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Profile - David Becker
A BBSRC Innovator of the Year 2010 finalist, Professor David Becker discusses how to turn the intricacies of cell biology into a healing product with great potential in clinical practice.
25 January 2011
What discovery led to your Nexagon Gel product?
I work on how gap junctions, which cells use to communicate to each other in embryonic development and disease, and found they have a central function in wound healing. We've discovered that a particular type of gap junction protein, known as Cx43, plays a pivotal role in healing and inflammation and have developed a bioactive gel to regulate Cx43 production for use in clinical practice, particularly for diabetic wounds and ulcers that are particularly difficult to heal. (See ‘How does the gel work?’)
David Becker has pioneered the art of confocal microscopy, as seen in the images below.
How did you end up commercialising your findings?
We formed a company, Coda Therapeutics, and so far we’ve raised $23M to take us through toxicity testing and good manufacture practice (GMP). We’ve just completed phase I and II safety trials and we're getting positive results from the treatment of venous leg ulcers – they’re healing about five times faster at the highest dose of our gel which reduces production of the Cx43 protein.
Have you tried the gel on any other wounds?
We've had some other incidences of fantastic results. One man in New Zealand was working on a building site and was squirting liquid concrete out of his gun. Nothing was coming out and so he looked down it and blasted himself in the eye with liquid concrete. He got severe alkaline burns which took off all the epithelium all over his cornea and all the blood vessels died back from the limbus region where the stem cells live that keep the cornea clear. There was no regrowth for eight days and he didn't respond to any of the conventional treatments so he was scheduled to have his eye removed.
We got permission to treat the eye and the blood vessels grew back to the limbus within a few days – within three days the whole of the epithelium had regrown. He's now back to the same eyesight as he had before. We've now repeated that with six other cases of corneal burns and they’re all looking pretty positive so we have FDA [US Food and Drug Administration] Orphan Drug Status approval for treatment of persistent epithelial defects of the eye.
Confocal microscope image of immune cells, (natural killer cells) and T cells.
Image: D. Becker
How did you get permission to use it so quickly?
From our collaborators in New Zealand. The ophthalmologists who were doing eye laser surgery for us in rodents, knew that if you applied the gel to the cornea we could speed healing. So they thought “this guy's eye is going to be put in the bin” so let's go for permission to try and save it. They effectively signed over responsibility for the drug working and it did – you need a clinician who is prepared to do that. You can get permission quite rapidly from the medical authorities for compassionate use when there's no other drug or other treatment available and you've tried everything.
We've saved limbs from amputation. There was another guy in San Diego with a large inflammatory wound following a below the knee amputation that he'd had for 18 months and it was not responding to any conventional treatments. His doctors arranged to have amputation above the knee which would severely compromise his mobility. They got permission to try Nexagon and just two applications kick started the healing process and within a few months it had healed.
How does that make you feel?
It's amazing we've managed to save peoples’ limbs and eyesight and are making a real difference. You've got something that you've been developing as a tool for experiments in embryology and now you can translate it into doing something really useful to man.
That must be a real sense of achievement…
Absolutely. But there's still a long way to go. We're going well in Phase II clinical trials and then onto Phase III and it looks like 2014 before we'll be on the market. The downside is that back in August 2010 there was an Associated Press article about the technology and I’m getting hundreds of letters from people all over the world wanting the gel; they're sending me pictures of their relatives legs dropping off and asking me to help them but I am not allowed to give it to them. It’s upsetting knowing that I’ve got something in my fridge which could potentially help these people but we can't use it yet.
That must be frustrating…
It is, but we have to go through the long, careful FDA process to make sure it's safe and we've still got to optimise the best treatment regime.
Confocal microscope image ofendothelial cells in culture.
Image: D. Becker
How did you raise the capital?
Following some basic research grants from BBSRC, we used a Wellcome Trust Catalyst Biomedica award for proof-of-principle studies and then raised our own money for clinical trials. It was incredibly difficult at the time in 2006 with the Enron collapse when we were starting to look.
Did you try a BBSRC Follow-on-Fund?
I’m not sure if Follow on Funds were available then. What I did find incredibly useful was the BBSRC Business Plan Competition when we were finalists in 2001/02. That was a fantastic tutorial system to learn how to translate the technology into a business plan. And it was really the basis of that business plan that was tweaked and raised the money for us in 2006. Really great training – I can't speak too highly of it.
Is the gel expensive to make?
It's expensive to develop. In 2-3 years we've spent $23M because any drug has to be manufactured to very high standards – gold pipette tips etc. – so what would cost a hundred pounds from Sigma or Invitrogen would cost hundreds of thousands.
How much will saving a limb or an eye cost?
I can't comment at all because I imagine we’ll need to spend another $30-40M before we get to a product. But it will be a matter of scale – the more you make the cheaper it will become. Typically, people with chronic wounds in America will spend around $200,000 over a couple of years. The minimum on small ulcers will be $20-30,000 whether they heal or not so conventional treatments are very expensive.
And you’re seeking permission first in the US before the UK?
Yes, we're doing the US FDA route and then permissions elsewhere. Mostly the UK would accept the FDA approval and we hope to run some diabetic foot trials in the UK in the future.
When did you first become interested in science?
I guess during my degree, my third year project in biology at Portsmouth University. I was gripped by gap junctions and went off to University College London (UCL) to do a PhD, then a short post-doc in Australia and then back to UCL.
So why gap junctions?
I thought the way cells could communicate to each other and sense different signals a fascinating topic. Papers to suggest a role in early embryonic development were inspirational so I learned to work on gap junctions and got a Royal Society University Research Fellowship for ten years to start my own group at UCL. During that period discovered the effects on wound healing. It's been ten years to show proof of principle and get funds to move through GMP manufacture, toxicity testing and into clinical trials. It's a long process and a hard process to convince people that it really works and that it's worth doing.
Along the way developed a strong interest in imaging…
I’ve been fascinated by imaging and confocal microscopy since it conception. We got one of the first confocal microscopes that were sold in the UK in the UCL Anatomy Department. I’ve helped develop that technology with novel uses, training courses for postgraduates, as well as advanced multi-photon imaging techniques.
Confocal microscope image of liver cells (hepatocytes).
Image: D. Becker
Do you like the popularity of the art and science fusion?
I think it’s really stimulating to look down a microscope and see something beautiful that no one else has seen. I never tire of it. If it makes people more aware of what’s going on and inspires them then all the better.
Does your gel have any other effects?
We’ve also found that Nexagon is neuroprotective against the secondary spread of cell death following neuronal injury. We applied the gel to the site of the injury in the central nervous system (CNS) and found that it reduces the spread of cell death from injured cells to healthy ones in that bystander effect.
We couldn’t get investment or funding to take it forward because of the massive variability in CNS injuries and the market not big enough to produce returns for the investors. This is also relevant to stroke and spread of damage following stroke but there is not much interest in research or investment in this area. It is surprising but most research in spinal cord injury doesn’t relate to preventing the spread of damage after the injury – they know that most of the spread of damage occurs in the first 24-48 hrs, but no one is really trying to prevent that, more “can I transplant stem cells in 5 years”. I think we really need to address how we can reduce that spread of damage after the initial insult and then there will be more functionality and less to repair in the future.
How does the gel work?
What are gap junctions?
A gap junction is a small channel between two cells so they can communicate with each other. They are found in all cells in the body except red blood cells and skeletal muscle – even immune cells have them when they get activated.
A gap junction contains protein subunits in a ring, and these protein subunits are called connexins (Cx) that are known according to their molecular weight; the connexin protein Cx43 weighs 43KD.
Cx43 is by far the most ubiquitous connexin and we find it in keratinocytes, fibroblasts, blood vessels and neutrophils – lots of different cell types.
Where do connexins come into wound healing?
Cx43 allows cells to communicate with each other. The bioactive gel targets the production of the Cx43 protein and transiently turns it off at the site of application, thus helping cells to migrate and heal the wound. In a normal wound, fibroblasts (which provide structural matrix for animal tissues) and keratinocytes (skin cells) decrease (downregulate) the amount of Cx43 as they become migratory and move toward the wound. What we’re doing with the gel is speeding it up so it gives them a kick start and down regulation happens in two hours rather than 24-48.
What does your gel contain?
Our gel contains a fragment of antisense DNA as a short single strand; it's very transient and only works at the site its applied to. Once it goes into the blood stream it's broken down very quickly – it has and a half life of about 20 minutes inside a cell but the gel we're applying it with gives you several hours of sustained release.
How does the antisense strand turn Cx43 off?
So this antisense strand, which is the mirror image of the messenger RNA (mRNA) base pairs that code for the Cx43 protein, binds to the target mRNA in a Crick-and-Watson fashion. Now, because you are not allowed to have double stranded RNA or DNA in the cytoplasm where this takes place, the Cx43 mRNA is then cleaved by an enzyme, RNase H, and destroys it. Thus, we don’t have the mRNA to make the protein Cx43 anymore which causes the cells to migrate faster into the wound and heal it.
The gel has a second effect on inflammation. When tissue is wounded Cx43 turns on in blood vessels as they become leaky and release inflammatory signals along with neutrophils (white blood cells that are the fight line of defence against infection and key promoters of the immune response) expressing Cx43. If we prevent that turn on of Cx43 in the blood vessels we reduce the leakiness of the vessels and so the whole inflammatory response and swelling is dampened down. We've evolved as cavemen to get rid of any inflammation in wound so we don't die of sepsis, but the result is we get so many neutrophils that they can cause damage to the tissue and so we might be preventing an over-the-top reaction.
Then we’ve got the twist to the story: wounds that don’t heal very well don’t do the turning off of Cx43 to get the healing process going – instead they turn it on and the cells fail to migrate. So we looked at healing in diabetic animals and patients, which is notoriously slow, and looked at diabetic rats and found that instead of an injury turning off Cx43 the diabetic rat turns it on and the results is a bulbous proliferation of cells that fail to migrate. But if we prevent the Cx43 turn on by applying the Nexagon gel then we get normal healing rates or better.
What's the secret of the actual gel?
It’s a pluronic gel – a liquid between 0-4 deg C – and we drip it, like water, into the wound chilled to this temperature and as soon as it touches the wound it sets to a consistency like toothpaste. Then it slowly breaks down giving a steady release of the antisense active ingredient. Pluronic gels are a family of gels with very interesting steady release characteristics. They’re actually a component of toothpaste so are safe and have FDA [US Food and Drug Administration] approval.
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