Owners of valuable thoroughbreds will do practically anything to get their mares in foal, but almost 10 per cent of mares do not become pregnant despite veterinary assistance. Two Danish researchers have now discovered what may be the root of the problem, and they have developed a product that will help horses become pregnant. It is ready for sale and will initially be launched in the USA.

This research project is about horses that cannot become pregnant, and it has resulted in the successful development of a product, Bactivate, that helps horses get in foal. The product is now ready to be sold across the world.

The two researchers behind this discovery are veterinary surgeon, PhD and specialist in reproduction Morten Rønn Petersen, who now works at Copenhagen University Hospital's Fertility Department, and Professor Anders Miki Bojesen at the Department of Veterinary Disease Biology/Microbiology at the University of Copenhagen.

The two researchers have developed a unique product for an exclusive clientele, as initially the product is aimed at some of the world's most valuable thoroughbred mares that cannot get pregnant and whose owners are willing to pay almost anything to get them in foal.

“There is no return on a mare that is unable to produce foals,” says Morten Rønn Petersen. “Very expensive mares are rare; the big money is found on the stallion side. The value of the stallion depends on the foals the mare has, which is why it matters which mare is selected for mating with the stallion.”

Bactivate has been tested in collaboration with the world's largest equine hospital, Hagyard Equine Medical Institute, which is located in the city of Lexington, Kentucky, USA, also known as the ‘Horse Capital of the World’.

Infected with streptococci
The very best racehorses can run home millions of dollars in winnings for their owners, and the owners can earn even more by using them in breeding.

However, some mares have trouble getting pregnant, or they never get in foal at all. “At Hagyard, I worked with veterinary surgeon Kristina Lu, who is a specialist in fertility and reproduction, on getting the valuable mares in foal. However, after we had done everything we could, about 5-10 per cent remained where we did not know what the problem was,” says Morten Rønn Petersen.

This is where the two researchers' special types of expertise combine in the best possible way: Morten Rønn Petersen is an expert in reproduction, particularly in horses, and Anders Miki Bojesen has worked with bacteria since 2000.

“The most frequent cause of reduced fertility in mares which have trouble getting pregnant is a chronic infection in the endometrium, which is caused by Streptococcus equi subspecies zooepidemicus,” Anders Miki Bojesen explains. “This is a known fact – we have had numerous Master's students who have worked with streptococcus infections in the endometrium of horses, and we have seen an awful lot of ups and downs in the related research over the years.”

Dormant infection
But then a fortunate coincidence helped the researchers along. They discovered that many horses that were unable to get in foal, and which tested negative for streptococci, actually had a dormant infection, which shows no clinical symptoms.

“We were working on an infection experiment and happened to find a substance that can awaken the dormant bacteria – and that's what it's all about,” says Anders Miki Bojesen.

This means that some horses with reduced fertility carry a streptococcus infection that no one has been aware of. Bojesen's and Petersen's discovery turns this situation upside down: If you can awaken the bacteria, you can also diagnose the infection and improve the treatment.

Triggers bacteria growth
“These streptococci are not resistant to antibiotics – that's not the problem,” says Anders Miki Bojesen. “Most antibiotics impede the metabolism in the bacteria, but if the bacteria are inactive, their metabolism is low, and they are not affected by antibiotics.”

“At first, we thought that we could only use the invention as a tool for improved diagnosis of dormant streptococcus infections,” says Morten Rønn Petersen. “But we tested it in collaboration with Kristina Lu and saw that fertility improves when you treat the mares after the activation of the dormant bacteria, and this makes good sense, because antibiotics work best when the bacteria divide.”

Bactivate consists of a transmitter substance that triggers the growth of the bacteria, which immediately start dividing and behaving like normal streptococci. “We made a solution with the substance and tested it. And now it was possible to make a diagnosis as the mares that were given the substance developed a serious inflammation of the uterus,” says Anders Miki Bojesen.

Tests in Iceland have given the same results.

Tested on 64 mares
The collaboration with Hagyard Equine Medical Institute inKentuckybegan when Morten Rønn Petersen went on a research visit to Kentucky. This was when he started working with the “extremely competent” veterinarian surgeon Kristina Lu.

“We wanted to see what would happen when we examined mares that were unable to get pregnant, in order to find out whether they were infected with dormant streptococci,” Anders Miki Bojesen explains. “We gave them our product, and if they then tested positive for streptococci, we would treat them as usual with antibiotics and try to get them in foal immediately after.”

It was Morten Rønn Petersen who tested the product at Hagyard. “We tested it on 64 breeding mares, which had gone through many attempts to get them in foal, and for which the likelihood of them getting pregnant was very low,” he says. “The mares were mated quickly after the treatment, and 83 percent of them became pregnant within six weeks and 72 percent gave birth to a live foal. Many of the mares had been without foal for many years, but they became pregnant after activation, treatment and mating.”

Veterinary surgeon Kristina Lu is “very excited and completely over the moon” as the two researchers put it.

“This is an important step forward, and we have learnt a lot that we didn't know before,” says Kristina Lu. “In the final analysis, it is a diagnostic tool, because it makes the bacteria start growing, and it will definitely play a role in future fertility treatment.”

“It has been fascinating to work with Morten Rønn Petersen, and the transition from research to a commercialised product is always an exciting challenge,” she says.

Aiming for exclusivity
“There is no doubt that the product works, and I think that many more will use it. Kristina Lu has told me that several horse owners have asked whether they can get hold of it, so that they can treat all their horses. It is a good screening tool, and they can make sure that they have done everything possible to get their mares pregnant. These are horses that cost millions of dollars, and the owners will do anything to get them in foal,” says Morten Rønn Petersen.

The two researchers contacted Hagyard Equine Medical Institute because they aimed for exclusivity right from the beginning. “We also consider the match with Hagyard a marketing advantage – it is the best possible recommendation in relation to other interested parties, because their vets are highly respected, and they specialise in horses only,” says Morten Rønn Petersen, adding: “After all, it is not only thoroughbreds that have trouble getting pregnant, so we expect to sell the product throughout the world.”

“There is no doubt that our collaboration with Hagyard has meant that we now have data that we would otherwise never have got anywhere near,” says Morten Rønn Petersen. “Our product has now been tested in the field, and we have shown that it works.

It is generally incredibly difficult to get access to field trials.”

“In principle, we just turned up with our scientific background and nothing else, and Hagyard took a chance by trusting us and bringing the product to their clients,” the two researchers say.

Sales starting in the USA
It will probably not be necessary to get the American Food and Drug Administration's approval of Bactivate before sales can start in the USA. Hagyard will sell the product in the USA, and the two researchers' newly formed company ‘Bojesen & Petersen Biotech ApS’ will produce it.

The researchers will not know whether Bactivate will be sold in Denmark until they have more information about the possibilities of obtaining an approval from the Danish Medicines Agency. “We have been given permission to produce a limited amount here at the Department. If everything works out well, we are going to need production facilities,” says Anders Miki Bojesen.

He takes a deep breath: “Having seen the first tender results and realising that this could become a commercial product, and then actually seeing five years later that this is happening, is hugely satisfactory.”

The road to commercialisation
When you look at it from this end, it sounds like the entire project has run smoothly. However, there were many difficulties along the way; for instance, it turned out to be practically impossible to get funding for developing the project for commercialisation. It was difficult to license the patent rights, and a lot of the work depended on Master's students who had Morten Rønn Petersen or Anders Miki Bojesen as their supervisors. “However, once the contact with Hagyard was established and the good pregnancy results started rolling in during 2012, things really took off, and here, the Tech Transfer Office Copenhagen Spin-outs initiative has been very helpful in getting us contacts and generally facilitating the process,” says Anders Miki Bojesen.

Important network
Asked whether they would recommend that other researchers who have a biotech invention contact the Tech Transfer Office and Copenhagen Spin-outs, Anders Miki Bojesen and Morten Rønn Petersen answer “yes, definitely!”. They say that it has been incredibly inspiring to follow a product from the initial idea, via the scientific work and through to a product and an actual business.

However, Anders Miki Bojesen believes it is essential that you think things through in advance so that you have an idea of where you want to get to – and how – and he stresses that you need to be quite tough when sorting through the possibilities that surface along the way and be particularly careful not to waste time on meetings with the ‘wrong’ people.

Naturally, it is also an advantage if you have a certain network within the field where you intend to establish yourself, Anders Miki Bojesen points out: “This makes it easier to act when the commercial agenda takes over.”

Anders Miki Bojesen stresses that it can be an uphill struggle if it is difficult to get funding during the phase where you work on the proof-of-concept – and that this may take several years.

The two researchers have applied for lots of funding, but have hardly received any, so the work has been idle during periods. “Quite often, it’s a Catch-22 situation, because you need to publish something in order to get funding, and this is difficult when you don't have any funds,” he says.

It is expensive to do research on horses, and according to Anders Miki Bojesen, you can easily blow off 200,000 Danish kroner on experimental work because it costs a lot to have the animals stabled.

The odd ideas
He is quite sure that a lot of ideas die shortly after their birth due to a lack of funding to help them along. This is particularly true of the slightly odd ideas that do not fit into a standard strategy, e.g. in a company that would otherwise be able to finance development costs. The two researchers have come across this several times, but if the university had a fund with risk capital that researchers could apply for during the development phase, that would be a tremendous help.

Via help from the Universityof Copenhagen's Tech Transfer Office, Morten Rønn Petersen and Anders Miki Bojesen have applied for and received grants from the Danish proof-of-concept pool.

With Copenhagen Spin-outs the Tech Transfer Office got more ressources for advicory and economic assistance. That was very useful for spin-out projects such as ‘Bojesen & Petersen Biotech ApS’, because ressources can provide the support that may be decisive for whether or not a spin-out-project is realised. “It is really important to have access to good sparring in relation to the development of the more business-related aspects, which researchers are typically not very well versed in,” concludes Anders Miki Bojesen.

Copenhagen Spin-outs is supported by Vækstforum (Growth Forum) and the European Regional Development Fund.


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