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Pro-Test: standing up for science
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Archives for: April 2008

30/04/08

Permalink 02:45:50 pm, by Tom, 388 words, 1595 views   English (UK)
Categories: Information

Animal research behind the headlines

The BBC has reported on calls for the new blood-thinning drug Pradaxa (dabigatran etexilate/BIBR 1048) to be used more widely in patients who are at risk of blood clots following surgery, a serious complication that kills 25,000 patients each year. This drug works be inhibiting the enzyme Thrombin, a key player in clot formation.

http://news.bbc.co.uk/1/hi/health/7354818.stm

Clinical trials indicate that the new drug is as effective at preventing clotting as existing treatments, but that it is easier to get the dose right and that overall it is significantly safer. Another advantage is that it is taken as a pill rather than requiring daily injections, such injections are often painful and can lead patients to stop taking anticoagulant drugs such as heparin. Several large scale trials of Pradaxa are underway, and it is undergoing assessment by the UK's National Institute for Health and Clinical Excellence, although it has already been licensed for patients undergoing knee and hip operations on the NHS.

http://www.medicalnewstoday.com/articles/101952.php

We hope that the larger trials go well and that this drug is approved for use by NICE. In the meanwhile it's worthwhile to take a look at the contribution made by animal research to its development, and the role of animals alongside other computational, chemical and in vitro methods.

As is usual the early design of this drug relied on computer aided analysis of the structure of thrombin and in vitro studies using human thrombin (1). This analysis yielded a number of candidate molecules which were assessed for their ability to inhibit thrombin in rats and rabbits, and eventually one was identified that combined a potent ability to inhibit thrombin with low toxicity, even at high doses. Unfortunately this molecule was not active when given orally, it needed to be injected, so it was further modified in an attempt to make a drug that could be given in pill form. Several candidate drugs were assessed in rabbits and subsequently in monkeys and one, BIBR 1048, was found to have very good anticoagulant activity when given orally (1). On the basis of these results, and of course additional regulatory toxicity tests, BIBR 1048 was selected to go into clinical trials.

1) Hauel N.H. et al. "Structure-based design of novel potent nonpeptide thrombin inhibitors." J Med Chem. Volume 45, Issue 9, Pages 1757-66 (2002) PubMed: 11960487.

28/04/08

Permalink 02:22:02 pm, by Tom, 559 words, 2655 views   English (UK)
Categories: Information

Gene Therapy for Blindness

There is much excitement in the news today about reports that doctors at Moorfields Eye Hospital have used gene therapy to dramatically improve the night vision of an 18-year-old man suffering from Leber's congenital amaurosis. This disorder leads to a progressive loss of vision, and in many patients blindness at an early age. Until now there has been no effective treatment available for the condition.

http://news.bbc.co.uk/1/hi/health/7369740.stm
http://www.guardian.co.uk/science/2008/apr/28/genetics.medicalresearch

Defects in several genes can cause Leber's congenital amaurosis. In this trial which is published in the New England Journal of Medicine (1) the scientists focussed on a gene called RPE65, an enzyme which is crucial to the production of 11-cis retinal that rod photoreceptor cells in the eye need so that they can respond to light. They hoped that injecting an andeoviral vector that produced healthy RPE65 gene into the back of the eye would slow down or even reverse the deterioration in vision. Accompanying this paper in NEJM is another by a group based in Pennsylvania who found that gene therapy with RPE65 improved vision in three patients with Leber's congenital amaurosis, though the benefits were more modest (2)

This work was underpinned by years of research in animal models of Leber's congenital amaurosis, which demonstrated that gene therapy could safely treat the disorder (1). While transgenic mice were used in some of this research, several key studies involved the Swiss Briard dog, which is prone to progressive loss of vision due to a naturally occurring defect in the RPE65 gene (3,4). While these first human trials are underway further animal research is continuing to develop new vectors that deliver RPE65 specifically to cells of the retinal pigmented epithelium, the cells where loss of RPE65 causes the most problems, and which may produce better results than the method reported today (5). Interestingly the animal studies indicate that there is a window of opportunity within which therapy must be started for benefits to be seen, and it is probably no coincidence that in the Moorfield's Eye Hospital trial the patient who responded to the therapy had the least advanced disease of the three trial participants.

The trial results announced today are very encouraging, but it's important to remember that this is only the beginning. Research, both in animals and humans, will continue to improve gene therapy for Leber's congenital amaurosis, and in the near future we will no doubt be hearing more about the use of gene therapy to treat other once incurable diseases.

Regards

Paul Browne

1) Bainbridge J.W.B. et al. "Effect of Gene Therapy on Visual Function in Leber's Congenital Amaurosis" NEJM Online April 27 2008, http://content.nejm.org/cgi/content/full/NEJMoa0802268, DOI:10.1056/NEJMoa0802268

2) Maguire A.M. et al. "Safety and Efficacy of Gene Transfer for Leber's Congenital Amaurosis" NEJM Online April 27 2008, http://content.nejm.org/cgi/content/full/NEJMoa0802315, DOI:10.1056/NEJMoa0802315

3) Acland G.M. et al. "Gene therapy restores vision in a canine model of childhood blindness." Nat. Genet. Vol. 28, Issue 1, Pages 92-95 (2001), DOI:10.1038/88327

4) Jin M. et al. "Rpe65 Is the Retinoid Isomerase in Bovine Retinal Pigment Epithelium" Cell Vol 122, Pages 449-459 (2005), DOI:10.1016/j.cell.2005.06.042

5) Le Meur G "Restoration of vision in RPE65-deficient Briard dogs using an AAV serotype 4 vector that specifically targets the retinal pigmented epithelium" Gene Ther. Volume 14, Issue 4, Pages 292-303 (2007) DOI: 10.1038/sj.gt.3302861

19/04/08

Permalink 06:10:33 am, by Tom, 506 words, 2428 views   English (UK)
Categories: Information

Calming the storm

In recent years we have become all too aware of the danger posed by viruses avian H5N1 influenza and SARS. The high death rate associated with such infections is due to the infection causing acute respiratory distress syndrome (ARDS), where the infected individuals own immune system overreacts to the presence of the virus in what is termed a "cytokine storm". This cytokine storm does terrible damage to the lungs and is believed to have been responsible for killing over 20 million people during the 1918 Spanish flu pandemic.

While considerable effort has gone into developing vaccines and anti-viral drugs that may help prevent infection there is also an awareness that it will be difficult to roll out enough of these treatments in time in the event of a pandemic, so researchers have also turned their attention to trying to prevent or lessen the cytokine storm that actually kills most patients.

In a paper published this week in Cell (1) a multinational team led by Joseph Penninger have identified a key pathway that is involved in triggering the cytokine storm. Penninger and his colleagues knew that ARDS is a problem common to many species infected with influenza or SARS, so they carried out a series of experiments with knockout mice in order to identify genes required for severe lung damage in an experimental model of ARDS. They observed that deletion of a gene for the cell surface receptor TLR4 resulted in less damage to the lungs. Next a particular pathway mediated by the adaptor protein TRIF was discovered to lead from activation of TLR4 to increased production of the Interleukin-6 (IL-6), a cytokine previously associated with ARDS in humans (2).

So what activates TLR4 to set the chain of events in motion? The researchers examined a series of possible agents, and identified oxidized phospholipids (OxPLs) as the activators of TLR4. The amount of OxPLs was greatly increased in the lungs of mice with experimentally induced ARDS and mice exposed to H5N1 flu virus. Blocking TLR4 lessened the damage to the lungs of mice exposed to H5N1.

The relevance of this research to humans with ARDS was supported by analysis of tissues taken from SARS patients, which showed greatly increased levels of OxPLs, and by in vitro experiments showing that exposing human lymphocytes to H5N1 triggers oxidative stress and consequently increased OxPLs.

This study, which ably demonstrates how animal research helps make sense of clinical observations in humans, should lead to the development of new treatments for ARDS that target the TLR4 mediated inflammatory pathway. While these treatments will not stop the spread of a new pandemic they should help to reduce the toll of death and injury that follows in its wake.

Cheers

Paul

1) *Yumiko Imai et al "*Identification of Oxidative Stress and Toll-like Receptor 4 Signaling as a Key Pathway of Acute Lung Injury" Cell Volume 133, Issue 3, Pages 235-249 (2008) doi:10.1016/j.cell.2008.2.043

2) Madhav Bhatia and Shabbir Moochhala "Role of inflammatory mediators in the pathophysiology of acute respiratory distress syndrome" J. Pathol. Volume 202, Issue 2, Pages145-156. (2004) doi:10.1002/path.1491

11/04/08

Permalink 04:14:13 pm, by Tom, 512 words, 1609 views   English (UK)
Categories: Information

Avoiding the side effects of radiotherapy.

Radiation therapy has been a mainstay of cancer treatment for over a century, and in that time has saved the lives of countless patients, but at high doses can have serious side effects when it damages healthy tissue as well as killing cancer cells. A study published this week in the journal Science (1) describes a new drug that may help reduce these side effects, by activating a pathway that stops healthy cells exposed to radiation from initiating a process of programmed cell death.

A bacterial protein named flagellin can bind to and activate TLR5, a cell surface receptor that in turn activates a protein called NF-kappaB that is known to protect against radiation damage. The scientists lead by Dr Andrei Gudkov tested whether flagellin could protect mice against otherwise lethal doses of radiation. They observed that flagellin could protect the mice, but also that flagellin has undesirable side effects, so they next engineered a series of molecules based on flagellin and tested them for their ability to protect against radiation and whether they caused side effects. Tests in mice indicated that one of the molecules, named CBLB502, could protect against radiation as well as flagellin but without the side effects, and follow on studies also indicated that it was safe and effective in monkeys.

Of course if CBLB502 is to be useful in reducing radiation damage in cancer patients it is also vital that it doesn't interfere with the ability of radiotherapy to kill cancer cells. The ability of radiation to shrink tumours in mice treated with CBLB502 was compared to that in untreated mice, and no difference was observed between the two groups, indicating that CBLB502 will not interfere with radiotherapy.

These results are very promising, and clinical trials in cancer patients are expected to begin soon. This drug may not only reduce the side effects of radiotherapy but also enable doctors to use higher radiation doses when treating patients than is currently possible. As discussed in news reports CBLB502 may also be useful when treating people exposed to radiation due to an accident or terrorist attack.

http://news.bbc.co.uk/1/hi/health/7341336.stm

Animal tests indicate that it must be administered within an hour of exposure to be of benefit, which may limit its use in large incidents when many people are exposed, but it could be given to people at risk of radiation exposure or kept in readiness at workplaces where radioactive materials are present.

In other news the Wellcome Trust has published its annual report for 2007, available at http://www.wellcome.ac.uk/About-us/Publications/Annual-review/index.htm. Among many other topics it includes several examples of where animal research is advancing medical knowledge, for example in the development of a new class of antibiotics known as the lantibiotics. The report provides an excellent overview of the varied activities of the UK's largest medical research charity and is well worth a read.

1. Burdelya L.G. et al. "An agonist of Toll-Like Receptor 5 has radioprotective activity in mouse and primate models" Science Vol. 320, no. 5873, pages 226-230, DOI: 10.1126/science.1154986

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