Blurring the lines

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How helping our pets can help us help ourselves

Pip steps onto a treadmill.

Brett Rice, called the treadmill “horse whisperer,” coaxes Pip through a range of speeds — walk, trot, canter, gallop.

Yes, Pip is a horse, and yes, that horse is on a treadmill. Rice, with the UF College of Veterinary Medicine’s department of large animal clinical sciences, is a research assistant tasked with familiarizing horses such as Pip with that treadmill.

The purpose? To evaluate how inflammation in the horse’s carpal joint — the knobby joint just above a horse’s hoof analogous to the human wrist — could lead to osteoarthritis, and how to prevent that progression.

Andrew Smith, D.V.M., a graduate student in the UF College of Veterinary Medicine, is leading the study in horses. He hopes his findings can one day translate into treatment for humans who suffer traumatic injury to their joints, which can also often turn into osteoarthritis.

This kind of research is taking place all over UF Health’s campus. Researchers are studying diseases that occur both in us and in our pets — called parallel diseases — because dogs, horses and cats are more genetically similar to humans than rats and mice. Rodents, which don’t naturally develop diseases such as diabetes or eczema, often aren’t a good model for studying how a drug may combat these conditions in humans, says Ammon Peck, Ph.D., associate dean of research and graduate studies at the UF College of Veterinary Medicine.

“These diseases in mice probably aren’t going to be anything similar to what you’d normally see in a human,” Peck says. “But these diseases show this beautiful parallel between humans and a certain kind of animal that develops them naturally.”

From examining skin disease in beagles to studying osteosarcoma and melanoma in cancer-stricken dogs, researchers are joining together across the human-animal boundary to develop better therapies for our pets — and for ourselves.

Looking a gift horse in the

Andrew Smith, D.V.M., is a resident in the large animal surgery department of the UF College of Veterinary Medicine

Andrew Smith, D.V.M., is a resident in the large animal surgery department of the UF College of Veterinary Medicine

Treadmills for horses look like oversized people-movers at an airport.

This treadmill at the UF College of Veterinary Medicine is specially designed to accommodate a galloping horse. Smith studies Pip’s gait, both visually and objectively, with sensors placed on Pip’s head, forelimb and back. The sensors show Smith how Pip may be subtly favoring her right front leg.

Smith, who is pursuing his Ph.D. at UF in equine osteoarthritis imaging, is studying how gene therapy may combat inflammation in those joints — inflammation that could lead to osteoarthritis.

The same kind of inflammation in humans, brought on by acute injury, can lead to osteoarthritis as well, Smith says. An ankle break or a tear in knee ligaments can turn into arthritis much earlier than a person should develop the condition.

“Athletes have a high incidence of osteoarthritis at 30 years old,” Smith says. “That’s not the ideal time to replace a joint.”

By treating the acute inflammation that occurs in the first few weeks to months following a traumatic joint injury, the researchers hope to prevent or delay the development of traumatic osteoarthritis. Smith is studying how dampening this inflammation after an acute injury in horses could one day be translated to treating inflammation — potentially averting arthritis — in humans.

Smith’s study is funded by the U.S. Department of Defense. Why the Department of Defense? Because of
trauma inflicted on the knees of soldiers, who vault out of airplanes and helicopters on a regular basis.

“A lot of them have developed knee osteoarthritis later on, and this has a lot to do with traumatic incidences — tears to the knee’s anterior cruciate ligament or meniscus,” Smith says. “So what we’re trying to do is develop a drug that inhibits that trauma-induced osteoarthritis.”

Racehorses are prone to similar acute — and therefore long-term — injuries. After inducing inflammation in the carpal joint of 20 horses, Smith treated the group with a harmless virus loaded with a gene that stimulates the production of a protein that blocks inflammation in the knee.

Developed by Steve Ghivizzani, Ph.D., the leader of the Gene Therapy Laboratory in the UF College of Medicine’s department of orthopaedics and rehabilitation, gene therapy targets a protein called interleukin-1. interleukin-1 triggers a cascade of inflammatory enzymes that flood the knee. But the body also produces a protein that blocks these inflammatory proteins from binding to the interleukin-1 receptor. This protein mitigates inflammation, dampening the response.

“What we’re trying to do is dumb down the inflammatory component and inhibit the inflammatory cascade,” Smith says.

Ghivizzani’s gene therapy overstimulates the protein that blocks inflammation, with the goal of preventing acute inflammation that may lead to osteoarthritis. To see how it could apply to people in the future, Smith is studying the effect over a period of a year in horses.

Andrew Smith, D.V.M., images the stifle joint of a horse. The stifle joint is analogous to a human knee.

Andrew Smith, D.V.M., images the stifle joint of a horse. The stifle joint is analogous to a human knee.

First, Smith induces inflammation in the horse’s carpal joint. For the first two weeks of the yearlong study, the horses rest. Then, they are exercised on the treadmill. At 12 weeks, the researchers treat the horses’ middle carpal joints with the gene therapy. Just before treatment, the horses’ joints are scanned in an MRI the size of a Volkswagen Beetle. The researchers image the joint again at six months and at 12 months.

Smith is only partway through his study, but he believes what he finds in horses can be applied to humans. And the horses? They were either unsafe to handle, not athletic enough to be used as racehorses or taken from situations of neglect. At UF, they’re fed well, given preventive nutrition, undergo physical rehabilitation and trained to be safely handled by people. After their year at UF, most will be paired into new homes.

“Most of our horses, when they come to us, aren’t in any condition to be homed with people,” Smith says. “But after the study, they will be able to go to new homes.” — Morgan Sherburne

Teaching an old disease new tricks

Rowan Milner, Hill's Associate Professor of Oncology and Chair

Rowan Milner, Hill’s Associate Professor of Oncology and Chair

In the hunt for cancer treatments, dogs are man’s best friend yet again.

At the UF College of Veterinary Medicine, researcher Rowan Milner, D.V.M., Ph.D., is immersed in two clinical trials that could ultimately improve the survival time for bone cancer and melanoma, a form of skin cancer. Milner is about halfway through a two-year study that uses a vaccine to induce an immune system response that slows the spread of osteosarcoma, a type of bone cancer.

For Milner, studying osteosarcoma is the natural extension of an earlier success. The ongoing study of 400 dogs with melanoma has already showed that a vaccine containing a particular antigen provoked the desired anti-cancer immune response that looks promising.

“You can stimulate the body to mount an immune response, and then see a significant response,” says Milner, the Hill’s associate professor of oncology and chair of the department of small animal clinical sciences.

Hundreds of pet owners with naturally occurring cancer have enrolled their dogs into Milner’s melanoma clinical trial, while others are participating in the early stages of the osteosarcoma trial. Because the immune responses and some cancers in dogs and humans are somewhat similar, what’s good for a cancer-stricken dog may also one day be good for its master.

“I get to do therapies in dogs that may result in me helping people’s pets. If we get the right answers, it could go into use in humans,” Milner says.

In the osteosarcoma trial, 20 dogs are receiving standard of care plus a vaccine containing an antigen similar to the one that has already created a positive immune response in dogs with melanoma. For comparison, 20 other dogs are receiving standard osteosarcoma treatment, allowing Milner to gauge the vaccine’s effectiveness.

Osteosarcoma is the most common malignant bone tumor, affecting 10,000 mostly large-breeds dogs a year in the United States. In humans, osteosarcoma usually affects children and young adults, attacking areas where the bone is growing quickly. Some 800 new cases are diagnosed in the United States each year. The five-year survival rate for humans can range from 60 percent to 80 percent for localized tumors, or less than 30 percent if it has already spread, according to the American Cancer Society. In the case of dogs, 80 percent to 90 percent will not survive past two years.

Milner says osteosarcoma is particularly challenging because it can regulate how the body tolerates cancer’s existence and might be switching off the body’s normal anti-cancer immune reaction. That’s why Milner and collaborators in the UF College of Medicine are also looking at another approach. They are developing a unique way to generate specialized cells that specifically target osteosarcoma. The technique, known as chimeric antigen receptor T-cell therapy, works this way: T-cells, a type of immune cell, are harvested from a patient and genetically modified to recognize a protein on targeted tumor cells. The engineered cells are then multiplied and returned to the patient’s bloodstream, where they go on to attack and kill cancerous cells.

The T-cell approach has the potential to significantly improve outcomes for osteosarcoma patients, something Milner says is urgently needed because survival outcomes for humans and dogs with osteosarcoma has not changed significantly in the last 20 to 30 years. Studying its effects in dogs is an important step toward being able to test it in humans during a clinical trial, according to Milner.

While the T-cell research is ongoing, Milner says he sees significant potential.

“We have just begun, but it’s possible that this kind of T-cell therapy could someday result in significant reductions in the cancer load in humans,” he says. — Doug Bennett

Taking a bite out of eczema

Rosanna Marsella, DVM, a professor in the COVM's department of small animal clinical sciences. Marsella studies atopic dermatitis, or eczema, in dogs, which has translated to work in humans.

Rosanna Marsella, DVM, a professor in the COVM’s department of small animal clinical sciences. Marsella studies atopic dermatitis, or eczema, in dogs, which has translated to work in humans.

At the grocery store, we wipe down our shopping carts with antibacterial wipes. At home, we sanitize our kitchen with bleach wipes. Our kids are scrubbed until they shine.

Researchers are starting to think this attention to cleanliness may be causing more harm than we may think.

“Skin isn’t meant to be washed every day. It sounds gross, but a little bit of dirt is good,” says Rosanna Marsella, D.V.M., Ph.D., a professor in the UF College of Veterinary Medicine’s department of small animal clinical sciences.

It’s an idea that you may have heard before: Rather than an entirely antiseptic environment, it’s good to expose your children to various microbes. This allows the child’s immune system to develop resistance to many different kinds of microbes and bacteria. An overly protected immune system could go haywire and start recognizing all kinds of things as enemies: grass, cats, dogs, peanuts.

Researchers are also starting to believe that the skin disease eczema develops because a person’s immune system is underdeveloped. In some areas of the United States and the United Kingdom — places where hygiene may be a little too enforced — eczema in children is being diagnosed at a rate of 20 to 30 percent, says Marsella. Marsella studies the condition in beagles, which naturally develop the disease, but hopes her research can also be applied to helping humans battle the disorder.

In 2014, Vladimir Vincek, M.D., Ph.D., the chair of the UF College of Medicine’s department of dermatology, joined the cause.

Vincek began to consider ways to get his dermatology residents involved in research. He approached Marsella with a new idea: What if medical residents within the department of dermatology collaborated with Marsella’s lab in the UF College of Veterinary Medicine?

That way, Vincek thought, the department of dermatology students and residents would receive much-needed experience in research while Marsella’s researchers would benefit from an exchange of ideas.

Marsella’s research seemed like a perfect fit: Eczema develops in kids very similarly to how it develops in dogs, and the problem in children is growing. Eczema is more than just a condition of the skin. In time, the disease can potentially trigger asthma and a host of skin sensitivities.

A collaborative effort between veterinary medicine researchers and medical researchers could help move promising drugs forward faster, Marsella said. Mice don’t develop the disease naturally, so it’s difficult for researchers to test drugs for humans in mice. Dogs, which are genetically more similar to humans than mice, Marsella says, also share our environment. And because the approval time for drugs in animals is much faster, there are already more drugs available to treat eczema in dogs than in humans. One such drug that is currently being tested in dogs uses an antibody to block a protein
that helps communicate the feeling of itchiness in eczema.

“By testing these drugs, we can both benefit pets and benefit kids,” Marsella says.

The researchers, both in medicine and veterinary medicine, work in a large, open lab in the UF College of Veterinary Medicine’s Small Animal Clinic.

Dogs have their own ‘preferred’ staph, we have our own staph — and the truth is, staph is not that picky…we have these two-way relationships between pets and people when it comes to staph and when it comes to antibiotic resistance.”“When we expanded the lab, we knocked down all the walls,” Marsella says. “By creating proximity, you also facilitate brainstorming. If you have the opportunity to see someone on a daily basis, when you’re able to talk with them, you’re able to have more ideas — these come from this exchange.”

The collaboration between the UF College of Medicine’s dermatology researchers and Marsella’s researchers officially began in October 2014 with the opening of Marcella’s and Vincek’s renovated lab space in the UF College of Veterinary Medicine.

Improving our understanding and developing effective drugs to treat the root of eczema provides more than relief to an individual; it is a public health benefit, Marsella says. People with eczema tend to have an overabundance of the bacteria staphylococcus on their skin, and can develop staph infections. To quell outbreaks of staph, clinicians prescribe antibiotics, increasing the risk of creating antibiotic-resistant staphylococcus.

“Dogs have their own ‘preferred’ staph, we have our own staph — and the truth is, staph is not that picky,” Marsella says. “What happens is that we have these two-way relationships between pets and people when it comes to staph and when it comes to antibiotic resistance.”

In other words, there is a concern that people may pass antibiotic-resistant staphylococcus to their pets, and their pets can pass it back to them. Developing effective drugs for people could help address antibiotic resistance, and putting researchers who study particular diseases in humans together with researchers who study these conditions in animals could help develop those drugs faster.

“If you combine multiple brains and skills and different points of view, the benefit is much larger than the individual effort,” Marsella says. “When you are exposed to both worlds, and you learn to interact both groups, you bridge that distance that otherwise would never have been bridged.” — Morgan Sherburne