Baylor Awarded $5 Million to Study Promising OA Therapy

A team from the Baylor College of Medicine has been awarded a four-year Technology/Therapeutic Development Award for more than $5 million from the Department of Defense Congressionally Directed Medical Research Programs. The researchers will investigate late-stage preclinical testing of a viral gene therapy treatment for osteoarthritis (OA).

Baylor researchers had already laid the groundwork with the earlier development of the first gene therapy using a helper-dependent adenovirus vector and in vivo testing using mouse and horse OA models. The researchers have written previously that this therapy leads to long-term expression of the IL-1RA protein, which can block joint inflammation, but is different in that it activates the protein expression only when inflammation is actually present in the joint.

The current study focuses on a combination therapy approach using a vector that expresses both IL-1RA and the protein lubricin, and is a collaboration between GeneQuine Biotherapeutics, Baylor and Cornell University College of Veterinary Medicine. Ther researchers will compare the combination therapy delivered in a single virus to therapies expressing IL-1RA and lubricin alone in both mouse and horse OA models.

Brendan Lee, M.D., Ph.D., principal investigator of the study, is professor and chair of the Department of Molecular and Human Genetics and Robert and the Janice McNair Endowed Chair and Professor in Molecular and Human Genetics at Baylor.

Detailing the history of this work, Dr. Lee told OTW, “Helper-dependent adenovirus gene therapy vectors have been developed at Baylor College of Medicine since the mid 1990s as a safer and less immunogenic version of first- and second-generation adenovirus gene therapy vectors that have been used in now thousands of individuals in clinical trials- primary in the context of cancer.”

Long-Term Expression Sets Stage for Further Work

“Because these types of vectors are the most efficient vehicles for infecting non-dividing cells such as in joint tissues like cartilage,” Dr. Lee explained, “we tested their ability to express therapeutic in the joint space after a single injection.”

“Much like what we had seen in many other applications, like in the liver and the brain, a single injection can lead to long-term expression (over a year in the mouse joint). Given this robust long-term expression, we could now study its ability to deliver therapeutic genes.”

“Another important advantage is that they have a large carrying capacity—up to seven times the capacity of what can be carried for example in the adeno-associated virus—which is another commonly used gene therapy vector.”

“The work takes advantage of the large carrying capacity and low immunogenicity of helper dependent adenovirus vectors to test combinatorial therapy, i.e., the delivery of multiple therapeutic proteins in the treatment of OA.”

“Given the complexity of OA, targeting different mechanisms of disease is likely to be needed. This is akin to our therapeutic approach to other chronic diseases like hypertension, high cholesterol, HIV, etc.”

“In our approach, we combine a well validated molecule to block inflammation (IL1-RA) and a cartilage protective-anti-catabolic treatment called lubricin. It is the first combination gene therapy approach to OA that we are aware of.”

“Importantly, we also take a different approach to expressing IL1-RA. We do so under a control element that is turned on only if there is inflammation. We hypothesize that this is important as chronic immune suppression may be detrimental as inflammation can also help to regenerate tissues.”

“The new gene therapy approach takes advantage of a version of low toxicity and high carrying capacity, so it is optimal for joint-targeted, long-term expression of multiple therapeutic genes. In our preclinical study, we are expressing IL1-RA in a controlled inflammation dependent fashion while over expressing a naturally occurring protective protein of lubricin at high levels.”