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

23/06/08

Permalink 03:19:44 pm, by Tom, 699 words, 2291 views   English (UK)
Categories: Information

How mice helped develop a new drug for MS

In the news today there have been reports that laquinimod, a new drug developed to treat multiple sclerosis (MS), has performed well in an early (Phase IIb) (1). An MS patient's immune system attacks their central nervous system, leading to impaired communication in the nervous system and finally to physical and cognitive disability. A key feature of MS are the lesions where the myelin sheath that protects nerve cells is damaged, and in this trial patients who took a 0.6 mg per day dose of laquinimod showed a 40% decrease in the number of lesions. Few patients suffered side effects, and those side effects were relatively mild and disappeared when treatment was stopped.

http://news.bbc.co.uk/1/hi/health/7462896.stm
http://www.mssociety.org.uk/research/potential_therapies/laquinimod.html

This is good news since at present there are only a few treatments available to block progression of MS and they have serious drawbacks. Current reatments need to be injected and can have cause serious side effects, and some have a general immunosuppressive effect and can leave the patient more vulnerable to infection or cancer.

The team at Active biotech who developed laquinimod knew that they needed a drug that could be given orally and reduced damage caused by the malfunctioning immune system in MS without suppressing the immune system more generally. Their starting point was a drug called linomide (roquinimex) which had shown promising effects against MS before the clinical trials were halted due to severe side effects in some patients. Subsequent studies in beagle dogs indicated that these side effects were, rather ironically, due to the fact that linomide can cause severe inflammation in some circumstances. By making a series of modifications to the chemical groups at different positions on the molecule the Active Biotech team generated numerous chemical derivatives of linomide (2)*. The next step was to determine structure–activity relationship of these derivatives, in other words to determine the relationship between the different structural changes and the ability of the molecule to inhibit the development of symptoms in an experimental model of MS. Since they needed to determine the effect of the modified compounds on the intact immune system they needed to use a whole animal model, and the model they chose was an acute experimental autoimmune encephalomyelitis (aEAE) mouse that reproduces some of the characteristics on MS but develops much more quickly. The new compounds that showed the greatest activity against aEAE were then tested for proinflammatory responses in beagles. These studies resulted in the identification of laquinimod, which has more potent anti-aEAE activity than linomide but a far lower tendency to induce inflammation.

Laquinimod was then evaluated against chronic relapsing experimental autoimmune encephalomyelitis (crEAE) in mice and rats (3) and found to be effective. This was an important result since crEAE is considered to be a more accurate model of MS than aEAE, though it takes longer to develop and is therefor not as suitable for large scale screening of drug candidates. Furthermore it was observed that unlike some current MS treatments laquinimod does not have a more general immunosuppressive effect.

On the basis of these results in animal studies and additional safety and pharmacokinetic data Laquinimod went into clinical trials in MS patients, the early results of which were announced today. A phase III trial involving over a thousand patients is now underway and will with luck confirm these results and demonstrate an effect on the progression of the disease over a longer time period.

Cheers

Paul Browne

* Although this paper was published in 2004 the work it describes was undertaken several years earlier and predates the work described in the 2002 paper by Brunmark G. et al.

1) Comi G. et al. "Effect of laquinimod on MRI-monitored disease activity in patients with relapsing-remitting multiple sclerosis: a multicentre, randomised, double-blind, placebo-controlled phase IIb study" The Lancet, Volume 371, Pages 2085-2092 (2008), DOI:10.1016/S0140-6736(08)60918-6

2) Jönsson S. et al. "Synthesis and biological evaluation of new 1,2-dihydro-4-hydroxy-2-oxo-3-quinolinecarboxamides for treatment of autoimmune disorders: structure-activity relationship." J. Med. Chem., Volume 47(8), Pages 2075-2088 (2004). PubMed 15056005

3) Brunmark G. et al. "The new orally active immunoregulator laquinimod (ABR-215062) effectively inhibits development and relapses of experimental autoimmune encephalomyelitis." J Neuroimmunol., Volume130(1-2), Pages 163-172 (2002). PubMed 12225898

19/06/08

Permalink 03:18:07 pm, by Tom, 466 words, 1658 views   English (UK)
Categories: Information

Oxford and the amphioxus genome

A commentary by Henry Gee in the scientific journal Nature this week (1) opens with the sentence "One might be forgiven for never having heard of the amphioxus, a small, vaguely fish-shaped creature , which spends most of its life buried in sand filtering detritus from seawater". While it's indeed unlikely that amphioxus will ever compete with lions or chimpanzees in the public imagination the commentary makes it clear that sequencing of the amphioxus genome (2) is an important milestone in genome science. As both Henry Gee's report and a post on the Oxford Science Blog make clear, Oxford Scientist Professor Peter Holland and his group at the Department of Zoology must take much of the credit for taking this project to its successful conclusion.

http://www.ox.ac.uk/media/science_blog/080619.html

Compared with vertebrates such as humans amphioxus is a simple organism, but it does have a dorsal tubular nerve cord and the flexible rod known as the notochord that characterize the phylum Chordata to which both it and vertebrates belong. In the more than 500 million years since we last shared a common ancestor with amphioxus both our genomes have undergone considerable evolutionary change, and as explained in the Oxford Science Blog post above the sequencing of the amphioxus genome has enabled us to start to make sense of these changes.

The importance of this work is by no means limited to improving our understanding of vertebrate evolution, it also has more general relevance to our understanding of how our genome controls development and influences health. Since the draft sequence of the human genome was published in 2001 scientists have been busy working out what it means, and attempting to answer such basic questions as how many genes are present and how are genes regulated. In doing so a lot has been learned by comparing our genome with that of other species, and then relating the similarities and differences seen there to the characteristics of the organisms. This enables scientists to pinpoint regions of the genome that have functions important in human or animal disease. While much research compares the human genome to that of closely related species such as monkeys or mice, comparisons to more distantly related organisms such as flies and even fungi can yield valuable information since regions of the genome that are conserved over such long evolutionary distances are likely to have important functions. With its interesting location on the vertebrate evolutionary tree the amphioxus genome is a valuable addition to the repertoire of genomes available for analysis.

Pro-Test congratulates Peter Holland and his co-workers on their achievement.

Cheers

Paul Browne

1) Gee H. "Evolutionary biology: The amphioxus unleashed" Nature Volume 453 (7198) , Pages 999-1000 (2008) doi:10.1038/453999a
2) Putnam N.H. "The amphioxus genome and the evolution of the chordate karyotype" Nature Volume 453 (7198), Pages 1064-1071 (2008) doi:10.1038/nature06967

12/06/08

Permalink 03:53:01 pm, by Tom, 459 words, 2231 views   English (UK)
Categories: Information

Animal research and the Millennium Technology Prize.

Yesterday in Helsinki Professor Robert Langer was awarded the 2008 Millennium Technology Prize for his work on intelligent drug delivery. The Millennium Technology Prize is the world's largest award for technological innovation and is considered by some to be the unofficial Nobel Prize for technology*. Prof. Langer was up against some very strong competition for the prize, including Sir Alec Jefferys whose invention of DNA fingerprinting helps to solve thousands of crimes every year.

http://news.bbc.co.uk/1/hi/technology/7448215.stm
http://www.millenniumprize.fi/news/89/66/d,news/
http://web.mit.edu/newsoffice/2008/langer-millennium-0611.html

For more than thirty years Prof. Langer has pushed the boundaries of biomaterials research; his work on controlled drug release has benefited millions of people worldwide, but his more recent work on areas as diverse as tissue engineering and ultrasound drug delivery (think Dr. McCoy in Star Trek) is also acknowledged to be world-leading. His research group at MIT includes over 100 scientists, making it the largest biomaterials laboratory in the world.

http://web.mit.edu/langerlab/

Obviously such research draws on a huge range of scientific disciplines, but in a review published a few years ago (1) Prof. Langer makes clear the important role played by animal experiments in the development and evaluation of technologies such as polymer microspheres used to deliver drugs to treat prostate cancer and polymer scaffolds used to engineer tissues such as cartilage. Animals are not only vital to the research process, but can also inspire new developments. In a recent publication by Prof. Langer and a team lead by his colleague Dr. Jeff Karp describes a waterproof adhesive bandage inspired by the sticky feet of the gecko lizard (2) and discusses the tests in rats that evaluated the adhesive properties and safety of different tissue adhesive designs. The bandage can hold together tissues but dissolves over time after the wound heals, which should make it ideal for the treatment of internal injuries and a safer alternative to stitches that are usually used today.

http://news.bbc.co.uk/1/hi/health/7250209.stm

Yesterday's award is further evidence of the enormous contribution made by animal experiments to exciting and innovative medical research. We congratulate Professor Langer and his colleagues on winning this award, and wish them well in their ongoing research.

* There are other awards that compete for this title, notably the Charles Stark Draper Prize awarded every year by the National Academy of Engineering which Prof. Langer won in 2002. http://en.wikipedia.org/wiki/Charles_Stark_Draper_Prize

Cheers

Paul Browne


1) Langer R. "Biomaterials in drug delivery and tissue engineering: one laboratory's experience." Acc Chem Res. Volume 33(2), pages 94-101 (2000) PubMed:10673317.

2) Mahdavi A. et al. "A biodegradable and biocompatible gecko-inspired tissue adhesive." Proc Natl Acad Sci U S A. Volume 105(7), pages 2307-2312 (2008). PubMed: 18287082.

06/06/08

Permalink 02:11:05 pm, by Tom, 477 words, 1948 views   English (UK)
Categories: Information

Calming the storm...while killing the virus

A couple of months ago we blogged about some interesting research that may lead to new drugs that to prevent the lethal "cytokine storm" that was responsible for most deaths in the SARS outbreak.
http://www.pro-test.org.uk/b2evo/index.php?blog=7&title=calming_the_storm&more=1&c=1&tb=1&pb=1

However SARS is not the only virus that kills by inducing an excessive immune response; the threat posed by the H5N1 strain of bird flu is of grave concern to many public health officials http://www.cdc.gov/flu/avian/. With an observed mortality rate of between 45% and 80% in infected humans here is little doubt that if it was to mutate into a form that was highly contagious in humans it could pose a great risk to the population, and possibly cause a pandemic on the scale of the 1918 Spanish flu. During outbreaks it has been observed that although some anti-viral medicines can kill the virus they did not reduce mortality rates, probably because they were administered too late to stop the virus from provoking the cytokine storm.

A study published online in Proceedings of the National Academy of Sciences of the United States of America (PNAS) this week (1) by Prof. Kwok-Yung Yuen and colleagues at the University of Hong Kong shows that it should be possible to both kill the virus and prevent the cytokine storm. Working with mice infected with the H5N1 virus compared administering the anti-viral drug zanamivir alone or in combination with anti-inflammatory drugs. A key element in their study was a decision to delay treatment for 48 hours after infection in order to mimic the real world clinical situation where the illness may not be diagnosed until some time after infection. Their results confirmed that zanamivir alone did not reduce mortality when compared to an untreated control group, and even though viral levels were a lot lower than in the control group only 13% of mice survived. In contrast when zanamivir was combined with the anti-inflammatory drugs celecoxib and mesalazine 53% of the mice survived, a very significant improvement, without compromising the ability of zanamivir to kill the virus.
Since all the drugs this study are already approved for human use this result should make a real difference to how we respond to any future H5N1 outbreaks, and indeed to outbreaks of other viruses that kill in the same way. It is sobering to reflect that even with this improved treatment the mortality rate was still frighteningly high, more research is clearly needed to help develop better drugs for the treatment of virus induced cytokine storms.

Cheers

Paul Browne

1) Zheng B.-J. et al. "Delayed antiviral plus immunomodulator treatment still reduces mortality in mice infected by high inoculum of influenza A/H5N1 virus" Proc. Natl. Acad. Sci. USA, Published online on June 3, 2008 DOI:10.1073/pnas.0711942105

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