Research projects
The Musculoskeletal Gene Therapy Research Laboratory has several ongoing research projects related to osteoarthritis and musculoskeletal injuries.
A phase 1 study evaluating the safety of intra-articular sc-rAAV2.5IL-1Ra in patients with moderate osteoarthritis of the knee
In collaboration with Jacob L. Sellon, M.D., we recently completed a phase 1 clinical trial to determine the safety of three different doses of a gene therapy vector called sc-rAAV2.5IL-1Ra. These doses were delivered by intra-articular injection into one knee joint of nine trial participants with moderate osteoarthritis of the knee.
The vector, derived from adeno-associated virus (AAV), transfers a gene encoding an antiarthritic protein, the interleukin-1 receptor antagonist (IL-1Ra), to cells within the joint. These cells then produce IL-1Ra for an extended period of time, with the expectation of producing a sustained antiarthritic effect. This vector has been shown to be safe and effective in preclinical testing.
Participants were followed for one year to assess safety, IL-1Ra expression and, in a preliminary manner, efficacy. This study confirmed safety and showed that in the majority of participants, IL-1Ra was present in joints at elevated concentrations for the entire year of follow-up. Participants reported improved pain and function.
Funding for the lab's knee osteoarthritis clinical trial was provided by the U.S. Department of Defense and Mayo Clinic's Transform the Practice initiative. We're now conducting a larger phase 1b trial of this gene therapy under the auspices of a company co-founded by Dr. Evans.
Healing of critical size segmental defects in bone by gene transfer
Although fractures usually heal on their own, they don't if a large segment of bone is missing. Bone lesions that are too large to heal spontaneously are known as critical size defects. These bone (osseous) defects are typically treated by a procedure in which bone is taken from elsewhere in the body, usually the pelvis, and placed in the defect.
While this treatment for bone defects can be effective, obstacles include considerable donor-site morbidity and limited supplies of autologous bone for harvesting. Allograft bone also is available, but this is dead bone that lacks intrinsic regenerative capacity.
Our lab aims to provide new, reliable and inexpensive ways to treat large osseous defects.
Building on our team's experience in gene therapy, members of the lab are using an animal model to determine whether the delivery of a gene encoding the osteogenic protein bone morphogenetic protein-2 (BMP-2) promotes bone healing. This study also uses AAV as the vector.
During the course of these experiments, we discovered that the osteogenic properties of BMP-2 were greatly potentiated when interleukin-1 (IL-1) was inhibited. In response, we developed a bicistronic AAV vector that expresses both BMP-2 and IL-1Ra. We're now conducting experiments to determine the vector's potency as an improved agent of bone healing.
Healing of critical size segmental defects in bone using chemically modified RNA
We're developing new strategies for bone healing based on the delivery of messenger RNA (mRNA) rather than DNA. This work is being done in collaboration with investigators from RWTH Aachen University Medical Center in Aachen, Germany, and Maastricht University in the Netherlands.
The mRNAs are chemically modified to enhance stability, reduce toxicity and lower immunogenicity. Data from our animal bone healing model confirm the potency of this product. Our current experiments use single-cell RNA sequencing to determine which cells within the fracture site are transfected by the RNA and which cells respond to it in an osteogenic fashion.
The success of mRNA as a COVID-19 vaccine confirmed the utility of this technology in human medicine and thereby helped pave the way for clinical use in other applications, such as bone healing.
Improved tendon healing by administration of growth factors
Preclinical studies in our lab showed that healing of the Achilles tendon is improved by implanting a collagen sponge. Healing is further improved if the sponge is first impregnated with purified, recombinant growth factors. Healing is assessed by morphometry, histology and mechanical testing. This work was done in collaboration with researchers at the University of Basel in Basel, Switzerland.
Separately, we're using an animal model to explore the use of BMP-5 for healing rotator cuff injuries. This work is being done in collaboration with Mayo Clinic investigators Scott M. Riester, M.D., Ph.D.; Emily T. Camilleri, Ph.D.; and John W. Sperling, M.D.