Herceptin: When personalized medicine and animal research meet.

Posted on September 2, 2010 by Blue Sky Science

Personalized medicine is very popular among medical researchers these days, and it’s not hard to see why. By tailoring treatment to fit an individual patient, for example by using information about their genetic makeup, scientists hope to make treatments more effective while at the same time avoiding or minimizing adverse effects.

Anti-vivisectionist Dr. Greek writes about personalized medicine as if one could do this work without relying on animal research at all.

For example, he writes:

When will personalized medicine become a reality?

We are already seeing it, with breast cancer being a prime example. Breast cancer treatment is now determined in part based on a patient’s genetic makeup. About 25-30 percent of breast cancer patients overexpress the HER2 oncogene, which is a gene involved in the development of cancer. The overexpression results in an increase in the replication of the cancer cells. Physicians are now able to identify which breast cancer patients overexpress HER2 and give them Herceptin, a monoclonal antibody that inhibits HER2

This is true…  but where did Herceptin come from?   Does he know?

Herceptin, a humanized mouse monoclonal antibody. Image courtesy of Andrey Ryzhkov.

The basic research that led to the development of Herceptin (Trastuzumab) goes back to work by Milstein and Kohler who discovered the potential for using antibodies to fight disease.    They developed the first methods to produce monoclonal antibodies using mice.   Both Milstein and Kohler went on to win the Nobel Prize partly for this work.

Harold Varmus (now back as Director of the National Cancer Institute) showed that disturbances in some gene families could turn the cells cancerous.  He also went on to win the Nobel Prize for this work.  Robert Weinberg subsequently discovered in rats that a mutant gene (named “neu”) encoding a tyrosine kinase promoted cancer features in cells, contributing to the development of neuroglioblastoma tumors.

Later, Axel Ullrich and collaborators at Genentech cloned the human HER2/neu gene.  Work at UCLA Dennis Slamon and colleagues showed HER2 over-expression in 25% of patients with aggressive breast cancer.

Through screening studies on monoclonal antibody candidates in vivo in mice implanted with HER-2 positive human tumors the group at Genentech then developed the mouse 4D5 (parent of Herceptin) and showed that 4D5 could suppress the growth of HER2 tumor cells as well as enhance the ability of the host immune system to kill them.   A collaboration between UCLA and Genentech then demonstrated that radio-labeled 4D5 localized to HER2-expressing tumors in both mice and human patients.

With the information obtained from animal experiments, Genentech created Herceptin by humanizing the 4D5 mouse antibody directed at HER2.   The ability of Herceptin to prevent tumor growth was then assessed in mice implanted with HER-2 positive human tumor xenografts, and the concentration of Herceptin required in the blood to achieve anti-tumor activity was determined before starting human clinical trials.

So, you see…  Herceptin was derived from a mouse antibody.

Let me repeat: a mouse antibody!

Clinical trials in humans subsequently showed the effectiveness of Herceptin to treat HER2 positive breast cancer.

Perhaps, Dr. Greek and other animal rights activists should carefully listen to the experts that were actually involved in the process of developing Herceptin (a drug he appears to thinks highly of) which, indeed, benefits so many women battling breast cancer.   A drug derived from mice, and developed in mice.

Here is what Robert Weinberg had to say about Dr. Greek’s views on research:

Dr. Greek says the silliest things, [...] implying that people are not studying human tumors, and implying that the kinds of experiments that one can do in mice can be done as well in humans — truly mindless!

I couldn’t have said it better.

Dario Ringach

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Heart failure breakthrough: animal research paved the way!

Posted on August 31, 2010 by Blue Sky Science

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.

Ivabradine can lower the heart rate while maintaining a normal blood pressure - good news for heart failure patients. Image courtesy of the CDC Public Health Image Library.

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

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Mice, rats, and the secrets of the genome.

Posted on August 17, 2010 by Blue Sky Science

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.

Blood flowing through the heart, but the cholesterol building up in an artery can cause a heart attack. Image courtesy of the British Heart Foundation

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.

The humble lab rat, now available in GM. Image courtesy of Understanding Animal Research.

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

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Of mice and mTOR: Can damaged spinal cords be tought to repair themselves?

Posted on August 10, 2010 by Blue Sky Science

There’s an interesting story on the BBC website about new research on nerve cell regeneration after spinal cord damage in mice, work undertaken by a team led by Dr. Zhigang He of the F.M. Kirby Neurobiology Center at Children’s Hospital Boston.

Nerve regeneration in mice requires mTOR. Image courtesy of Understanding Animal Research.

Those of you who follow developments on the field of spinal cord repair may find this story familiar. The study published online in Nature Neuroscience this week (1) follows up on work by the same team published two years ago (2) which examined whether regeneration of the optic nerve of mice could be promoted by using an adenovirus-based vector to locally delete several genes known to suppress cell growth. They found that knocking out gene named PTEN in the optic nerve encouraged regeneration of nerve cells following damage. PTEN inhibits the activity of the enzyme mTOR which is an important promoter of cell growth and survival, so removing PTEN increases mTOR activity and promotes regrowth of damaged nerve tissue. In agreement with this that found that mTOR levels are high in nerve cells of the central nervous system (CNS) in mice seven days after birth, when nerve cells are still naturally capable of regeneration and repair, but far lower two months later when such nerve regeneration is no longer observed. mTOR is a key regulator of cell growth throughout the body, and it’s activity is highly conserved throughout the evolutionary tree.

The latest study demonstrates that nerve regeneration through activation of the mTOR pathway does not only happen at the optic nerve but can also be induced in other parts of the CNS, with obvious implications for repairing spinal cord damage.

As the BBC report points out this is still quite preliminary work; the study demonstrated that the regenerated nervous tissue had all the features of normal nervous tissue, including the ability to form synapses that are needed to transmit signals from one nerve cell to another, but they have yet to show that it improves the function of the damaged nerve tissue. Other factors will need to be used alongside PTEN inhibition to encourage the regenerating cells to form a bridge across the damaged section of the spinal cord. The authors point out several promising approaches to achieving this are currently under development, for example growth factors that guide the growth of regenerating nerve cells to the correct location.

The PTEN knock-out approach used in these two studies, while useful in laboratory studies, is not suitable for the clinic because its effects are permanent. It should, however, be possible to develop a drug, perhaps using RNAi or Morphilinos, to temporarily turn off PTEN activity at the site of injury and promote nerve regeneration. Whatever approach is used it will be important to be able to target the increase in mTOR activity to the site of injury. mTOR is involved in the regulation of cell growth throughout the body and indiscriminate activation of it might have adverse consequences, after all several drugs are under development that turn off mTOR activity in cancer cells.

All in all it is an interesting piece of work, even if it only goes part of the way towards developing a therapy that can repair damaged spinal cords and prevent paralysis. This is an exciting time for research on treating paralysis, with a variety of techniques under development. These range from transplantation of stem cells such as Olfactory ensheathing cells or embryonic stem cells, to the development of robotic limbs controlled through brain-machine interfaces. Such a variety of approaches is entirely justified by the complexity of the problem that needs to be solved, not every technology will be appropriate for every patient, and furthermore it is likely that the regeneration-promoting technique described in this week’s report may help to increase the effectiveness of stem cell transplants.

It’s just another example of how important animal research is to progress in one of today’s most exciting areas of medicine.

Paul Browne

1)      Liu K. et al. “PTEN deletion enhances the regenerative ability of adult corticospinal neurons” Nature Neuroscience, published online 8 August 2010; doi:10.1038/nn.2603

2)      Park K.K. et al. “Promoting axon regeneration in the adult CNS by modulation of the PTEN/mTOR pathway.”  Science, Volume 322(5903), Pages 963-966 (2008) doi:10.1126/science.1161566

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Leicester – The New British Battleground?

Posted on August 3, 2010 by speakingofresearch

Back across the pond, in Leicester (pronounced “les-ter”), animal rights activists are warming up for a battle against a new £15 million (around $24 million) biomedical facility which the University of Leicester is building. Looking through the local rags, an interesting article came up in “this is Leicestershire” from a reporter who took a look round the current facilities.

So let’s set some context to the story:

The university has never let the media in before. They’re allowing it, they say, to set the public record straight.

Access was accepted with no preconditions and no promise to push the university’s side of the story.

So, here we are, on the threshold, fumbling into surgical scrubs, pulling on polythene overshoes that will stop us contaminating the facility with the outside world.

A security card is swiped, a pin code punched and a pair of heavy orange doors slowly part.

[...]

The facility manager says: “Treat this like a royal visit. If you see a door you want us to open, we’ll open it for you.”

Conditions - like similar labs across the country – are second to none:

Cages are clean, relatively roomy and well-stocked with plenty of things to gnaw at, burrow through or make nests in.

Clipboards full of completed job sheets show they’ve been inspected daily and had their cages changed at least weekly.

A big stainless steel cage-washer runs almost constantly in a room down the corridor.

Animals can be monitored every five minutes if the experiment they are undergoing puts them at risk of suffering or stress, says the facility manager.

Home Office inspectors come in every six to eight weeks. They can also make unannounced spot checks.

Every experiment, even on a humble mouse, has to clear a university ethics committee.

These ethics committees are comparable to the IACUC committees that exist in labs across the United States.  In this Leicester Lab (which is looking to improve its facilities with a new £15 million lab) the 3Rs are at the forefront of researchers:

The more you see, the more you realise everything in here is controlled and moderated.

Nothing, not even the wood shavings these rodents use as a bed and toilet, contains a rogue variable.

The shavings are sourced from Finland. They are ground down from white wood aspen trees because red woods contain chemicals that can be harmful to mice.

The chippings are sterilised and irradiated so no bugs or bacteria can influence the results of experiments.

That makes for better science, says Prof Barer.

Fortunately, the author also makes mention of the benefits which animal research brings to society.

The benefits of animal research are there for us all to see, say animal test supporters.

Foods which help to prevent cancer have been identified in this Leicester lab, as have new ways to get oxygen into bodies after lung failure. That’s the kind of science that is helping desperately premature babies to survive and could yet save thousands in a flu pandemic.

Prof Barer works in the field of TB research.

“Tuberculosis kills two million people every year,” he says.

“If I see an opportunity to reduce the suffering caused by that disease through the careful, considered use of animal research, then I will.

“I don’t like it, but I think it is justified. As a diabetic, I’m someone whose life expectancy is directly related to discoveries made in animals.

What is more interesting is the absolute steadfast blindness shown from animal rights activists in the area:

Protestor Chris Williams believes animal experimentation is wrong morally and ethically, and is driven by bad science.

He also believes they are experimenting on dogs and primates in the University of Leicester.

[...]

“I’m 110 per cent certain they’ve got dogs in that building and 90 per cent sure they’ve got primates”, he says.

Unless the university is lying to the Home Office and funding the research covertly, he is mistaken.

Chris is a spokesman for the Stop the Leicester Animal Lab protest.

He doesn’t have a job. He’s been campaigning, pretty much full-time, for the best part of two years.

Fortunately the reporter actually gathers his facts, rather than creates them.

Chris accuses the university of being economical with the truth.

The same could be said of the Stop the Leicester Animal Website.

None of the horrific photographs it contains – dogs and rats in desperate states – come from the facility at Leicester.

“It wouldn’t be a very effective website if we didn’t have photos,” says Chris.

But the suffering shown on their website doesn’t come from Leicester. Perhaps people should be told that.

The article is a nice piece which looks at some of the conceptions and misconceptions surrounding animal research. Perhaps animal rights activists need to spend more time being reporters themselves and finding out what actually happens in labs themselves rather than trusting every YouTube video they find.

Cheers

Tom

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Hopping rabbits herald breakthrough in tissue engineering

Posted on July 30, 2010 by Blue Sky Science

A team of NIH-funded scientists and veterinarians at Columbia University, the University of Missouri, Clemson University, and the Medical University of South Carolina, have this week announced a significant advance in tissue engineering, for the first time they have used cutting–edge tissue engineering technology to produced a moving joint, in this case the hip, in rabbits.  A press release on the NIH website discusses the work in some detail, and those with a subscription can read the original research article in the Lancet.  This is not the first paper to describe the production of bone or cartilage using tissue engineering, but it is the first time that the two tissues have been regenerated together to produce a moveable joint, and represents a significant step forward in terms of the complexity of tissue that can now be engineered.

Rabbits are a popular experimental model for the study of bone repair and regeneration; the structure of their bones is very similar to that seen in larger animals including humans, for example unlike some smaller rodents they have structures known as  Haversian canals that affect bone growth and repair, while their size allows more complex surgery than is possible with smaller rodents.

Tissue engineering techniques we have discussed previously, such as the artificial trachea and lung involved seeding a scaffold, were created by stripping cells from donor tissue, seeding with stem cells, and then allowing the cells to grow in vitro to produce a functioning organ. The technique reported this week differs in that the scaffold was made from an artificial bio-polymer, and rather than implant stem cells into the scaffold and growing the tissue in vitro, they coated the scaffolds with the growth factor known as TGFβ3 and then implanted it into the rabbits. TGFβ3 attracts bone and cartilage precursor cells to the scaffold, where they multiply and after a few weeks have formed a functioning joint.  When they compared scaffolds coated with TGFβ3 to bare scaffolds, they observed that more precursor cells were recruited to the scaffold when TGFβ3 was present, and that the rabbits transplanted with TGFβ3-coated scaffolds moved more easily when assessed one to two months after surgery, indeed the joints were able to support the weight of the rabbits without any limping.

Rabbits play an important role in medical research. Image courtesy of Understanding Animal Research.

This technique is significantly simpler than those approaches that require stem cell seeding and in vitro growth prior to transplant, and might be especially useful for younger hip transplant patients, individuals aged 65 or younger. Younger patients would be expected to recover more quickly, have fewer co-morbidities that would be aggravated by staying in bed for a prolonged time to allow the tissue to regenerate, and would benefit more from not having to have hip operations every 10-15 years as is currently the case with metal hip joints.  For more elderly patients metal hip joints are likely to remain the best option.

So does this technique replace that used in the tissue engineering studies we have previously discussed? Well, the answer is no, for some applications either approach might work, but for others, for example the trachea, artery and lung transplants, the tissue needs to be capable of functioning immediately following transplant. One aspect that is being evaluated elsewhere is the use of biopolymer scaffolds, which are being used with stem cells to produce replacement blood vessels, and may provide a more flexible and reliable alternative to the use of decellularized tissue.

It’s an interesting development, and one that again highlights how quickly things are happening in the field of tissue engineering. Of course it will be some time before clinical trials in humans start, before then this technique must be evaluated in a larger animal, probably a pig, to determine whether tissue regeneration on the scaffold is rapid and effective enough in a model of comparable sizes to humans. Only if these tests are successful will this technique warrant evaluation in a human clinical trial.

Paul Browne

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Microbicide gel cuts HIV infection rates…thank the monkeys!

Posted on July 21, 2010 by Blue Sky Science

There was exciting news on Monday when it was announced at an international AIDS conference in Vienna that microbicide gel had dramatically reduced the transmission of HIV in a Phase 2 clinical trial involving 889 women in South Africa.  If confirmed by  larger phase 3 trials this gel will offer millions of women a way to protect themselves against this dread disease that blights communities around the world.

Dr Abdool Karim explains how to use a microbicide gel applicator. Image courtesy of CAPRISA.

Unlike previous microbicide gels that failed to offer significant protection against HIV infection this gel included the anti-retroviral drug tenofovir. Regular readers of this blog may recognize tenofovir, it was discussed in an article on the role of non-human primate research in developing HIV prophylaxis by virologist Dr. Koen Van Rompay that we posted last year.  Dr. Van Rompay’s article looked at the use of oral tenofovir in pre- and post-exposure prophylaxis rather than its use in a microbicide gel.

So did the research on preventing SIV transmission in monkeys influence the decision to use tenofovir in this microbicide gel? You betcha! In the first report of a Phase 1 trial of this tenofovir-containing microbicide gel published in 2006 (1) the authors state that the success of tenofovir in preventing SIV infection on monkeys – the same research discussed by Dr. Van Rompay – was a deciding factor when they took this gel into clinical trials.

‘Tenofovir gel, 9-[(R)-9-(2-phosphonylmethoxyprophyl) propyl]adenine monohydrate, a nucleotide reverse transcriptase inhibitor, has demonstrated ability to inhibit retroviral replication in animals and humans, and it has been well tolerated when used orally, as tenofovir disoproxil fumarate, (tenofovir DF; Viread) [16–20]. Tenofovir DF has been approved for treatment of HIV-1 infection and is increasingly used as part of therapeutic regimens for HIV-positive individuals [21]. Tenofovir has been proven to be effective in blocking the transmission of SIV in animal models when given as pre- or postexposure prophylaxis systemically or when applied as an intravaginal gel [22–25]. Tenofovir bisphosphate, the active intracellular moiety, has a very long intracellular half-life (> 72 h), which could allow for more convenient, coitally independent intravaginal use [26]. Given the data showing animal protection with tenofovir gel, and the extensive human safety data with oral tenofovir in HIV-positive patients, the HIV Prevention Trials Network (HPTN) decided to assess the safety and tolerability of tenofovir gel in HIV-negative and HIV-positive women and their male sexual partners (HPTN 050).’

The above passage also mentions that they tested whether the microbicide gel containing tenofovir could prevent vaginal SIV transmission in monkeys*, and the finding that it could drove their subsequent decision to take the gel into clinical trials.  This was an important decision, a review of HIV microbicide gels published in the journal Science (2) two years ago pointed out the failure to evaluate other microbicide gels in monkey models of HIV transmission allowed these gels to proceed into clinical trials where they subsequently failed.  It is notable that the microbicide PRO 2000, also evaluated in monkeys, is the only other microbicide to demonstrate an ability (albeit less dramatic) to prevent HIV infection in clinical trials.

So what now? Well the tenofovir containing gel will go on into larger phase 3 trials to further evaluate its ability to prevent HIV infection in women. In the meantime following a study showing that it can prevent the transmission of rectal SIV transmission in macaques (3) this gel is now in phase 1 safety trials in men.

This is welcome news after years of disappointment, and further evidence that where HIV is concerned there can be no shortcuts; all therapies whether microbicide gels or vaccines must be thoroughly evaluated in stringent animal models before being taken to human clinical trials. Perhaps now we can start to turn realism into optimism.

In other news this week, Americans for Medical progress have announced the 2010 Michael D. Hayre Fellows in Public Outreach. Neuroscientists Elizabeth Burnett and Scott Dobrin will use the fellowship grant to develop their project “Speaking Honestly – Animal Research Education (SHARE)”, which is designed to guide educators in leading classroom discussions on the humane use of animals in research in an engaging and interactive manner. We wish them the very best as they follow in the footsteps of the first Hayre fellow, Speaking of Research founder Tom Holder.

* Unfortunately this study was never published in the scientific literature, this is something that sometimes happens with pre-clinical studies performed by biotechnology and pharmaceutical companies…usually because they wish to keep the work confidential for commercial reasons…and is a source of great frustration to people like me who write about this work!

Paul Browne

1)      Mayer K.H. et al. “Safety and tolerability of tenofovir vaginal gel in abstinent and sexually active HIV-infected and uninfected women.” AIDS. volume 20(4), pages 543-551 (2006), DOI:10.1097/01.aids.0000210608.70762.c3.

2)      Grant R.M. “Whither or wither microbicides?”  Science. Volume 321(5888), pages 532-534 (2008), PubMed Central:PMC2835691.

3)      Cranage M. et al. “Prevention of SIV Rectal Transmission and Priming of T Cell Responses in Macaques after Local Pre-exposure Application of Tenofovir Gel” PLoS Med. Volume 5(8):e157(2008) DOI:10.1371/journal.pmed.0050157

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Shots without jabs: The future of vaccination.

Posted on July 19, 2010 by Blue Sky Science

Vaccines make a crucial contribution to public health, saving hundreds of millions of people from deadly or debilitating diseases every year, but it’s also fair to say that getting your shots is not the most pleasant of experiences. It’s not just a question of short term discomfort, many people suffer from needle phobias that can prevent them from getting necessary vaccination, and wherever you have used used hypodermic needles there is always the question of safe disposal of this biohazardous waste and the risk of needle stick injury. Now research conducted on mice and pigs at Emory University and the Georgia Institute of Technology shows that there may be a safer and less painful way to administer vaccines (1).

Dissolving polymer microneedle patch for vaccine delivery. Image Courtesy of the Georgia Institute of Technology.

The new vaccine patch uses an array of one hundred tiny needles to deliver the vaccine painlessly into the skin, but the clever part is that having done so the needles, which are made from a polymer material known to be safe for clinical use, dissolve within a few minutes so there is no hazardous sharps waste to be disposed of.  This is a significant advantage over previous microneedle patches that used metal or silicon needles. The vaccine is also injected in a solid form which makes it stable and less likely to break down in storage, an important consideration for clinics in developing nations and remote areas of the world.

So how do they know it works? Well they first had to make sure that the needles could deliver the vaccine into skin without breaking, and then quickly dissolve. The team led by Sean Sullivan assessed this using skin obtained from freshly slaughtered pigs, because pig skin is very similar to human skin in thickness and structure, and found that the microneedles delivered the vaccine successfully and then quickly dissolved.

Microneedles immediately after application of the patch to pig skin. Image courtesy of Georgia Institute of Technology.

Of course delivering a vaccine into the skin is not enough, you have to know if that vaccine will stimulate the desired response from the immune system. The team needed to assess whether the vaccine patch could provoke an immune response that is strong enough to protect against subsequent infection, and this is something that can only be properly done in a living animal.  When the vaccine patch was used to immunize mice with an influenza virus vaccine it provoked a robust and sustained response from the immune system, one that was in fact better than that observed with traditional intramuscular injection. Furthermore the vaccine patch immunized mice survived when infected with influenza virus three months after immunization, whereas all non-immunized control mice died.

Microneedles dissolving one minute after application of patch to pig skin. Image courtesy of Georgia Institute of Technology.

Vaccine patches promise a safe, painless and cheap alternative to vaccination via hypodermic needle, and as someone who likes to keep their shots up to date I’m hoping that this new method will succeed in human trials and soon be available in the clinic.

Paul Browne

1)      Sullivan S.P. et al. “Dissolving polymer microneedle patches for influenza vaccination”  Nature Medicine, Published Online 18 July 2010 DOI:10.1038/nm.2182

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