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16/12/10

Permalink 11:26:30 am, by Tom, 993 words, 8841 views   English (UK)
Categories: Information

From the bench and the bedside; how animal research is taming Multiple Sclerosis

Multiple sclerosis (MS) is one of the most common diseases of the central nervous system – the brain and spinal cord - affecting about one person in every thousand in the USA. It is an inflammatory condition, where the immune system attacks the myelin sheath that surrounds the axons of nerve cells. Myelin is a fatty material that insulates nerves, acting much like the covering of an electric wire and allowing the nerve to transmit its impulses rapidly. It is the speed and efficiency with which these impulses are conducted that permits smooth, rapid and co-ordinated movements to be performed with little conscious effort. Loss of myelin interrupts these impulses, and the nerve cells themselves are also damaged and eventually die.

The consequences for people with MS can be devastating, and MS is associated with a wide variety of symptoms, including muscle weakness, spasms, ataxia, problems with speech and vision, acute and chronic pain, and fatigue. MS is a very variable disorder, and the rate at which it progresses varies considerably from one patient to another, but a defining characteristic of it is the lesions that are visible by MRI where the myelin has come under attack. The relapses, attacks of worsening neurological function that are often found in MS, are closely associated appearance of new lesions in the CNS, although not all new lesions cause a relapse.

Until about 20 years ago there were no treatments available that could prevent relapses or slow the progression of MS – known as disease modifying treatments - but thanks to the efforts of scientists working around the word this situation has begun to change. A number of effective disease modifying treatments are now available, the most recent to receive FDA approval is Fingolimod (known as FTY720 during its development), a drug whose immunosuppressant properties in reducing transplant rejection and as a treatment for MS were evaluated in a range of animal models during its development.

These drugs may soon be joined by another. A couple of years ago I wrote about the crucial role of studies in mice, rats, and dogs in the development of a new disease modifying treatment called Laquinimod, and last week the manufacturers of laquinimod announced that it had performed well in a phase III clinical trial, safely reducing the number of relapses and slowing progression of disability. This is excellent news, and one more step towards turning MS form being an incurable disease to being a manageable disease.

One reason I say manageable rather than curable is that while these treatments are effective in reducing the number of relapses for many patients they do not work for all patients and all forms of MS (particularly for primary progressive MS), and can sometimes have serious side effects that prevent patients from continuing treatment. That is why scientists are continuing to study the biological mechanisms in MS, a disease whose origin is still not fully understood, though clinical and animal research indicates that both genetic and environmental factors play a role, their ultimate goal is to develop treatments that can stop relapses altogether.

Another reason for not referring to disease modifying treatments as “cures” is that they do not directly repair the damaged myelin sheath at the lesions. Spontaneous repair of the damaged myelin sheath in MS lesions does happen and plays an important role in limiting neurological damage, but until now the molecular basis of myelin regeneration by cells called oligodentrocytes, in the central nervous system (CNS) has been poorly understood. The Guardian reports on how scientists at the University of Cambridge have discovered how to promote remyelination in MS lesions by activating a population of stem cells in the CNS called oligodentrocyte precursor cells (1).

The team led by Professor Robin Franklin generated a comprehensive transcriptional profile of 22,000 genes during the separate stages of spontaneous remyelination that follow focal toxin-induced demyelination in the rat CNS, and found that the level of retinoid acid receptor RXR-gamma expression was increased during remyelination. Cells of the oligodendrocyte lineage expressed RXR-gamma in rat tissues that were undergoing remyelination, in both active lesions and in older remyelinated lesions. By examining post-mortem brain samples from MS patients, they were able to show that RXR-gamma expression was also elevated in oligodendrocyte precursor cells at the active lesion sites, supporting a general role for RXR-gamma in remyelination. Interesting as these findings were they did not demonstrate that RXR-gamma is actually required for remyelination, so they next performed studies to determine whether blocking the function of RXR-gamma would prevent remyelination.

Knockdown of RXR-gamma by RNA interference or RXR-specific antagonists severely inhibited the differentiation of oligodendrocyte precursor cells into mature oligodendrocytes in culture. In mice that lacked RXR-gamma, adult oligodendrocyte precursor cells efficiently repopulated lesions after demyelination, but showed delayed differentiation into mature oligodendrocytes. The next question was whether increasing the activity of RXR-gamma would speed up remyelination. Administration of the RXR agonist 9-cis-retinoic acid to demyelinated mouse cerebellar slice cultures and then to aged rats in vivo after focal demyelination caused an increase in remyelinated axons. Focal toxin-induced demyelination was used to produce the lesions, rather than an immunity mediated model of demyelination such as experimental autoimmune encephalomyelitis, in order to determine that the increased remyelination was due to promotion of oligodendrocyte differentiation rather than to the anti-inflammatory effects of 9-cis retinoic acid.

The results indicate that RXR-gamma plays an important role in endogenous oligodendrocyte precursor cell differentiation and remyelination, and might be a pharmacological target for regenerative therapy in MS. The discovery that 9-cis-retinoic acid, a compound already in limited clinical use, can be used to stimulate myelin regeneration raises the possibility that within the next decade treatments that repair the neurological damage in MS will begin to enter clinical trials.

For people with MS these scientific and clinical advances are a great source of hope for a better future.

Paul Browne

1) Huang J.K. et al. “Retinoid X receptor gamma signalling accelerates CNS remyelination” Nature Neuroscience Published Online 05 December 2010 DOI: 10.1038/nn.2702

29/10/10

Permalink 02:04:51 pm, by Tom, 603 words, 10498 views   English (UK)
Categories: News

The First Decade of the Human Genome: What’s on the Horizon?

To mark the 10th anniversary of the sequencing of the human genome the BBC aired a documentary yesterday evening entitled “Miracle cure: a decade of the human genome” that can be viewed on the BBC iPlayer. It was an enjoyable look at what has been accomplished since the famous announcement at the White House in June 2000, and while I think the program could have done with exploring some of the science in more depth, it gave a good overview and didn’t shrink from the sheer complexity of many of the questions that face scientists who are now attempting to understand the genome.

The program followed three individuals as they sought to understand what impact the knowledge gained from studying the genome could have on illnesses that have affected them, breast cancer, cystic fibrosis, and alcoholism, and what basic, applied, and clinical research is currently underway. The case of a woman whose breast cancer is linked to a defective BRCA1 gene turned to discussion of the potential for the development of personalized medicine – treatments that are tailored to the genetic makeup of an individual patient’s cancer cells. Animal research plays a very important role in the development of targeted therapies that can be used in personalized medicine, and an early example of this is the drug Herceptin, which is used to treat cancers that express the HER2 gene.

The cystic fibrosis thread focussed on the development of gene therapy and clinical trials now underway under the direction of Professor Eric Alton of the UK Cystic Fibrosis Gene Therapy Consortium. These gene therapy trials use lipid spheres to transport working copies of the CFTR gene – defective in cystic fibrosis – to the lungs of patients, and the particular lipid formulation used in these trials, known as GL67A was selected after careful evaluation against other candidates, first in CF mice and then in sheep (1). Mice models of cystic fibrosis have helped researchers to understand more about the disease and to assess therapies, but until very recently research has been hampered by the lack of a large animal model of cystic fibrosis that models the lung pathology of cystic fibrosis. This situation finally changed in 2008 when scientists at the Universities of Iowa and Missouri produced genetically modified pigs that lack the CFTR gene and develop all the pathologies that are characteristic of cystic fibrosis in humans. This new animal model for cystic fibrosis will be very useful for evaluating the safety and efficiency of new gene therapy techniques as the science advances.

Finally the thread on the influence on genetics on alcoholism was a reminder of just how complex the interaction between an array of genetic variations and the environment can be, and that while it may be possible to identify factors that predispose an individual towards a particular condition it is often difficult, if not impossible, to identify a single cause that tips the balance. Considering the enormous damage caused to society by addiction, and the high failure rate of addiction treatment programs, there is no doubt that addiction research is a neglected area within biomedical science. This is sad because research into the physiological underpinnings of addiction can aid the development of more effective treatment programs. Hopefully the identification of genes that predispose certain individuals to addiction will help society to realise that science can make an important contribution to solving this medical and social problem.

Paul Browne

1) Griesenbach U, Alton EW; UK Cystic Fibrosis Gene Therapy Consortium. "Gene transfer to the lung: lessons learned from more than 2 decades of CF gene therapy." Adv Drug Deliv. Rev. Volume 61(2), Pages 128-39 (2009) DOI: 10.1016/j.addr.2008.09.010.

04/10/10

Permalink 03:02:48 pm, by Tom, 354 words, 10573 views   English (UK)
Categories: News

Bob Edwards wins 2010 Nobel Prize for developing IVF: Thank the mice, rabbits, hamsters...

Professor Robert G. Edwards of the University of Cambridge has long been recognized as one of the pioneers of reproductive medicine. His most famous accomplishment, along with surgeon Patrick Steptoe*, came in 1978 with the birth of Louise Joy Brown, the first baby born through in-vitro fertilization. This achievement has now been recognized by the Nobel Assembly who awarded him the Nobel Prize in Physiology or Medicine 2010 for “the development of in vitro fertilization”.

As Dario discussed in an article for the Speaking of Research blog a few months ago the development of IVF by Bob Edwards depended on basic and applied research undertaken in rabbits and hamsters by pioneers including Gregory Pincus and Min Chueh Chang, who identified the essential conditions required for IVF.

In advanced information accompanying today’s announcement the Nobel Assembly notes the importance of this research in laying the foundations for the development of human IVF by Bob Edwards and Patrick Steptoe, and also discusses how Bob Edwards' own extensive research on the reproductive biology of mice - and animal research he and his colleagues conducted in a variety of species while working on IVF - aided progress. In particular the Nobel Assembly highlights how his experience with mice in enabled Bob Edwards to solve a critical problem that was preventing successful IVF, by developing a way to harvest human egg cells at the optimal stage of their maturation prior to in vitro fertilization.

Without the decades of careful animal research undertaken by Bob Edwards, Gregory Pincus, Min Chueh Chang, and scores of their colleagues it is unlikely that IVF would ever have become a reality.

We heartily congratulate Professor Edwards on his Nobel Prize, an award that recognizes his outstanding contribution to a medical advance that has brought joy to hundreds of thousands of families around the world.

* Sadly Patrick Steptoe died in 1988 and therefore could not share the Nobel Prize with Robert Edwards.

Paul Browne

p.s. If you haven't done so already please take a few seconds to sign the Science is Vital petition, and, if you can, join the rally in London on Saturday 9th October.

Permalink 12:40:27 pm, by Tom, 321 words, 2227 views   English (UK)
Categories: Information

Bob Edwards wins 2010 Nobel Prize for developing IVF: Thank the mice, rabbits, hamsters...

Professor Robert G. Edwards of the University of Cambridge has long been recognized as one of the pioneers of reproductive medicine. His most famous accomplishment, along with surgeon Patrick Steptoe*, came in 1978 with the birth of Louise Joy Brown, the first baby born through in-vitro fertilization. This achievement has now been recognized by the Nobel Assembly who awarded him the Nobel Prize in Physiology or Medicine 2010 for “the development of in vitro fertilization”.

As Dario discussed in an article for the Speaking of Research blog a few months ago the development of IVF by Bob Edwards depended on basic and applied research undertaken in rabbits and hamsters by pioneers including Gregory Pincus and Min Chueh Chang, who identified the essential conditions required for IVF.

In advanced information accompanying today’s announcement the Nobel Assembly notes the importance of this research in laying the foundations for the development of human IVF by Bob Edwards and Patrick Steptoe, and also discusses how Bob Edwards' own extensive research on the reproductive biology of mice - and animal research he and his colleagues conducted in a variety of species while working on IVF - aided progress. In particular the Nobel Assembly highlights how his experience with mice in enabled Bob Edwards to solve a critical problem that was preventing successful IVF, by developing a way to harvest human egg cells at the optimal stage of their maturation prior to in vitro fertilization.

Without the decades of careful animal research undertaken by Bob Edwards, Gregory Pincus, Min Chueh Chang, and scores of their colleagues it is unlikely that IVF would ever have become a reality.

We heartily congratulate Professor Edwards on his Nobel Prize, an award that recognizes his outstanding contribution to a medical advance that has brought joy to hundreds of thousands of families around the world.

* Sadly Patrick Steptoe died in 1988 and therefore could not share the Nobel Prize with Robert Edwards.

Paul Browne

22/09/10

Permalink 11:39:12 am, by Tom, 479 words, 3187 views   English (UK)
Categories: Information

Lasker awards highlight the contribution of animal research to medical progress

Each September the Albert and Mary Lasker Foundation recognizes the contribution made by scientists and doctors to medicine by awarding prizes to those who have made outstanding contributions to our understanding of disease, and to its treatment and prevention. The list of past recipients of these awards reads as a veritable who’s who of the greatest minds in medical research over the past 65 years, so it’s not surprising that the Lasker prizes are often called the “American Nobels”, indeed many Lasker prize winners have gone on to pay a visit to Stockholm not long afterwards.

As one might expect the Lasker prizes have often been awarded for discoveries and medical advances that relied on animal research, and this year is no exception.

The Albert Lasker Basic Medical Research Award went to Douglas Coleman and Jeffrey M. Friedman for their work on the hormone leptin, work that has led to a revolution in our understanding of the regulation of appetite and metabolism. The story of leptin is the story of how decades of careful research in mice led to an important discovery that is now helping to improve the lives of patients with rare genetic disorders, and more recently to help patients whose own leptin levels are too low as a result of HIV-related loss of fat tissue.

Napoleone Ferrara won the Lasker-DeBakey Clinical Medical Research Award for his discovery of the Vascular Endothelial Growth Factor (VEGF) and its role in regulating the growth of blood vessels. The description of Dr. Ferrara’s research on the Lasker website shows how Dr. Ferrara identified VEGF through research on cattle, and how his subsequent research using mice and rats ultimately resulted in the development of effective monoclonal antibody treatments for wet age related macular degeneration, a leading cause of blindness.

The third prize, the Lasker-Koshland Special Achievement Award in Medical Science, was awarded to Sir David Weatherall, a pioneer in the field of human genetics who has made invaluable contributions to our understanding of inherited blood disorders including α-or β-thalassemia and sickle cell anemia. His research laid the foundations for successful programs to reduce the incidence of these disorders, and of course to the development of treatments, some of which we discussed here just last week. Sir David may not have performed any animal research in his own career, but he recently chaired the committee which wrote an influential report on the role of primates in medical research. The report concluded that primate research has made an important contribution to medical progress, and is still needed in several important areas of medical research including neuroscience and vaccine development.

The message from this year’s Lasker prizes is clear; for medicine to continue to advance many different approaches to research must be applied, and among the many techniques that are necessary to progress animal research has an honored place.

Paul Browne

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