Tag Archives: gene therapy

Defeating Leukemia: A smile that says “Thank the mice”

Posted on December 12, 2012 by | 1 Comment

A couple of days ago the New York times published a heart warming story about a young girl named Emma Whitehead whose acute lymphoblastic leukemia – which had previously defied all therapies – has gone into full remission following treatment with a novel gene therapy that programmed her immune system to target the cancer cells. The New York Times report noted that the therapy used a vector based on the HIV-1 virus to deliver genes – known as a chimeric antigen complex (CAR) – to modify  Emma’s T-cells so that they would destroy the leukemia cells.  This isn’t the first example of how scientists are using the properties of this deadly virus to develop powerful new therapies, back in 2009 we discussed how such a lentiviral vector was used to treat the genetic disease cerebral X-linked adrenoleukodystrophy. Emma wasn’t the only patient to benefit from this therapy developed by scientists at the University of Pennsylvania, 9 other patients with intractable leukemia have experienced partial or full remissions.

Emma2

Earlier today I received an e-mail from a long-time reader of this blog asking:

Did I dream there was an SR post on this already?”

Well my friend, you were not dreaming.

Last year we published a post entitled “A breakthrough against Chronic Lymphocytic Leukemia…thank the mice!” which discussed the role of animal research in the development of this therapy, and in particular that of mice the evaluation of chimeric antigen complexes in order to identify a complex that would induce a long-lasting immune response against the cancer cells. Our post also linked to an article on the Weizmann Wave Blog entitled “Cancer Breakthrough 20 Years in the Making” which described the basic biomedical research – mice were again crucial – that underpinned this field.

At the time I concluded the post by saying:

So there you have it, behind the headlines are years of graft by hard-working and innovative scientists, who utilised a wide range of experimental approaches – among which animal studies figure prominently – to develop a novel therapy for CLL.”

And I say the same again today. At a time when funding of medical research in the US is facing the threat of very damaging cuts, Emma’s story is a reminder of why you should write to your Senator and Congressional Representative today!

Paul Browne

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New gene therapy for mitochondrial diseases a step closer thanks to ONPRC

Posted on October 25, 2012 by | 1 Comment

Mitochondria are fascinating. These tiny organelles that reside within almost all of the cells in our bodies (mature red blood cells being an exception) generate the supply of a molecule called adenosine triphosphate (ATP) which is the principle source of energy that cells, and ultimately ourselves, need to survive. They also have an intriguing evolutionary history, being descended from bacteria that over one and a half billion years ago formed a symbiotic relationship with primitive eukaryotic cells that are the ancestors of today’s plants and animals. A legacy of this ancestry is that animal mitochondria contain a tiny genome that encodes 37 genes that are crucial to the mitochondria’s function, and separate from the main genome which is found in the nucleus of the cell and contains just over 20,000 coding genes. Unlike nuclear genes, half of which are inherited from our mother and half from our father, mitochondrial genes are almost always inherited from the mother only, which means that if a mother has a mitochondrial genome mutation it will always be passed on to her children.  However, since a human egg cell contains many mitochondria, and only some of them may be defective, there is usually a threshold level of defective mitochondria which must be reached before the defects cause disease in children, and the severity of disease can be very variable. Nevertheless inherited mitochondrial disorders affect as many as 4,000 children born in the USA every year, and for almost all of them treatment options are limited.

One way in which the transmission of mitochondrial diseases can be prevented is by screening embryos during IVF, and earlier this year we reported on how a team at the Oregon National Primate Research Centre (ONPRC) led by Dr. Shoukhrat Mitalipov discovered through studies performed on Rhesus macaques how to improve the efficiency of this screening. However in cases where screening does not identify eggs that are free from mitochondrial genetic defects other ways of preventing transmission of the disorders are being examined, and one of these is the possibility of replacing the damaged mitochondria with healthy mitochondria from a donor.

Yesterday in a publication in Nature (1), Dr. Mitalipov’s team at ONPRC announced another major advance made possible through research on Rhesus monkeys, the first demonstration that it is possible to replace the faulty mitochondria of a human egg cell before fertilization and create healthy looking human embryos, from which embryonic stem cells could be derived that were identical to controls created through normal IVF.

Mitochondrial Gene Therapy. Source Mitalipov Lab/OSHU

Briefly, the procedure involved the removal of the nuclear genetic material from the egg of a patient whose mitochondrial DNA contains mutations, and its transplantation into an egg containing normal mitochondrial DNA from which the nuclear genetic material has been removed.  More detailed descriptions and discussion of the process used in this therapy and the team’s results can be found on the Oregon Health and Science University website, reports on the BBC and LA Times, and in Nature News, it’s clearly been a study that has caught the imagination of a lot of people!  It’s worth noting that a child born after fertilization with the partner’s sperm would be free of risk from maternal mtDNA mutations as well as being the biological child of the patients, since the mitochondrial genome accounts for only 37 of over 20,000 coding genes in the body it is inaccurate to refer to these as 3 parent embryos.

The news reports make it very clear that research on monkeys was crucial to this advance, indeed the potential of the technique used – which they term spindle–chromosomal complex transfer – was first demonstrated when they were able to produce 3 healthy monkey infants in 2009 (2).  They started by examining the distribution of Rhesus monkey mitochondria during the process of meiosis – the type of cell division through which gametes (sperm and egg cells) are produced – using confocal laser scanning microscopy, and observed that at a particular late stage in the process termed the  metaphase II stage the mitochondria were distributed relatively uniformly throughout the cytoplasm,  except immediately around the chromosomes and the spindle apparatus (a protein structure segregates chromosomes between daughter cells during cell division), which were devoid of mitochondria.  This suggested that it might be possible to isolate the spindle–chromosomal complex at this stage and transfer it to an egg cell from which the egg had been removed without transferring any mitochondria at the same time.

A significant challenge was how to avoid damaging the spindle-nuclear complex during this operation, but the team had recently developed new techniques to transfer the nuclei of adult skin cells from monkeys into egg cells and successfully derive embryonic stem cells from the resulting clones.  By modifying these techniques they were able to reconstructed eggs that were capable of being fertilized normally, undergoing embryo development and producing healthy offspring. Genetic analysis confirmed that nuclear DNA in the three infant macaques originated from the spindle donors whereas mitochondrial DNA came from the cytoplast donors. This set the stage for the work announced yesterday.

In addition to reporting the production of human embryos through spindle–chromosomal complex transfer (ST) this week’s Nature paper (1) also reported the outcome of follow-up examination from birth to 3 years of four monkeys born through ST – the 3 reported in 2009 and one born subsequent to that publication – and found that they were developing normally and were in good health.

Because egg cells only remain viable for a short period of time after they are harvested from a donor, it is considered crucial that ST can be performed successfully using frozen egg cells for this technique to be clinically viable, so the team also examined if it was possible to do this using thawed Rhesus macaque cells. They were successful; the experiment resulted in the birth of a healthy monkey. More surprisingly they also found to their surprise that while the spindle–chromosomal complex could withstand prior cryopreservation the technique failed when the egg into which the spindle-chromosal complex is transferred had been frozen – indicating that most of the damage to the frozen egg is to its cytoplasm, rather than to the nucleus as had previously been thought, a discovery that may have wider implications for the future improvement of human egg cryopreservation and IVF techniques.

Impressive as this study is it is by no means the end of the road, this technique needs further refinement and optimization before anyone should attempt to use it in the clinic, but it does provide both scientists and ethicists with very valuable information.  This is particularly true in the UK, where the Human Fertilisation and Embryology Authority is reviewing this technique and another that is being developed by Professor Mary Herbert at the University of Newcastle. Speaking to the BBC yesterday, Peter Braude, Professor of Obstetrics and Gynaecology at King’s College London, said:

It is exactly the sort of science that the HFEA expert committee recommended needed doing, and demonstrates further the feasibility of this technique.”

We at Speaking of Research congratulate Dr. Mitalipov and his team at ONPRC on their groundbreaking work.

Paul Browne

1)      Masahito Tachibana, Paula Amato, Michelle Sparman, JoyWoodward, Dario Melguizo Sanchis, Hong Ma, Nuria Marti Gutierrez, Rebecca Tippner-Hedges, Eunju Kang, Hyo-Sang Lee, Cathy Ramsey, Keith Masterson, David Battaglia, David Lee, Diana Wu, Jeffrey Jensen, Phillip Patton, Sumita Gokhale, Richard Stouffer& Shoukhrat Mitalipov “Towards germline gene therapy of inherited mitochondrial diseases” Nature Published online 24 Oct 2012, doi:10.1038/nature11647

2)      Masahito Tachibana, Michelle Sparman, Hathaitip Sritanaudomchai, Hong Ma, Lisa Clepper, Joy Woodward, Ying Li, Cathy Ramsey, Olena Kolotushkina & Shoukhrat Mitalipov “Mitochondrial gene replacement in primate offspring and embryonic stem cells” Nature 461, 367-372 (2009) doi:10.1038/nature08368

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ERV blogs on GMO Herpes vs severe cancer pain

Posted on September 18, 2012 by | 3 Comments

As gene therapy emerges as one of the hottest areas of medical research, one thing that is striking is how it employs viruses – sometimes very nasty viruses - to deliver the gene to where it is needed in the human body.

Yesterday virologist Abbie Smith discussed another excellent example of this on the ERV blog in a post entitled “GMO Herpes vs. severs cancer pain”, describing how scientists at the Universities of Michigen and Pittsburgh have used a genetically modified herpes virus to deliver the preproenkephalin gene – which produced a precursor to pain-killing opiates – to the nerve cells of terminal cancer patients who were suffering from severe pain.

Abbie remarks that “This was one of the most depressing, yet hopeful, papers I have ever read.”. It’s difficult to disagree, after all most of the patients participating in the trial died within 3 months of it starting. But to focus on this sobering statistic would miss the reason for this study, namely that the pain-relief available to patients with severe chronic pain is often inadequate, as the drugs are not specific enough and cause unacceptable side effects when used at the high doses often required for prolonged periods of time. By targeting the opiate molecules to the nerve ccells themselves these side effects can be avoided, and more effective pain relief provided.

The paper “Gene Therapy for Pain: Results of a Phase I Clinical Trial” is available for anyone to read in PubMed Central and makes it very clear that this is a therapy that was discovered, evaluated and refined in animal models of different types of pain before entering this first clinical trial. The first two paragraphs of the introduction noting that:

A significant limitation to the development of analgesic drugs is that off-target effects at doses below the maximal analgesic threshold restrict the ability to selectively interrupt nociceptive neurotransmission1. To address this limitation, we developed a series of replication defective HSV-based vectors to deliver gene expression cassettes directly to DRG neurons from skin inoculation 2, 3. The anatomically defined projection of DRG axons allows targeting of specific ganglia by injection into selected dermatomes. In preclinical studies, the release of anti-nociceptive peptides or inhibitory neurotransmitters in spinal dorsal horn from the central terminals of transduced DRG neurons effectively reduced pain-related behaviors in rodent models of inflammatory pain, neuropathic pain, and pain caused by cancer4-9.

The human PENK gene encodes for preproenkephalin, a precursor protein proteolytically cleaved to produce the endogenous opioid peptides met- and leu-enkephalin. In the spinal cord, enkephalin peptides inhibit pain signaling through actions at presynaptic opioid receptors located on central terminals of primary afferent nociceptors and postsynaptic opioid receptors on second order neurons involved in nociceptive neurotransmission10. HSV vectors expressing opioid peptides appear to be particularly effective in animal models of inflammatory and cancer pain4, 5, 8.”

And in the conclusion:

In preclinical animal studies, skin inoculation of HSV vectors expressing PENK reduce acute hyperalgesic responses27, and reduce pain-related behaviors in models of arthritis28, formalin injection4, peripheral nerve damage6 and bone cancer5. Because this was the first human trial employing HSV vectors to achieve gene transfer, we elected to carry out the phase 1 clinical trial for safety and dose-finding in patients with pain caused by cancer…This Phase I clinical trial primarily addressed the question of whether intradermal delivery of NP2 to skin would prove to be safe and well tolerated by subjects. The small number of patients and the absence of placebo controls warrant circumspect interpretation of the secondary outcome measures. But the observation that subjects in the low dose cohort had little change in the NRS or SF-MPQ while subjects in the higher dose cohorts reported substantial reduction in NRS and improvement in SF-MPQ is encouraging.”

Encouraging is possibly an understatement, seeing clear evidence of therapeutic benefits in a Phase I trial like this is very promising, or as Abbie puts it “A trial turning out this successful is a great starting point for optimizing this kind of therapy.”.

Paul Browne

p.s. Those interested in a more detailed account of the research that led to this clinical trial can find it in this review published in 2008 and available to read online for free.

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Hypothermia in stroke: EuroHYP moves from rats to man

Posted on March 19, 2012 by | Leave a comment

Earlier today the BBC reported that European Stroke Research Network for Hypothermia (EuroHYP) has announced the launch of a major clinical trial – involving 1,500 patients in 15 centers across Europe – to evaluate whether cooling the body by 2 degrees can reduce the risk of death and disability in ischaemic stroke.

CT image of an ischemic stroke. The dark area in top left quadrant of brain shows the damaged brain area. Welcome Images.

The trial, known as EuroHPY-1, is being lead by Professor Malcolm McLeod of the University of Edinburgh, and its design is supported by very strong evidence from studies in animals – mostly rats -that we discussed on this blog just over a year ago, with the trial synopsis stating that:

Systematic review of animal studies modelling ischaemic stroke suggests that cooling is the most promising intervention identified to date. In these animal studies, cooling to 35˚C reduced infarct size by about one third, and cooling to 34°C by around 45%.”

We are very pleased to learn that this trial – which has the potential to radically alter and improve the way in which ishaemic stroke is treated – has now received sufficient funding to go ahead.

In another interesting report on the BBC today, scientists at the University of Colorado have reported that they have used studies of genetically modified mice to identify the mechanism through which the brain-derived neurotrophic factor (BDNF) interacts with other regulatory proteins to control appetite and body fat levels.  In some people with the genetic disorder WAGR syndrome it was observed that having only one copy of the gene encoding BDNF was associated with excessive appetite and obesity, but until now the mechanisms through which BDNF regulates appetite was not clear.

This research fills in another important gap in our understanding of how genetic differences between individuals influence the risk of becoming obese, and we know already that genetics makes a very large contribution to that risk. While the complex nature of the influence of genes on obesity means that it is rarely possible for a single medication to have a dramatic impact – though there are a few examples such as the treatment of leptin deficiency with recombinant leptin (following studies in the leptin-deficient Ob/Ob mouse) – increasing understanding of the influence of the impact of an individuals genetic makeup on their risks of becoming obese will aid the development of both new medicines to help combat obesity, and the development of more targeted lifestyle interventions that are more likely to be successful for that individual.

Taken together these two items reported in the BBC highlight the importance of animal research to medical progress, both as a way to uncover the processes involved in health and disease in basic research, and as a way to evaluate potential therapies in order to obtain sufficient information to proceed to trials in human patients.

Addendum:

More good clinical trial news that I missed earlier!

On Friday the Cystic Fibrosis Trust announced that thanks to major grants from the Medical Research Council (MRC) and National Institute for Health Research (NIHR) they will soon launch their clinical trial of non-viral gene therapy for Cystic fibrosis.

We briefly discussed the important role played by animal research in the development of this therapy in a blog post last August, and it is great to see that the UK Cystic Fibrosis Gene Therapy Consortium (UK CFGTC) has now raised sufficient funds to proceed with this exciting trial.

The UK CFGTC has also announced that it received a further £1.2 million fund research to develop a lentiviral vector for improved delivery of gene therapy in cystic fibrosis, much of which will like earlier work on this vector require the use of animal models.

Paul Browne

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Merry Christmas for Patients with Hemophilia B

Posted on December 22, 2011 by | Leave a comment

That was the headline of an editorial in the New England Journal of Medicine (NEJM) which discussed the very promising results of a small clinical trial of gene therapy to treat hemophilia B – also known as Christmas Disease*. Patients with haemophilia B suffer bleeding in the joints and muscles due to deficiency in a coagulation factor IX, which blocks the coagulation cascade that normally leads to blood clots forming and prevents bleeding. Hemophilia B can be successfully managed by intravenous infusion of factor IX several times a week, but this therapy is very expensive – it has to be isolated from donated human blood plasma – and causes allergic reactions at the injection site in some patients.

Studies in mice were key to developing gene therapy for hemophilia B

Clearly a more permanent solution to factor IX deficiency is highly desirable, and to develop one scientists at University College London and the St Jude Children’s Research Hospital in Memphis turned to a technology that we have discussed on several occasions on this blog in recent years – gene therapy. The results of their clinical trial, published in NEJM, were impressive, all the patients were able to stop regular factor IX injections to maintain adequate factor IX levels, or to greatly reduce the frequency of injections.

As the NEJM editorial points out, this therapy has the potential to not only improve the lives of people with hemophilia B, but also to save millions of dollars over their lifetime.

In an excellent post discussing the clinical trial science blogger ERV notes that:

This treatment is not perfect yet– but its a huge step in a right direction, and only possible because of viruses.”

A very good point, in medicine we usually think of viruses as the enemy, but when it comes to gene therapy they are an ally.

But they are not always the easiest of allies to campaign alongside, and that is where another scientific technique without which this advance would not have been possible comes in – animal research!

A key choice when developing any virus-based gene therapy is the vector used to deliver the replacement gene to the cells of the body.  The vector must deliver enough copies of the gene to the target tissue to be effective, enable the gene to express in sufficient quantity to ameliorate the condition, and do so safely. Adenoviruses are often chosen for this task, with the serotype AAV 2 being the most widely studied in animals and humans. But there is a serious problem with AAV2, roughly half the population have been exposed to AAV2 naturally, and mount an immune response that clears the vector from the bloodstream before it can deliver its gene cargo to the target tissue.

The researchers addressed this problem by turning to another adenovirus serotype AAV8, which was isolated from rhesus monkeys a decade ago.  They chose AAV8 for three reasons, firstly earlier studies in mice showed that AAV8 injected into a peripheral vein delivered genes to the liver – the natural site of factor IX production – much more efficiently than AAV2, secondly the mouse studies also showed that AAV8 uncoats and delivers its  gene payload to cells more swiftly that AAV2, helping to ensure that the gene is delivered before the body can mount an immune response, and thirdly prior immunity is far less common in the human population than immunity to AAV8.

The AAV8 vector wasn’t perfect though, it would still require a large number of virus particles to be injected – potentially enough to trigger liver damage or stimulate a larger and more rapid immune response – so they designed a modified AAV8 vector known as a self-complementary (SC) vector that delivers the gene to liver cells even more efficiently.  Injection of mice with an SC vector containing the factor IX gene was found to lead to a 20-fold increase in liver of factor IX expression compared to the same amount of standard AAV8 vector, with no increase in toxicity. Since the ability of vectors developed from different adenovirus serotypes to target gene expression to particular tissues can vary between mice and primates, they then evaluated this vector in rhesus monkeys, finding that the SC vector could drive safely therapeutic levels of factor IX production in the monkey liver, and that prior immunity to one adenovirus serotype did not diminish the efficiency of factor IX production by a vector based on another serotype.

These studies paved the way for the clinical trial that caused so much excitement in the scientific and popular press earlier this month. Hopefully further development and larger clinical trials in people with hemophilia B will confirm the potential of this exciting new therapy, a therapy that was developed thanks to viruses and to animal research!

* after a patient named Stephen Christmas from whom factor IX was first isolated.

Paul Browne

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A breakthrough against Chronic Lymphocytic Leukemia…thank the mice!

Posted on September 13, 2011 by | 4 Comments

A challenge that science communicators frequently face when discussing the process whereby a scientific discovery eventually leads to a medical breakthrough is the time that this often takes, indeed by the time that the reports of exciting clinical trial outcomes start to appear in the press the role of the scientists who made the initial discoveries is often relegated to a passing comment…if it is mentioned at all. An example of this comes from the Weizmann Wave blog, produced by the Weizmann Institute of Science.

You may remember reports last month on the very promising results of a small clinical trial where a new immunotherapy technique was used to eradicate cancer cells in patients with Chronic Lymphocytic Leukemia (CLL), a blood cancer for which currently available treatments are often inadequate.  That trial, conducted by scientists at the University of Pennsylvania led by Professor Carl June, involved removing T-cells from the patient, treating the cells with a lentiviral vector that encodes for a Chimeric Antigen Receptor which recognises a protein named CD19 that is found on B-cells, including the cancer cells responsible for CLL, and then infusing the transformed T-cells back into the patients.  As the reported in the Los Angeles Times the results were dramatic, within a few weeks of the infusion the modified T-cells expanded rapidly and targeted the cancer cells in all three paients, so that a year later two of the three patients were still in complete remission.

It’s exciting stuff but as the Weizmann Wave reports the Press Release issued by Penn Medicine noted that this was a “cancer treatment breakthrough 20 years in the making” but “didn’t, however, explain those “20 years in the making.””. The Weizmann Wave goes on to discuss the pioneering basic scientific research undertaken by Professor Zelig Eshhar at theWeizman Institute of Science in the late 1980’s, which you can read about here.

Of course between the basic research undertaken by Prof. Eshhar and his colleagues in the 1980’s and the clinical trial whose outcome was announced last month there was a lot of work to be done. It would be impractical to describe all the different discoveries that made this immunotherapy possible, but one discovery in particular highlights the importance of animal research to this breakthrough.

There have been previous attempts to use Chimeric Antigen Receptors to target T-cells to attack cancer, but these had disappointing results in clinical trials.  A major improvement made by the University of Pennsylvania team was to include an additional motif – named the CD137 co-stimulatory molecule- which greatly enhances the cancer killing ability of the infused T-cells.  In a recent paper published in the Journal of Cancer the University of Pennsylvania team point out that the decision to include CD137 (called 4-1BB in mice) in their Chimeric Antigen Receptor construct was based on promising results in studies undertaken in mice:

 Our group has tested a CAR directed against CD19 linked to the CD137 (4-1BB) co-stimulatory molecule signaling domain to enhance activation and signaling after recognition of CD19. By inclusion of the 4-1BB signaling domain, in vitro tumor cell killing, and in-vivo anti-tumor activity and persistence of CART-19 cells in a murine xenograft model of human ALL (acute lymphocytic leukemia) is greatly enhanced”

Indeed, in a paper published by Professor June and colleagues in the journal Molecular Therapy in 2009 they describe this work in much more detail, highlighting just how groundbreaking the results were:

Previous in vitro studies have characterized the incorporation of CD137 domains into CARs.10,11,29 Our results represent the first in vivo characterization of these CARs and uncover several important advantages of CARs that express CD137 that were not revealed by the previous in vitro studies. We demonstrated that CARs expressing the CD137 signaling domain could survive for at least 6 months in mice bearing tumor xenografts. This may have significant implications for immunosurveillance, as well as for tumor eradication. For example, in a mouse prostate cancer xenograft model, survival of CAR+ T cells for at least a week was required for tumor eradication.30

Long-term survival of the CARs did not require administration of exogenous cytokines, and these results significantly extend the duration of survival of human T cells expressing CARs shown in previous studies.17,31 To our knowledge, this is the first report demonstrating elimination of primary leukemia xenografts in a preclinical model using CAR+ T cells. Furthermore, complete eradication was achieved in some animals in the absence of further in vivo therapy, including prior chemotherapy or subsequent cytokine support.

The long-term control of well-established tumors by immunotherapy has rarely been reported. Most preclinical models in a therapeutic setting have tested tumors that have been implanted for a week or less before initiation of therapy.32 After establishing leukemia 2–3 weeks before T cell transfer, we found that many animals had long-term control of leukemia for at least 6 months. The efficacy of targeted, adoptive immunotherapy in this xenograft model of primary human ALL compares favorably to our prior experience testing the antileukemic efficacy of single cytotoxic (ref. 27 and data not shown) or targeted agents,26 where we have observed extension of survival but not cure of disease. Additionally, we have not previously observed the ability to control xenografted ALL for a period of as long as 6 months.”

These results led directly to the clinical trial reported last month.

So there you have it, behind the headlines are years of graft by hard-working and innovative scientists, who utilised a wide range of experimental approaches – among which animal studies figure prominently – to develop a novel therapy for CLL. As Professor Bruce Levine points out in the video above, the key to success is often keeping one hand in the basic research lab and the other in the clinic.

Paul Browne

Addendum: Scienceblogger Erv has written an excellent commentary on this study

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Honoring a fallen hero in the struggle against Cystic Fibrosis and AR extremism

Posted on August 5, 2011 by | 5 Comments

Yesterday I learned some sad news via the Understanding Animal Research blog, that a young woman named Laura Cowell had died, succumbing to cystic fibrosis at the age of just 25.  To see a life so full of promise end so prematurely is always sad, but what makes this death so gutting is that Laura is one medical research’s heroes. I never met Laura, but back in the bad old days a decade ago – when the animal rights extremist campaign against medical research in the UK was at its height – she had the courage to stand up and voice public support for the animal research that is so crucial to progress against diseases such as cystic fibrosis.  For this Laura and her mother Vicky, who chaired the now-disbanded (after a job well done!) patient advocacy group Seriously Ill for Medical Research, have my unwavering respect and admiration.

Laura Cowell - a brave campaigner for cystic fibrosis research

In an article in the Times yesterday science correspondent Mark Henderson wrote about Laura’s bravery:

Most researchers who worked with animals were reluctant to fight back. Their fears were far from unreasonable: Professor Colin Blakemore, one of the few to have done so, was repaid with letter bombs addressed to his children. Politicians deplored the threats while doing nothing about them. Cravenly, the governing Labour Party dropped HLS shares from its pension fund portfolio, and Blakemore was blackballed for a knighthood because of his “controversial” stance on vivisection.

It was against this background that a 16-year-old girl decided to speak out. Laura Cowell was born with cystic fibrosis, and took 40 pills a day to keep her illness and its complications at bay. “I rattle,” she used to joke. Animal research, however, she took seriously. Drugs developed through vivisection were keeping her alive. In 2002, she agreed to front a campaign that aimed to explain the benefits of animal experiments, as living proof of their contribution to medicine. ”

As Mark points out it was the willingness of people like Laura Cowell and Colin Blakemore to speak out, despite the threat from extremists and petty insults from more mainstream animal rights groups, in favour of animal research that turned the tide of public opinion in the UK favour of animal research, culmination in Laurie Pycroft’s stand against animal rights extremists in Oxford and the founding of Pro-Test.

Ipsos-MORI polls show unconditional support for animal research has almost doubled since 1999, and growing trust in the regulations that govern it. In 2005, laws against harassment were introduced and a police extremism unit was tasked with targeting violent activists. As ringleaders were jailed, the intimidation stopped. The Oxford lab was built. A climate of fear no longer threatens an important branch of British science. ”

Mark then goes on to criticize the failure of some medical research charities to respond to a recent attempt by the animal rights group Animal Aid to persuade people to stop donating to medical research charities (at a time of declining income for many charities because of the recession) that support animal research, which focused on the British Heart Foundation (BHF), Cancer Research UK (CRUK), the Alzheimer’s Society and Parkinson’s UK. I’m not sure that Mark is being fair, the BHF (who also highlight animal research in a new campaign), CRUK and Parkinson’s UK all issued strong statements explaining the value of animal research to their work, and while the Alzheimer’s Society didn’t issue a specific statement on this occasion they frequently discuss animal research in their research news and in 2010 wrote in a position statement that:

However, the Alzheimer’s Society and its trustees believe that funding medical research with animals remains essential if we are ultimately going to understand the causes of dementia and develop effective treatments.”

It is clear that medical charities in the UK are increasingly prepared to stand up for the importance of animal research to medical progress, something that is very refreshing to those of us who remember how things were a decade ago, and as Mark points out medical charities are uniquely well placed to act as advocates for animal research due to the respect and admiration that the public have for their work. For this sea change in attitudes towards animal research in the UK we have to thank the courage of individuals like Laura Cowell.

So how should we honor Laura?

We have discussed the contribution of animal research to the development of existing therapies – and future cures – for cystic fibrosis research on the Speaking of Research Blog in a couple of occasions, including the promising research being undertaken by the UK Cystic Fibrosis Gene Therapy Consortium. The consortium is planning to launch in 2012 the first ever clinical trial to examine if gene therapy can improve lung function in people with cystic fibrosis, using a vector whose development relied on information obtained from studies in mice, and which has already had promising results in a pilot study in CF patients. This clinical trial is being supported by the Cystic Fibrosis Trust who recently launched a fundraising campaign to raise the £6 million required to pay for the trial.

Laura Cowell died before gene therapy for cystic fibrosis could become a reality in the clinic, but there are many cystic fibrosis patients alive today – and many more yet to be born – who may in future benefit from it.

So I invite you to remember Laura by making a donation to the Cystic Fibrosis Trust – Gene Therapy fund.

Paul Browne

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Advancing gene therapy, debunking AR propaganda.

Posted on February 18, 2011 by | 2 Comments

The promise of curing genetic diseases by replacing damaged genes with healthy ones is slowly becoming a reality. One recent story is the development of therapy in humans to reverse a form of childhood blindness called Leber congenital amaurosis, or LCA.

OregonLive reports on the story of Alexe Webb who, soon after birth, was diagnosed with LCA the most common cause of inherited blindness in children. Her doctor, Dr. Richard Weleber, said “With this trial, she has the opportunity to have much better vision. We hope the treatment is very durable, that it will last for many decades, even for life.”

As detailed at the National Eye Institute web site:  

The groundbreaking clinical trials to restore vision in patients with LCA rest on 15 years of basic research with animals. Long before the gene transfer procedure could be tested in people, four critical milestones had to be met: the discovery of the RPE65 gene; creation of a mouse model that illustrates the gene’s functions and what happens when it’s missing; development of a safe way to carry healthy replacement genes to the target within the eye; and studies of the procedure in a large animal model — dogs.”

 

The report continues:

Dogs carrying a nearly identical mutation to Alexe’s were the first test subjects. Within two weeks of treatment, three nearly blind dogs were able to navigate with little problem, Dr. Jean Bennett, a professor of ophthalmology at the University of Pennsylvania Medical School in Philadelphia told the Journal of the American Medical Association in October. The effects of a single injection persisted for more than 10 years in the first dog treated. Researchers learned that retinal cells may be ideal targets for gene therapy because they don’t divide much, allowing replaced genes to persist.”

 

This isn’t the first time that this use of gene therapy to treat LCA has caught our attention, back in 2009 Anna Matynia wrote a piece which highlighted the value of the briard dog to this research. All in all it is a great example of how gene therapy is starting to change the face of medicine.

The briard dog, crucial to the development of gene therapy for LCA

In other news we reported last week on how the animal rights zealots at PCRM were willing to endanger the lives of preterm babies by attacking an important training program at the University of Washington.  We were pleased to note an editorial in the Seattle Times which comes down firmly on the side of the University of Washington, the Seattle Times clearly recognizes that Dr. Dennis Maycock and his colleagues at the University of Washington are the real responsible and ethical physicians in this debate.

The problem of specialist pediatric training programs coming under attack from AR activists is not however limited to Seattle, PeTA are attempting to close down a similar training program at Primary Children’s Medical Center (PCMC) in Salt Lake City. The Daily Herald has reported how PeTA have resorted to false claims that PCMC have conceded to their demands. Once again doctors have had to confront misleading animal rights propaganda, with Dr. Bonnie Midget of PCMC pointing out that:

There is no simulator for a 2-pound premature infant,We would love it if someone would make one.”

 

We at Speaking of Research applaud the responsible physicians at the University of Washington and PCMC who brave threats and harassment to stand up for the welfare of their youngest patients.

Dario Ringach and Paul Browne

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