Osteoarthritis gene therapy
shows promise for humans, animals

 By Czerne Reid

University of Florida researchers are developing a gene therapy technique that could help both humans and horses fight osteoarthritis, a debilitating condition that causes inflammation and deterioration of the joints. The goal is to create a one-time treatment that works long term.

Steven Ghivizzani, Ph.D., and Patrick T. Colahan, DVM, DACVS, observe a horse’s gait at the University of Florida’s Large Animal Hospital. (Photo by Jesse Jones/University of Florida)

Steven Ghivizzani, Ph.D., and Patrick T. Colahan, DVM, DACVS, observe a horse’s gait at the University of Florida’s Large Animal Hospital. (Photo by Jesse Jones/University of Florida)

The research team received a highly competitive one-year, $900,000 grant from the National Institute of Health’s National Institute of Arthritis, Musculoskeletal and Skin Disease to fund the work. The new effort will expand laboratory studies into trials that better approximate osteoarthritis in humans.

The work will involve the use of viruses, called adeno-associated viruses, or AAV, as vehicles to deliver genetic material to the joints of horses, where it would produce a therapeutic protein directly at the site of the disease.

“We’re uniquely poised to do this study, because UF has a leading program in equine medicine and research and is one of the homes of AAV technology,” said principal investigator Steven Ghivizzani, Ph.D., a professor of orthopaedics and rehabilitation in the UF College of Medicine, and a member of the UF Genetics Institute. Researchers at UF’s Powell Gene Therapy Center are among the pioneers of AAV technology and gene therapy applications for a number of diseases.

Osteoarthritis, the most common type of arthritis, is a chronic condition that affects large weight-bearing joints such as the knees and hips. In osteoarthritis, the cartilage in the joints that usually allows bones to move smoothly over each other wears away, causing bones to rub. The result is pain, stiffness and swelling. About 27 million Americans age 25 and older have the disease, according to the National Institutes of Health. The economic cost of arthritis and other rheumatic conditions is estimated at close to $130 billion a year, according to the Centers for Disease Control and Prevention.

There is no cure for osteoarthritis.

Joint replacement surgery can help ease the disabling effects of the condition. The few medicines that exist for osteoarthritis mostly offer only limited symptom relief. In addition, those drugs can have unwanted consequences. Corticosteroid injections, for example, which are given to both people and horses, also suppress other healthy activities in the joint, such as processes important for healing. The injections also have to be administered repeatedly, which increases the chance of infection.

In contrast, the new gene therapies being developed at UF would require a one-time treatment and would not hinder the body’s healing processes.

Research suggests that the pain, joint inflammation and loss of cartilage associated with osteoarthritis are linked to a protein called interleukin-1. A therapeutic gene used to treat the arthritic joints produces a second protein that naturally counteracts the effects of interleukin-1, but that has not yet translated into effective treatments for patients because of difficulty getting high enough concentrations inside affected joints.

The UF researchers are devising a gene therapy approach that would allow continued production of therapeutic protein within the joints, directly at the disease site. Unlike existing drugs, the potential one-time treatment would not just address symptoms, but change the course of the disease.

“Dr. Ghivizzani is at the forefront of trying to develop new technologies for treating osteoarthritis and other joint diseases by gene therapy,” said Christopher Evans, D.Sc., Ph.D., the Maurice Müller professor of orthopaedic surgery at Harvard Medical School, who is not involved in the UF study. “There’s a lot riding on this.”

Previous studies in small animals such as rats demonstrated that delivery of the gene therapy resulted in meaningful levels of gene expression within affected joints. The researchers will examine how that translates to the larger joints of horses, which are more similar to human joints in terms of size, tissue structure and weight-bearing stance.

The new studies will determine the therapy dose that can be given safely, how much of the therapeutic protein is produced in the joint — and for how long — and the effectiveness of the therapy.

The researchers will use techniques such as a minimally invasive procedure called arthroscopy, imaging studies such as MRI and X-ray, as well as hands-on clinical evaluations to check for inflammation and cartilage degradation. Motion capture analysis will help with evaluation of changes in gait, a good measure of pain.

“We hope that this will be at least the first step in a therapy that will benefit both people and animals,” said Patrick Colahan, D.V.M., a board-certified equine surgeon in the UF College of Veterinary Medicine and co-investigator on the study. “It has the potential to help lots of different species, and from a veterinarian’s perspective, that’s what we’d like.”

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