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Pro-Test: standing up for science
Pro-Test: Standing Up For Science
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17/09/10

Permalink 05:10:54 pm, by Tom, 1244 words, 12907 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

08/09/10

Permalink 05:11:44 pm, by Tom, 307 words, 3331 views   English (UK)
Categories: News

EU Parliament approves new directive on animal research

Back in June we reported on the progress of the new European Union (EU) directive on the use of animals in research. Representatives of the EU Commission, Council, and Parliament had agreed on the text of the new directive, and it just awaited a final vote by the EU Parliament before becoming law.

As our colleagues at Understanding Animal Research have reported MEPs voted this morning to approve the directive. At this stage the text can no longer be ammended, and will become law as soon as it is formally signed and published by the EU Council. It will be then be the duty of the member state governments to transpose the new directive into national law.

The directive approved today represents a huge improvement on the early draft that was proposed back in 2008, and much of the credit for that improvement must go to EU scientists who took such an active part in the debates, discussions and consultations that were part of this process. Without this crucial intervention by thousands of scientists we could have been looking at a very different directive today, one very likely to be harmful to European science. Instead, we now have a directive that strike an excellent balance between ensuring good animal welfare standards and facilitating excellence in scientific research.

At this time of grave concerns about the effects of cuts in government funding of science the new EU directive is a welcome reminder of what the scientific community can achieve when it pulls together.

Addendum: Some news just in, four more animal rights extremists affiliated with the group Stop Huntingdon Animal Cruelty (SHAC) have pleaded guilty to conspiracy to blackmail. Let's hope that they receive sentences that will serve as a warning and deterrent to other activists who may be tempted to cross the line between legitimate protest and extremism.

31/08/10

Permalink 08:36:28 pm, by Tom, 669 words, 2679 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

18/08/10

Permalink 02:53:44 pm, by Tom, 1426 words, 2060 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

27/07/10

Permalink 05:17:09 pm, by Tom, 572 words, 3265 views   English (UK)
Categories: News

Home Office Statistics for 2009: Challenges ahead for UK Science

This morning the Home Office published the statistics on animal research for 2009 , and they make interesting reading. One change is that after a decade which has seen a steady rise in the number of animals used, and a sharp rise of 14% in 2008, the total number of procedures performed fell by 1% to just over 3.6 million. The rise in 2008 and subsequent fall in 2009 may represent a statistical blip, but it may also reflect the impact of the recession as projects were moved forward in anticipation of reduced funding in the future. With government funding of all scientific research in the UK facing cuts of up to 25% in the years ahead, it is likely that we will see further falls, since government funding through the research councils pays for about a third of projects involving animal research. After all, the increase we have observed over the past decade was due to a large extent to increases of about 50% in real terms in spending on biomedical research by the government, and we cannot now expect animal research to be immune from funding cuts. A lot will depend on whether spending by medical research charities and industry, which account for the remainder of the funding and also saw large increases in the past decade, can fill the gap left by government spending cuts.

One milestone passed this year was that for the first time over 50% of procedures involved the breeding or study of genetically modified animals (mainly rodents), which reflects a trend that we have noted before and reflects the growing importance they have to fields as diverse as cancer research and developing treatments for Duchenne Muscular Dystrophy.

One comment that stands out in the statement by Home Office Minister Lynne Featherstone is that the Government is“committed to ending the testing of household products on animals”, a frequent demand of animal rights groups. This would seem to be an easy promise to fulfill since, as our friends at Understanding Animal Research have pointed out, no such tests were performed in 2009, and very few, or none, in previous years of the past decade. The safety testing of household products on live animals has effectively already been ended by changes in the regulatory framework for chemicals, for example to the European REACH regulations and the recent development of alternatives that use cultured cells or tissues from dead animals and are sufficient for the evaluation of most cosmetics or household products. This is a perfect example of the 3Rs in action.

Overall this is a report that reflects both the profound changes that are happening in how and why animal research and toxicity testing is done, and the challenges facing British science as a whole in this time of austerity.

Turning to the activities of animal rights campaigners, we find that the Leicester Mercury has noted the tendency of a campaign by the National Anti-Vivisection Alliance* against a new laboratory at the University of Leicester to be economical with the truth. This will be no surprise to those of us who have been watching NAVA’s increasingly desperate attempts to stir up opposition to the new laboratory in Leicester, but will I’m sure be an eye-opener for Leicester citizens not yet familiar with degree to which some animal rights groups will misrepresent and distort the truth to advance their cause.

* NAVA is a new group, and is not to be confused with the more established National Anti-Vivisection Society

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