluating these cells – clinical studies – may not be long in the offing. Goldman, along with a team of researchers and clinicians from Rochester, Syracuse, and Buffalo, are preparing to launch a clinical trial using OPCs to treat multiple sclerosis. This group, titled the Upstate MS Consortium, has been approved for funding by New York State Stem Cell Science (NYSTEM). While the consortia’s initial study – the early stages of which are scheduled to begin in 2015 – will focus cells derived from tissue sources, Goldman anticipates that hiPSC-derived OPCs will eventually be included in this project.
(Source: eurekalert.org)
In the brain, broken down ‘motors’ cause anxiety
When motors break down, getting where you want to go becomes a struggle. Problems arise in much the same way for critical brain receptors when the molecular motors they depend on fail to operate. Now, researchers reporting in Cell Reports, a Cell Press publication, on February 7, have shown these broken motors induce stress and anxiety in mice. The discovery may point the way to new kinds of drugs to treat anxiety and other disorders.
The study in mice focuses on one motor in particular, known as KIF13A, which, according to the new evidence, is responsible for ferrying serotonin receptors. Without proper transportation, those receptors fail to reach the surface of neurons and, as a result, animals show signs of heightened anxiety.
In addition to their implications for understanding anxiety, the findings also suggest that defective molecular motors may be a more common and underappreciated cause of disease.
"Most proteins are transported in vesicles or as protein complexes by molecular motors," said Nobutaka Hirokawa of the University of Tokyo. "As shown in this study, defective motors could cause many diseases."
Scientists know that serotonin and serotonin receptors are involved in anxiety, aggression, and mood. But not much is known about how those players get around within cells. When Hirokawa’s team discovered KIF13A at high levels in the brain, they wondered what it did.
The researchers discovered that mice lacking KIF13A show greater anxiety in both open-field and maze tests and suggest that this anxious behavior may stem from an underlying loss of serotonin receptor transport, which leads to a lower level of expression of those receptors in critical parts of the brain.
"Collectively, our results suggest a role for this molecular motor in anxiety control," the researchers wrote. Hirokawa says the search should now be on for anti-anxiety drug candidates aimed at restoring the brain’s serotonin receptor transport service.
Number of People with Alzheimer’s Disease May Triple by 2050
The number of people with Alzheimer’s disease is expected to triple in the next 40 years, according to a new study by researchers from Rush University Medical Center published in the February 6, 2013, online issue of Neurology, the medical journal of the American Academy of Neurology.
“This increase is due to an aging baby boom generation. It will place a huge burden on society, disabling more people who develop the disease, challenging their caregivers, and straining medical and social safety nets,” said co-author, Jennifer Weuve, MPH, ScD, assistant professor of medicine, Rush Institute for Healthy Aging at Rush University Medical Center in Chicago. “Our study draws attention to an urgent need for more research, treatments and preventive strategies to reduce the impact of this epidemic.”
For the study, researchers analyzed information from 10,802 African-American and Caucasian people living in Chicago, ages 65 and older between 1993 and 2011. Participants were interviewed and assessed for dementia every three years. Age, race and level of education were factored into the research.
The data was combined with U.S. death rates, education and current and future population estimates from the U.S. Census Bureau.
The study found that the total number of people with Alzheimer’s dementia in 2050 is projected to be 13.8 million, up from 4.7 million in 2010. About 7 million of those with the disease would be age 85 or older in 2050.
“Our projections use sophisticated methods and the most up-to-date data, but they echo projections made years and decades ago. All of these projections anticipate a future with a dramatic increase in the number of people with Alzheimer’s and should compel us to prepare for it,” said Weuve.
Fighting fat with fat: stem cell discovery identifies potential obesity treatment
Ottawa scientists have discovered a trigger that turns muscle stem cells into brown fat, a form of good fat that could play a critical role in the fight against obesity. The findings from Dr. Michael Rudnicki’s lab, based at the Ottawa Hospital Research Institute, were published today in the prestigious journal Cell Metabolism.
"This discovery significantly advances our ability to harness this good fat in the battle against bad fat and all the associated health risks that come with being overweight and obese," says Dr. Rudnicki, a senior scientist and director for the Regenerative Medicine Program and Sprott Centre for Stem Cell Research at the Ottawa Hospital Research Institute. He is also a Canada Research Chair in Molecular Genetics and professor in the Faculty of Medicine at the University of Ottawa.
Globally, obesity is the fifth leading risk for death, with an estimated 2.8 million people dying every year from the effects of being overweight or obese, according to the World Health Organization. The Public Health Agency of Canada estimates that 25% of Canadian adults are obese.
Globally, obesity is the fifth leading risk for death, with an estimated 2.8 million people dying every year from the effects of being overweight or obese, according to the World Health Organization. The Public Health Agency of Canada estimates that 25% of Canadian adults are obese.
In 2007, Dr. Rudnicki led a team that was the first to prove the existence of adult skeletal muscle stem cells. In the paper published today, Dr. Rudnicki now shows (again for the first time) that these adult muscle stem cells not only have the ability to produce muscle fibres, but also to become brown fat. Brown fat is an energy-burning tissue that is important to the body’s ability to keep warm and regulate temperature. In addition, more brown fat is associated with less obesity.
Perhaps more importantly, the paper identifies how adult muscle stem cells become brown fat. The key is a small gene regulator called microRNA-133, or miR-133. When miR-133 is present, the stem cells turn into muscle fibre; when reduced, the stem cells become brown fat.
Dr. Rudnicki’s lab showed that adult mice injected with an agent to reduce miR-133, called an antisense oligonucleotide or ASO, produced more brown fat, were protected from obesity and had an improved ability to process glucose. In addition, the local injection into the hind leg muscle led to increased energy production throughout the body—an effect observed after four months.
Using an ASO to treat disease by reducing the levels of specific microRNAs is a method that is already in human clinical trials. However, a potential treatment using miR-133 to combat obesity is still years away.
"While we are very excited by this breakthrough, we acknowledge that it’s a first step," says Dr. Rudnicki, who is also scientific director of the Stem Cell Network. "There are still many questions to be answered, such as: Will it help adults who are already obese to lose weight? How should it be administered? How long do the effects last? Are there adverse effects we have not observed yet?"
Green tea and red wine extracts interrupt Alzheimer’s disease pathway in cells
Natural chemicals found in green tea and red wine may disrupt a key step of the Alzheimer’s disease pathway, according to new research from the University of Leeds.
In early-stage laboratory experiments, the researchers identified the process which allows harmful clumps of protein to latch on to brain cells, causing them to die. They were able to interrupt this pathway using the purified extracts of EGCG from green tea and resveratrol from red wine.
The findings, published in the Journal of Biological Chemistry, offer potential new targets for developing drugs to treat Alzheimer’s disease, which affects some 800,000 people in the UK alone, and for which there is currently no cure.
"This is an important step in increasing our understanding of the cause and progression of Alzheimer’s disease," says lead researcher Professor Nigel Hooper of the University’s Faculty of Biological Sciences. "It’s a misconception that Alzheimer’s is a natural part of ageing; it’s a disease that we believe can ultimately be cured through finding new opportunities for drug targets like this."
Alzheimer’s disease is characterised by a distinct build-up of amyloid protein in the brain, which clumps together to form toxic, sticky balls of varying shapes. These amyloid balls latch on to the surface of nerve cells in the brain by attaching to proteins on the cell surface called prions, causing the nerve cells to malfunction and eventually die.
"We wanted to investigate whether the precise shape of the amyloid balls is essential for them to attach to the prion receptors, like the way a baseball fits snugly into its glove," says co-author Dr Jo Rushworth. "And if so, we wanted to see if we could prevent the amyloid balls binding to prion by altering their shape, as this would stop the cells from dying."
The team formed amyloid balls in a test tube and added them to human and animal brain cells. Professor Hooper said: “When we added the extracts from red wine and green tea, which recent research has shown to re-shape amyloid proteins, the amyloid balls no longer harmed the nerve cells. We saw that this was because their shape was distorted, so they could no longer bind to prion and disrupt cell function.
"We also showed, for the first time, that when amyloid balls stick to prion, it triggers the production of even more amyloid, in a deadly vicious cycle," he added.
Professor Hooper says that the team’s next steps are to understand exactly how the amyloid-prion interaction kills off neurons.
"I’m certain that this will increase our understanding of Alzheimer’s disease even further, with the potential to reveal yet more drug targets," he said.
Dr Simon Ridley, Head of Research at Alzheimer’s Research UK, the UK’s leading dementia research charity, which part-funded the study, said: “Understanding the causes of Alzheimer’s is vital if we are to find a way of stopping the disease in its tracks. While these early-stage results should not be a signal for people to stock up on green tea and red wine, they could provide an important new lead in the search for new and effective treatments. With half a million people affected by Alzheimer’s in the UK, we urgently need treatments that can halt the disease – that means it’s crucial to invest in research to take results like these from the lab bench to the clinic.”
Experimental Therapy Crosses Blood-Brain Barrier to Treat Neurological Disease
Researchers have overcome a major challenge to treating brain diseases by engineering an experimental molecular therapy that crosses the blood-brain barrier to reverse neurological lysosomal storage disease in mice.
Posted online in PNAS Early Edition on Feb. 4, the study was led by scientists at Cincinnati Children’s Hospital Medical Center.
“This study provides a non-invasive procedure that targets the blood-brain barrier and delivers large-molecule therapeutic agents to treat neurological lysosomal storage disorders,” said Dao Pan, PhD, principal investigator on the study and researcher in the Cancer and Blood Diseases Institute at Cincinnati Children’s. “Our findings will allow the development of drugs that can be tested for other brain diseases like Parkinson’s and Alzheimer’s.”
The scientists assembled the large molecular agents by merging part of a fatty protein called apolipoprotein E (apoE) with a therapeutic lysosomal enzyme called a-L-idurondase (IDUA). Naming the agents IDUAe1 and IDUAe2, researchers used them initially to treat laboratory cultured human cells of the disease mucopolysaccharidosis type I (MPS I). They also tested the agents on mouse models of MPS I.
MPS I is one of the most common lysosomal storage diseases to affect the central nervous system, which in severe form can become Hurler syndrome. In humans, patients can suffer from hydrocephalus, learning delays and other cognitive deficits. If not treated, many patients die by age 10.
Lysosomes are part of a cell’s internal machinery, serving as a waste disposal system that helps rid cells of debris to retain normal function. In lysosomal storage diseases like MPS I, enzymes needed to dissolve debris are missing, allowing debris to build up in cells until they malfunction.
In MPS I, cells lack the IDUA enzyme, allowing abnormal accumulation of a group of large molecules called glycosaminoglycans in the brain and other organs. Researchers in the current study used the new therapeutic procedure to deliver IDUA to brain cells. But first they had to successfully engineer the therapy to carry IDUA through the blood-brain barrier to diseased brain cells.
The blood-brain barrier is a physiological blockade that alters the permeability of tiny blood vessels called capillaries in the brain. Its purpose is to protect the brain by preventing certain drugs, pathogens and other foreign substances from entering brain tissues. The barrier has also been a persistent roadblock to treating brain disease with drugs.
The scientists experimented with a set of derivative components of the fatty protein apoE, which binds to fat receptors on endothelial cells that form the inside surface of capillaries in the blood-brain barrier. They discovered that tagging some of the apoE components to the IDUA enzyme allowed the modified protein to attach to endothelial cells and cross through the cells to reach brain tissues.
Researchers injected experimental IDUAe1 into the tail veins of MPS I mouse models. The tests showed that – unlike currently available un-modified enzyme treatments – the modified enzyme penetrated the blood-brain barrier and entered brain neurons and astrocytes in a dose-dependent manner.
The researchers also reported that brain cells in the treated mice exhibited normalized levels of the glycosaminoglycans and the lysosomal enzyme beta-hexosaminidase. With continued treatment through hematopoietic stem cell gene therapy, normalized levels persisted until the end of a five-month observation period, researchers said.
The scientists are continuing their preclinical studies to further verify the use of the experimental IDUA-based agents for treating MPS I, cautioning that results in laboratory mice may face additional challenges when translating to clinical application in humans. Researchers are also testing whether the large-molecule therapeutic procedure used in the current study can be leveraged to develop other neurotherapeutic agents that cross the blood-brain barrier.
(Source: cincinnatichildrens.org)
Chemical reaction keeps stroke-damaged brain from repairing itself
Nitric oxide, a gaseous molecule produced in the brain, can damage neurons. When the brain produces too much nitric oxide, it contributes to the severity and progression of stroke and neurodegenerative diseases such as Alzheimer’s. Researchers at Sanford-Burnham Medical Research Institute recently discovered that nitric oxide not only damages neurons, it also shuts down the brain’s repair mechanisms. Their study was published by the Proceedings of the National Academy of Sciences the week of February 4.
“In this study, we’ve uncovered new clues as to how natural chemical reactions in the brain can contribute to brain damage—loss of memory and cognitive function—in a number of diseases,” said Stuart A. Lipton, M.D., Ph.D., director of Sanford-Burnham’s Del E. Webb Neuroscience, Aging, and Stem Cell Research Center and a clinical neurologist.
Lipton led the study, along with Sanford-Burnham’s Tomohiro Nakamura, Ph.D., who added that these new molecular clues are important because “we might be able to develop a new strategy for treating stroke and other disorders if we can find a way to reverse nitric oxide’s effect on a particular enzyme in nerve cells.”
Nitric oxide inhibits the neuroprotective ERK1/2 signaling pathway
Learning and memory are in part controlled by NMDA-type glutamate receptors in the brain. These receptors are linked to pores in the nerve cell membrane that regulate the flow of calcium and sodium in and out of the nerve cells. When these NMDA receptors get over-activated, they trigger the production of nitric oxide. In turn, nitric oxide attaches to other proteins via a reaction called S-nitrosylation, which was first discovered by Lipton and colleagues. When those S-nitrosylated proteins are involved in cell survival and lifespan, nitric oxide can cause brain cells to die prematurely—a hallmark of neurodegenerative disease.
In their latest study, Lipton, Nakamura and colleagues used cultured neurons as well as a living mouse model of stroke to explore nitric oxide’s relationship with proteins that help repair neuronal damage. They found that nitric oxide reacts with the enzyme SHP-2 to inhibit a protective cascade of molecular events known as the ERK1/2 signaling pathway. Thus, nitric oxide not only damages neurons, it also blocks the brain’s ability to self-repair.
Molecule key to sustaining brain communication
Scientists have discovered the powerful role the molecule Myosin VI plays in communication between nerve cells in the brain.
Researchers at the University of Queensland’s (UQ) Queensland Brain Institute (QBI) have found that Myosin VI is integral to maintaining the neurotransmitter release that allows neurons to pass on information to other neurons.
The discovery made by Vanesa Tomatis, a PhD student in Associate Professor Frederic Meunier’s laboratory, demonstrates how Myosin VI has the impressive ability to anchor secretory vesicles that are at least 5,000 times greater in size, near their release site.
"By tethering and anchoring secretory granules, Myosin VI helps to maintain an active pool of vesicles near the plasma membrane, which is key to sustaining communication between neuronal cells," Associate Professor Meunier said.
Associate Professor Meunier and his team are now looking to better understand how the Myosin VI manages to grab and hold vesicles through the use of super resolution microscopy.
They hope the discovery will lead to new ways to reinstate or regulate neuronal communication in various brain disorders.
The paper was published in The Journal of Cell Biology on February 4 2013
(Image credit: Wikipedia)