Stem cell therapy has been utilized in horses to help heal tendon, ligament and joint injuries for more than 25 years, and new uses are always being explored. These stem cells are mesenchymal stromal cells (MSCs), which are isolated from fetuses, foals or adult horses, as opposed to embryonic stem cells from embryos. The MSC stem cells can be isolated from almost any tissue, but are most commonly obtained from bone marrow, fat tissue, and from the umbilical cord of newborn foals.
The two main methods are use of the patient’s own cells (autologous cells) or cells from another horse (allogeneic cells).
The advantage of using autologous cells is that they are not rejected by the patient’s immune system, and there are fewer regulations for use. The disadvantage of using autologous cells is that it takes 2 to 3 weeks to expand the cells prior to use, to get enough. This involves a two-step process requiring the horse to return for treatment after initial sample collection. This may hamper optimal treatment time since an adequate number of cells are not readily available.
Allogeneic cells have the advantage of being already available, with time to select and potentially enhance cell functions prior to use.
The disadvantage is that cells from another horse are recognized by the patient’s immune system (and rejected) faster than autologous cells. Also, the regulations are different; allogeneic cell product development is considered drug development
Drugs vs Devices
A number of veterinarians, clinics and stem cell companies have treated thousands of horses with stem cells for many years. They started by treating soft tissue injuries and then progressed to treating joints. Some have also treated laminitis with stem cells.
There was such an expansion of stem cell therapy in veterinary medicine that the FDA became involved, to make sure it was regulated and that this kind of therapy wasn’t being used inappropriately. Use of stem cells was put on hold, and the FDA ruled that stem cells fell into the category of drug therapy. That meant regulations for bringing a new drug to market, apply which requires years and a lot of money. There was very little stem cell use in horses for a number of years.
Today, most commercial strategies are focused on developing frozen allogeneic cell products. One approach is use of allogeneic stem cells from umbilical cord blood that could be basically off-the-shelf/storable and given to any horse. Two products have been approved in Europe, and trials are underway in North America to get equine products approved here.
There are no approved stem cell products currently available in North. Other regenerative therapies like platelet rich plasma (PRP) or interleukin receptor antagonist protein (IRAP), fall under the FDA’s category of devices rather than drugs. “There is a big difference between getting a device approved by FDA and getting a drug approved,” says Dr. Thomas Koch, associate professor, Department of Biomedical Sciences, Ontario Veterinary College, University of Guelph, Canada. “It is very expensive and time-consuming to get a drug approved, which is a big impediment for veterinary medicine. From a pharmaceutical perspective it is a very small market,”
Koch is founder and CEO of eQcell, a company that is starting two trials using stem cells in equine synovitis and early stages of osteoarthritis–one at University of Guelph’s Ontario Veterinary College Equine Sports Medicine and Reproductive Centre, and the other trial at the University of California-Davis Veterinary Institute for Regenerative Cures (VIRC).
The Canadian study in equine fetlock and carpal joint osteoarthritis is authorized by Health Canada’s Veterinary Drug Directorate and is the first stem cell trial in Canada for treatment of equine osteoarthritis. The U.S. study in fetlock osteoarthritis is being conducted under VIRC’s Investigational New Animal Drug (INAD) with the FDA.
Collecting and Growing Stem Cells
“The cells we are working with are from umbilical cord blood of newborn foals,” Koch says. “My PhD work reported on the presence of these cells in 2007. This had been reported in humans, but we were the first to see if we could find similar cells in equine umbilical cord blood.”
Koch continued that work after he finished his PhD.
His company gets the cells from umbilical cord blood. Most people get it from bone marrow or fat tissue.
“These cells adhere to certain types of plastics. In the lab we use plastic culture dishes. In the first few days a lot of cells are just floating in the media and don’t attach, and then some start attaching to the plastic. When we aspirate the media off and replace it with fresh media, this gets rid of all the floating cells. We end up with a cell population stuck to the plastic.”
After 8 to 12 days some of the cells on the dish start to form colonies, undergo cell division and expand. “We use enzymes to lift them off the plastic; the enzymes cleave the binding without damaging the cells. We harvest them this way and split them into 3 to 5 flasks of the same size. Those cells reattach and keep growing. We can eventually grow them into billions of cells,” he says.
The original cells from umbilical cord blood come from breeding farms. “I work with Standardbred and Thoroughbred farms in southern Ontario. During foaling season they have eQcell’s collection kits, and whenever a foal is born, the attendant clamps the umbilical cord. When the foal stands up, the cord simply breaks at its natural breaking point. With the clamp across it (toward the mare side) the blood is not gushing out from the placenta, and is saved.”
The attendants use a blood transfusion bag to collect it. “These bags come preloaded from the company, with anticoagulant and a needle on the end. The attendants clean the cord and put the needle into the blood vessel within it, and the blood can drain into this collection bag. It’s non-invasive; you are just saving the blood that would otherwise drain out and be lost.” The infusion bag can be stored in a refrigerator overnight, then shipped by FedEx to the lab.
“What’s nice about this source of cells is that they are as young as we can get them, and consistent. The cells are from newborn foals, and mares that have no signs of disease during the pregnancy,” he says.
There are advantages to having very young cells. “If you get cells from fat tissue, blood or bone marrow from adult horses, they may be damaged. All cells age, so even if you have a healthy, normal animal, there are stringent requirements for donor testing.” With foal cells, there is some variability between one foal and another, but these cells are more consistent.
Koch says the many treatments being used for OA indicate there’s not one really good answer to the problem of osteoarthritis.
“There are many products being used for OA, and veterinarians have different preferences in treatment,” Koch says. “This indicates that no one treatment has been shown to be superior. There is interesting data in humans and animals, however, showing that stem cells may be useful in treating some joint conditions.”
Stem cell therapy holds a lot of promise because it has several advantages over traditional pain medications like phenylbutazone, “bute,” which merely mask pain and has a narrow window of safety and can have damaging side effects, and can’t be legally used in competition.
Some biologic products, like PRP and IRAP can be injected into joints, and there are fewer regulations regarding their use, as opposed to stem cells. “But it’s hit or miss whether they work, depending on the individual horse,” says Koch. Steroids have also been used for treating OA, but there is controversy about using those in joints because they may damage the cartilage.
Stem cell therapies are gaining interest because they have several advantages. “There are now two cell products approved in Europe for treating inflammatory joint pain in horses caused by synovitis and early OA,” Koch says. “These are HorStem and Arti-Cell Forte. They both use culture expanded MSCs. HorStem utilizes cells from equine placental umbilical cord tissue, and Arti-Cell Forte isolates MSCs from peripheral blood of adult horses. These two products are both approved for use in horses with joint pain due to early stage synovitis but are slightly different in formulation.
“HorStem contains only the cells (15 million stem cells) and Arti-Cell Forte is a combination product. It actually has only 2 million cells, plus PRP. So it’s difficult to know if the healing effect is due to the cells or the PRP, or whether the two may have a synergistic effect working together,” says Koch.
Arti-Cell Forte was acquired by Boehringer Ingelheim (a large international pharmaceutical company) last summer. “This is a boost, to know that this big company thinks stem cells and regenerative medicine have a role to play in veterinary medicine,” Koch says.
At Cornell University a research trial studied the effect of mesenchymal stem cells on damaged cartilage in research horses. “In the follow-up, the researchers saw that the cartilage in the joints that received the cell formulation were much more preserved than the joints that did not get those cells,” Koch said.
“I’m not sure if these therapies can turn a damaged joint into a less-damaged joint, but the Cornell study indicates that maybe we can arrest the damage and prevent further damage.”
Every new effective treatment offers more hope for horses with damaged joints. “There’s possibility now for more consistent disease management, with joint injections, to keep a horse comfortable. It might only have to be every 6 to 8 months or even longer. It might depend on the horse, but for horses that do respond, we may be able to manage their disease more consistently and have some degree of joint disease arrest,” Koch says. This could be career-extending for some horses.