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Permalink 05:10:54 pm, by Tom, 1244 words, 9982 views   English (UK)
Categories: Information

Animal research: At the forefront of modern medicine

Several reports in the news over the past week have highlighted yet again the importance of animal research to medical advances.

The BBC reports that gene therapy has been used successfully to treat a patient with severe β-thalassemia. β-thalassemia is an inherited disorder caused by mutations in the β-globin chain of haemoglobin that lead to ineffective production of red blood cells and profound anaemia, and currently bone-marrow transplant is the only effective long term treatment for severe β-thalassemia. Unfortunately suitable donors are not easy to find, and in their absence patients depend on frequent blood transfusions that in turn lead to problems due to iron overload. Against this background the news that this disease may be treated by gene therapy in the future is most welcome.

The team of scientists and doctors led by Dr. Philippe Leboulch, of Harvard Medical School in Boston, used a lentiviral vector, based on elements of the HIV virus, to insert copies of a functioning β-globin gene into the patient’s haematopoietic stem cells (HSCs), and then transplanted the modified HSCs back into the patient. Lentiviral vectors have become popular in gene therapy in recent years, indeed last year we discussed the use of a similar vector to treat the brain disorder X-linked adrenoleukodystrophy, and this popularity is due mainly to their improved safety compared to other vectors. Early trials of gene therapy for X-linked severe combined immunodeficiency (X-SCID) were called into question when several patients developed leukemia when the retroviral vector used integrated into a location in the genome that activated an oncogene – though ultimately the treatment was of great benefited to most patients – and research comparing retroviral vectors with lentiviral vectors in mice found that the latter had a much lower tendency to activate oncogenes and promote tumor growth (1).

As Dr. Leboulch and colleagues point out in their Nature Biotechnology paper (2) reporting this work, research on mice was not confined to evaluating the safety of the lentiviral vector. Years of work went into developing and refining the β--globin lentiviral vector in mouse models of β-thalassemia and sickle-cell disease (also caused by a mutation in the β-globin gene) before it was ready to test in a human patient.

Lentiviral vectors have proven capable of transferring these elaborate structures with fidelity and high titres (5, 6). Hence, several mouse models of the β-haemoglobinopathies have been corrected, long-term, by ex vivo transduction of haematopoietic stem cells (HSCs) with β-globin lentiviral vectors (5, 6, 7, 8, 9, 10). These advances have prompted the prudent initiation of a human clinical trial.

Such research is now bearing fruit, and it is hard to disagree with gene therapy expert Professor Adrian Trasher, quoted by the BBC as saying:

The good news is that technology is advancing rapidly, and it shouldn't be too long before diseases such as thalassaemia can be reliably and safely treated in this way.

Another report from the BBC provides hope for the many thousands of patients on waiting on organ transplant lists; speaking at the British Science Festival Professor Steve Sacks announced the development of a treatment using the drug mirococept to protect the transplanted organ from attack by the immune system , a technique that could potentially double the length of time it survives in the recipient before a new organ is required. Currently transplanted organs last for about 10 years, and patients requiring replacement organs make up about 20% of those on the waiting lists. A small clinical trial of the technique indicates that is safe and a larger trial is now planned. Mirocosept works by blocking the activation of the complement system, a complex set of approximately 20 interacting enzymes and regulatory proteins found in the blood plasma and body fluids. The complement system plays a key role in fighting infection, but its activation is also a key early event in organ rejection. Mirococept consists of a complement inhibitor peptide attached to a second peptide that allows it to attach to cell membranes, thus enabling it to remain on the surface of the transplanted organ and prevent complement activation.

Mirococept itself was initially developed for the treatment of rheumatoid arthritis and ischaemia and reperfusion injury, after basic research in mice and rats demonstrated that the complement system played a major early role in activating the inflammatory response that is characteristic of these conditions, identified the key components involved in this response, and showed that blocking complement activation in several animal models could reduce tissue damage (3,4). Mirococept targets complement inhibition to specific tissues concentrating it where it is needed most and avoiding a more general inhibition that could leave the body vulnerable to infection, and performed well in animal models or arthritis, organ transplant, and ischemia and reperfusion injury (4,5). On the back of these promising results Mirococept has been taken into human trails for rheumatoid arthritis and organ transplant, where as we have seen it has proven to be a safe and reliable treatment. Larger trials to evaluate the efficacy of Mirococept are now underway for rheumatoid arthritis and being planned for organ transplants.

The shortage of organs for transplant is a major challenge, and many approaches are being considered to increase the supply, I have written previously of tissue engineering to build new organs but it will be years before this technology is in widespread use. Until then I would urge you all to sign up as an organ donor, it only takes a few minutes and you might just save several lives.

Our final story comes from the Autism Science Foundation, who write that a new drug named arbaclofen (STX209) improved the social interaction of autistic children, reducing tantrums and agitation, in an early clinical trial. Unlike existing medications that treat specific symptoms of autism arbaclofen acts to correct an imbalance in the levels of two neurotransmitters, glutamate and GABA, in the brains of autistic children. This new approach comes from studies of a mouse model of fragile X syndrome, a common inherited form of mental impairment and a cause of some cases of autism, which demonstrated that excessive activation of group I metabotropic glutamate receptor played an important role in the disorder, as discussed in an overview on the Seaside Therapeutics website. STX209 acts to reduce the excessive levels of glutamate released in the brain and therefore reduce activation of the group I metabotropic glutamate receptor, an approach which worked well in a mouse model of fragile X syndrome.

At a time when the parents of autistic children are bombarded with ineffective, ethically dubious, or downright dangerous “cures”, the development of a treatment that is both safe and effective is very welcome, lets just hope that it works as well in larger trials.

So once again this week the medical news is full of exciting developments that depended on basic and applied medical research in animals, which is exactly the kind of work that Speaking of Research exists to support!

Paul Browne

1) Montini E. et al. "Hematopoietic stem cell gene transfer in a tumor-prone mouse model uncovers low genotoxicity of lentiviral vector integration" Nature Biotechnology Volume 24, Pages 687-696 (2006) doi:10.1038/nbt1216

2) Cavazzana-Calvo M. et al. "Transfusion independence and HMGA2 activation after gene therapy of human β-thalassaemia" Nature Volume 467, Pages 318–322 (2010) doi:10.1038/nature09328

3) Sahu A. and Lambris J.D. "Complement inhibitors: a resurgent concept in anti-inflammatory therapeutics." Immunopharmacology Volume 49, Pages 133-148 (2000) PubMed:10904113

4) Souza G.D. "APT070 (Mirococept), a membrane-localised complement inhibitor, inhibits inflammatory responses that follow intestinal ischaemia and reperfusion injury." Br J Pharmacol. 2005 145(8): 1027–1034. doi:10.1038/sj.bjp.0706286

5) Smith R.A. "Targeting anticomplement agents." Biochem Soc Trans. Vol.30(6), Pages 1037-1041 (2002) PubMed:12440967


Permalink 08:36:28 pm, by Tom, 669 words, 2327 views   English (UK)
Categories: Information

Heart failure breakthrough: animal research paved the way!

Heart failure, where the heart is unable to maintain a sufficient blood flow to supply the body’s needs, is a leading cause of death, especially among the over 65’s. Half of all chronic heart failure patients die within four years of diagnosis. It can have a number of causes, for example damage to heart tissue after a heart attack, and leads to a variety of problems in patients. Fatigue and muscle weakness are common as the muscles receive insufficient oxygen, and because waste products cannot be removed from tissues quickly enough fluid can build up in the lungs and other parts of the body, often the legs and abdomen. The extra strain placed on the heart as it tries to maintain adequate blood pressure can lead to further damage to the heart and ultimately cardiac arrest.

In heart failure the rate at which the heart beats is often increased, and group of scientists led by Karl Svedberg and Michael Komajda set up the SHIfT study, to evaluate whether a drug called Ivabradine, which lowers the heart rate, could reduce risk of death or hospitalization in a group of patients who had heart failure accompanied by an elevated resting heart rate. Significantly fewer patients taking Ivabradine in addition to their existing treatments required hospital admission during the course of the study, compared to a control group who were given a placebo in addition to their existing treatment. The most striking outcome was that Ivabradine cut the risk of death by 26%.

So what is Ivabradine, and where does it come from?

Ivabradine slows the heart rate by inhibiting an electrical current known as the If current* which is a major regulator of the activity of the sinoatrial node – better known as the pacemaker. Inhibiting the If current slows the generation of the electrical impulses by the sinoatrial node that trigger heart contraction, and therefore slows the heart rate itself. Ivabradine, then known as S16257, was first developed in the early 1990’s when it was found to be able to block the If current in-vitro in sinoatrial node tissue from rabbits and guinea pigs, and slowed the generation of electrical impulses in a manner that was safer than other bradycardic drugs (1). Ivabradine was then evaluated in live rats and dogs, where it safely reduced the heart rate, and moreover did so without reducing the blood pressure (2,3). While beta-blockers such as Propranolol can reduce the heart rate they also lower the blood pressure – indeed they are used to treat hypertension - and hence are not suitable for many patients, so the development of a drug that could reduce heart rate without affecting blood pressure was very welcome.

Following the successful animal studies Ivabradine entered human clinical trials and in 2005 was approved for the treatment of angina pectoris. In angina pectoris the heart muscle receives too little oxygen, a problem exacerbated by a fast heart beat that increases the need for oxygen, so lowering of the heart rate by Ivabradine reduced oxygen demand and prevents angina attacks. The success of Ivabradine in the treatment of angina pectoris in turn led to its evaluation in heart failure.

The successful outcome of SHIfT study is a major boost to the development of better treatment regimes for heart failure, and if it is confirmed by further clinical trials will improve and prolong the lives of many heart failure patients.

* Hence the name of the SHIfT study - Systolic Heart failure treatment with the If inhibitor ivabradine Trial

Paul Browne

1) Thollon C. et al. "Electrophysiological effects of S 16257, a novel sino-atrial node modulator, on rabbit and guinea-pig cardiac preparations: comparison with UL-FS 49." Br J Pharmacol. Volume 112(1), Pages 37-42 (1994) PubMedCentral:PMC1910295

2) Gardiner S.M. et al. "Acute and chronic cardiac and regional haemodynamic effects of the novel bradycardic agent, S16257, in conscious rats." Br J Pharmacol. Volume 115(4):579-586 (1995) PubMedCentral:PMC1908496

3) Simon L. et al. "Coronary and hemodynamic effects of S 16257, a new bradycardic agent, in resting and exercising conscious dogs." J Pharmacol Exp Ther. Volume 275(2), Pages 659-666 (1995) PubMed:7473152


Permalink 02:53:44 pm, by Tom, 1426 words, 1696 views   English (UK)
Categories: Information

Mice, rats, and the secrets of the genome.

It’s just over a decade since the completion of the first working draft of the human genome was announced, and seven years since the publication of the complete sequence, but in that short time the impact of this new knowledge on all areas medical research has been immense. Sequencing the human genome was a huge achievement, but having got the sequence an even greater task confronts scientists - working out what it all means. To do this scientists have studied the natural variations that exist between individuals, and have also sequenced the genomes of a wide variety of species, some closely related to us, others separated from us by hundreds of millions of years of evolution. Scientists can analyze the similarities and differences between the genes of different species, and examine how changes to the structure or regulation of these genes are reflected in physiology. In many cases it is also possible to use genetic modification to study the function of conserved genes in other species in ways that are just not possible, for technical and/or ethical reasons, in humans. A study published a couple of weeks ago in the scientific journal Nature provides an excellent example of how animal research contributes to our understanding of the human genome.

As the cost of technology such as DNA microarrays has fallen genome-wide association studies (GWAS) have become an increasingly popular way of examining the relationship between genetic differences between individuals and particular diseases. In a GWAS the whole genome of many individuals is screened for variations, and then any association between those variations and particular phenotypes or diseases is determined. Tanya M. Teslovich and colleagues (1) analysed the genomes of over 100,000 people who had been enrolled in 46 separate clinical studies, and identified 95 genes that have variants associated with increases in blood lipid (fat and cholesterol) levels. One of the problems with GWAS studies is that while they are often good at identifying genes that are associated with a disease, they are not so good at identifying which genetic variations actually cause disease, or explaining how the genetic variations contribute to disease. This is where Tanya Teslovich and colleagues scored highly; they were able to show that 14 of the 95 lipid-associated genes were also associated with the development of coronary artery disease, supporting the proposition that elevated blood lipids contribute to coronary artery disease. They also found that overall the effect of the variants was additive, the more risk variants of these 95 genes you have the greater your chance of having elevated blood lipids.

So that established that the gene variants were associated with elevated blood lipids, but to use that information to develop new treatments you need to know how the particular gene affects lipid levels. As you might expect many of the 95 genes identified were already known from previous studies to be involved in the regulation of blood lipids, and in several cases their precise role has been thoroughly studied. However, several of the genes had not been implicated in regulating blood lipids before, and the team decided to use genetically modified mice to investigate their function. They injected viral vectors into the liver of the mice that contained either an extra copy of the gene being studied, to increase expression of the gene, or a short-hairpin RNA, to target the gene for knockdown via RNAi. This allowed them to discover that one gene, GALNT2, decreases levels of high-density lipoprotein cholesterol (HDLC), the so-called “good cholesterol”, while two other genes, Ttc39b and Ppp1r3b, increase HDLC.

Another associated paper (2) in the same issue of Nature takes the analysis even further. Several studies, including the GWAS performed by Tanya M. Teslovich and colleagues, had demonstrated that variations in a particular region of chromosome 1 known as 1p13 were associated with high levels of Low-density lipoprotein “bad” cholesterol (LDLC) in the blood and heart disease, but that these variations were not within the coding sequence of any genes, so they would not affect the structure of any proteins. They first show through genetic studies of human subjects and human liver tissue culture that variations at 1p13 affect the expression of several genes – and hence the amount of protein produced by those genes - and that one particular variation creates a binding site for the transcription factor C/EBP. Transcription factors are proteins that regulate the expression of genes, and this particular site altered the levels of a gene named SORT1. But what does SORT1 do? To answer this they again turned to GM mice, using virus vectors that specifically reduced or increased the levels of SORT1 in the mouse liver. Reducing or eliminating SORT1 expression in the mouse liver led to a reduction in the levels of LDLC in the blood, and that this was found to be due to SORT1 regulating the production of very-low-density lipoprotein (VLDL), a precursor to low-density lipoprotein, in the liver. As a result of this work a whole new pathway for the regulation of blood lipids has been uncovered, one that may offer new opportunities to scientists developing treatments for hypercholesterolemia.

As a BBC news report indicates, the identification of these genes and the elucidation of their function may aid the development of better diagnostic tools to identify those at risk of heart disease, and ultimately the development of better treatments.

These studies illustrate how important animal models, particularly GM mice, are to efforts to decode the human genome. As the biosciences move towards a more systems based approach to biology, one where knowledge of how networks of genes interact to produce a particular physiological or clinical outcome is applied to areas such as toxicology, the information that studies of GM animals can yield will become increasingly important. This importance has not gone unrecognized by the wider scientific community, the 2007 Nobel Prize in Medicine was awarded to Mario Capecchi, Sir Martin Evans, and Oliver Smithies for their discoveries of " principles for introducing specific gene modifications in mice by the use of embryonic stem cells".

With this in mind let’s turn briefly to another GM animal that’s been in the news lately - the rat. While GM mice have become a mainstay of modern scientific research the rat has lagged behind, which is a shame since the larger size, longer lifespan, and more complex behavior of rats make them more effective animal models than mice for studying many human diseases, particularly neurological conditions. The lack of GM rats was due to the difficulty in growing rat embryonic stem cells (ESCs) in culture, a necessary first step in the most common methods of producing GM animals. Last year Matthew Evans wrote an article for the Pro-Test blog discussing how scientists at the University of Cambridge and the University of Southern California had developed a method for growing rat ESCs in culture, and how this achievement paved the way for the production of transgenic rats. Last week the same group of scientists announced that they had employed this method to produce GM rats whose p53 gene, a key tumor suppressor that is defective in several cancers, was deleted.

This is not the first time GM rats have been produced, as for the past few years scientists have been able to use zinc finger nucleases to knock-out rat genes. Zinc fingers, so called because one or more zinc ions stabilizes the finger like structure, are found in many proteins, allowing them to bind specifically to a structure within a cell, such as a particular DNA sequence. Scientists found that they could produce artificial zinc fingers that recognize particular genes, and then join a nuclease to that zinc finger so that it cuts out the target gene. This method, discussed in more detail in this excellent article by Elie Dolgin, allows scientists to knock-out genes in rat embryos. The downside of the zinc finger nuclease technique can only be used to knock-out genes, whereas the ESC method is more flexible – it can also be used to add extra copies of a gene, or to delete genes in specific tissues or stages of development.

It is now clear that the rat is joining the mouse at the forefront of the GM revolution in medicine, and that has to be great news for medical science and the patients that depend on it.

Paul Browne

1) Teslovich T.M. et al. "Biological, clinical and population relevance of 95 loci for blood lipids" Nature Volume 466, Pages 707-713 (2010) DOI:10.1038/nature09270

2) Musunuru K. et al. "From noncoding variant to phenotype via SORT1 at the 1p13 cholesterol locus" Nature Volume 466, Pages 714–719 (2010) DOI:10.1038/nature09266


Permalink 02:29:04 pm, by Tom, 886 words, 1842 views   English (UK)
Categories: Information

Septic shock: Mice show way to a new treatment

When we think of the immune system we usually think of the adaptive immune system - the B-cells and T-cells that recognize and destroy specific pathogens – which isn’t surprising since this is the arm of the immune system that vaccines are designed to stimulate. However working alongside the adaptive immune system is the innate immune system which protects us form infection in a non-specific fashion. Key to this system are phagocytes, a diverse set of cells whose primary characteristic is their ability to consume and digest invading microorganisms and secrete a range of chemical messengers known as the proinflammatory cytokines which stimulate other components of the immune system. This usually a useful part of the immune response, but sometimes there is an excessive release of cytokines which causes the patient to enter a condition known as septic shock where the immune system over-reacts and causes serious tissue damage, eventually leading multiple organ failure. As a consequence of the increase in complicated surgery, implantable medical devices, elderly patients and patients with weakened immune systems, there has been an increase in the incidence of septic shock in recent years, and with around half of septic shock cases proving fatal it is now the number one cause of death in intensive care units.

This week a multinational team of scientists based in Bern, Frankfurt, Glasgow and Singapore, and led by University of Glasgow physician Professor Alirio Melendeza, have published a paper in Science (1) announcing an important development in the struggle to reduce the death rate from septic shock.

They had previously used in vitro cell culture techniques to identify an enzyme called sphingosine kinase 1 (SphK1) in human phagocytes and demonstrated using both RNAi and a specific inhibitor of SphK1 called 5c that SphK1 was involved in stimulating the cellular signaling pathways that promote release of proinflammatory cytokines. In this study they began by examining phagocytes isolated from 30 septic shock patients, finding that SphK1 levels were higher in these patients than in a control group. They next found that treating the phagocytes from septic shock patients with the inhibitor 5c blocked the production of proinflammatory cytokines by these cells in response to exposure to bacterial lipopolysaccharide, a molecule found on the exterior of some bacteria that usually provokes a strong inflammatory response.

The ability of 5c to block SphK1 dependent inflammation in-vitro was impressive but would the same happen in a whole organism where other pathways might promote inflammation? The team led by Professor Melendez next examined if 5c or RNAi could protect mice which were injected with an otherwise lethal dose of lipopolysaccharide, and they found that both methods of blocking the action of SphK1 did indeed provide complete protection against septic shock.

This was a very exciting result but acute, one-off exposure to lipopolysaccharide in vitro or in vivo is not the same as bacterial infection, where bacteria are multiplying and constantly interacting with the immune system to induce inflammation. Of course it is also vital that when turning down the inflammatory response the treatment doesn’t also compromise the immune system’s ability to fight the infection. The team therefore assessed whether pre-treatment with 5c or RNAi could prevent systemic inflammation and mortality from septic shock in a mouse model that simulates microbial infection in humans following surgery or injury, and not only was the immune system’s ability to combat the infection not compromised but the infection was cleared more quickly.

Pre-treatment is all very well but in the clinic treatment almost always starts after sepsis develops, so it was cheering to note that the inhibitor 5c reduced mortality when given up to 12 hours after infection it reduced mortality from septic shock, though it was most effective when given within 6 hours. This was as effective as the broad-spectrum the antibiotic co-amoxiclav, a standard treatment for sepsis, and when co-amoxiclav was administered along with 5c the combination was observed to be considerably more effective than either treatment used alone.

Professor Melendeza and his colleagues have identified an exciting new approach to reducing the toll from septic shock, hopefully work is already underway to translate this promising study from the bench to the bedside.

In other news the 2010 Kavli Prize in Neuroscience has gone to three scientists, Richard H. Scheller, Thomas C. Südhof, and James E. Rothman, who have “used a creative multidisciplinary set of approaches to elucidate the key molecular events of neurotransmitter release”. Their work, which involved the study of tissues from a variety of species including rats and marine rays and studies of knockout mice, has made a huge contribution to our understanding of how the release of the molecules that carry messages between the cells of the immune system work. This research may sit squarely in the realm of basic science, but the understanding of nerve cell communication that these three scientists have provided is now informing the development of new therapies for a wide range of psychiatric and neurological disorders.

Both these news items may at first seem unrelated, but what they have in common is animal research at the heart of a multidisclipinary approach that is increasingly typical of how biomedical science is done in the 21st century.
Paul Browne

1) Puneet P. et al. "SphK1 Regulates Proinflammatory Responses Associated with Endotoxin and Polymicrobial Sepsis" Science Volume 328(5983), pages 1290 - 1294 (2010) DOI:10.1126/science.1188635


Permalink 04:56:32 pm, by Tom, 1255 words, 1881 views   English (UK)
Categories: Information

Finding animal research in medical news

One of the things that often strikes me when reading about medical advances or clinical trials is how variable the reporting of basic and applied research, including animal research, that underpins the clinical research is. In some cases it is discussed in some depth, but far too often it is either skimmed over or not mentioned at all. This is a shame since it makes it more difficult for readers to make the connection between what is happening in the clinic and animal research that may have begun years earlier. A few recent stories in the news illustrate this variability very nicely.

I’ll start with an excellent report by Miriam Falco on CNN entitled “Stem cell treatment goes from lab to operating room” which describes a clinical trial of fetal stem cells in the treatment of Amylotrophic Lateral Sclerosis (Lou Gehrig’s disease), a progressive neurodegenerative disease affecting the motor neurons that leads to severe muscle weakness and eventually death as the muscles that control breathing fail. As the CNN report points out research on rats was vital to the identification of the correct type of cells for this transplant, and Dr. Eva Feldman demonstrated that injecting fetal stem cells into rats with ALS preserved the large motor neurons and muscle strength.

'Lead researcher Dr. Eva Feldman, a neurologist at the University of Michigan, designed the trial just four years ago. After a lot of animal testing, her team determined that using fetal nerve stems rather than human embryonic or adult stem cells (such as bone marrow stem cells) was most effective, she says.

Stem cells have the ability to turn into different cells in the body. However, human embryonic stem cells, which come from 4- or 5-day-old embryos, also been found to sometimes turn into cancer cells. Fetal stem cells, such as those used in this trial, are a few weeks older and have already taken on a specific identity — in this case nerve cells.'

'Feldman says the fetal stem cells used in this trial did not become any of the unwanted cell types. “That’s very, very important,” she says.'

Basic animal research showed the potential of this therapy, but applied research also played an important part in making this clinical trial possible. Through studies on pigs Dr. Nicholas Boulis developed an apparatus that allows the stem cells to be injected at precise locations in the spine, and then practice the technique before attempting to use it on a human patient.

'Animal testing also proved very useful when it came to figuring out how to actually inject the stem cells. Emory University’s neurosurgeon Dr. Nicholas Boulis invented the device that holds the needle that injects the stem cells. The goal is to inject the cells without injuring the spine and causing even more paralysis. He practiced on 100 pigs before attempting the procedure on a human.'

Our second report is from the LA Times, and in an article entitled “A personal fight against a lethal childhood illness” reports on the work being done at the Centre for Duchenne Muscular Dystrophy at UCLA. It’s a nice report which shows how passionate scientists like Stan Nelson and Carrie Miceli are about finding effective treatments and cures for serious diseases. While the report does refer to experimental therapies such as exon-skipping and gene therapy it unfortunately does not discuss them or the research that led to their development in any depth.

Exon skipping is a particularly innovative approach to treating some cases of Duchenne Muscular Dystrophy (DMD) where the disease is due to a mutation in the dystrophin gene that stops translation from messenger RNA prematurely and prevents the production of the protein dystrophin. In exon-skippping a molecule known as an antisense oligonucleotide or morpholino acts to remove the portion of mRNA that contains the mutation and allows the translational machinery of the cell to read through and produce a working dystrophin protein. As I discussed in a post last year research in mice and dogs has been crucial to the development and refinement of exon-skipping and early versions of this therapy have already had promising results in clinical trials undertaken at Great Ormond Street Hospital in London and Royal Victoria Infirmary in Newcastle. Gene therapy, where the faulty dystrophin gene is replaced by a working version, is also being developed, though it has not yet entered human clinical trials. A recent review (1) available to read for free at PubMed Central discusses the progress that has been made in recent years, the challenges that remain before DMD can be cured, and the vital role played by animal models in overcoming these challenges. The review also covers stem cell therapy for DMD, another exciting approach to treating the disease that we have discussed previously.

The final news item is a BBC report on a successful clinical trial of stem cells to treat Multiple Sclerosis, this time using stem cells isolated from a patient’s own bone marrow. Multiple Sclerosis (MS) is an autoimmune disorder where the patient’s immune system turns on the myelin sheath that insulates the axons of nerve cells, leading to a range of often serious neurological problems. At present few effective treatments have been approved for MS, and several are currently being evaluated in clinical trials. While the improvements seen in the clinical trial were modest they do hold promise for longer and lager trials that are now being planned, and I suspect that as with other therapies the key might be to start treatment early to prevent damage as well as allowing damage to be repaired.

The trial at Frenchay Hospital in Bristol built on years of careful animal research, including research conducted by Professor Neil Scolding who lead this clinical trial. Interestingly the research, conducted in mice with experimental allergic encephalomyelitis that reproduces many of the features seen in autoimmune diseases that attack the myelin sheath, showed that rather than replacing the damaged cells that produce the myelin sheath or nerve cells the injected stem cells protected the myelin sheath and nerve cells by turning down the pathogenic immune response responsible for damaging the myelin sheath (2,3). This was important since it meant that it was not necessary to inject the stem cells directly into the site of the MS lesion, rather the cells could be as (if not more) effective if injected into the bloodstream so that migrate to tissues such as the lymph nodes where they can interact with cells of the immune system. This discovery paved the way for the clinical trial reported by the BBC.

There’s a lot of stories in the news that are relevant to animal research, the trouble is that it’s not always easy to see the connection. At Speaking of Research we believe that the onus is on scientists to make sure that when they talk to reporters they give the full picture of what their research involves, and what earlier studies it depended on. Only then can the public really begin to appreciate just how important animal research is to continued medical progress.

Paul Browne

1) Wang Z. et al. “Gene Therapy in Large Animal Models of Muscular Dystrophy” ILAR J. Volume 50(2), Pages 187-198 (2009). PMCID: PMC2765825

2) Matysiak M. et al “Stem cells ameliorate EAE via an indoleamine 2,3-dioxygenase (IDO) mechanism” J Neuroimmunol. Volume 193(1-2), Pages 12-23 (2008) DOI:10.1016/j.jneuroim.2007.07.025

3) Gordon D . et al “Human mesenchymal stem cells abrogate experimental allergic encephalomyelitis after intraperitoneal injection, and with sparse CNS infiltration.” Neurosci Lett. Volume 448(1), Pages 71-73 (2008) DOI:10.1016/j.neulet.2008.10.040

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