Pediatric limb deformities are clinically challenging disorders that result in lifelong disability, chronic pain, and often require multiple complex surgical reconstructions to restore function. Therapeutic strategies that can reversibly slow or accelerate the growth of the extremities by altering the biologic landscape of the epiphyseal growth plate have the potential to correct limb deformities while avoiding the complications and morbidity associated with current treatments. Epiphyseal growth plates initially grow at symmetrical rates within the body, but later in development begin to show changes in growth velocity based on their location within the body. We hypothesize that changes in the epigenetic state of the epiphyseal growth plate are responsible for the differential growth rates. MicroRNAs are small non-coding RNA molecules that are capable of mediating epigenetic shift by suppressing the activity of target transcription factors. This proposal will investigate the clinicl potential of microRNAs to induce epigenetic change within the epiphyseal growth plate to alter its growth velocity for applications in pediatric limb deformity correction by (i) defining gene regulatory parameters linked to growth rate in surgical biopsies of the human physis, (ii) validating the biologic activity of microRNA transcription factor regulatory networks on growth plate chondrocytes, and (iii) evaluating different drug delivery strategies that can potentially be used to treat limb length discrepancies and angular limb deformities. Completion of this investigation will identify small non-coding RNAs that can be therapeutically leveraged to treat pediatric limb deformities and leg length discrepancies by increasing or slowing limb growth. It will also identify transcription factor networks that can be therapeutically targeted to control lib growth using pharmacologic agents that are currently being used in clinical practice to treat other medical conditions. This proposal will also explore two different drug delivery strategies, one involving direct injection into the center of the epiphyseal growth plate to uniformly increase or decrease growth throughout the physis, and another delivery strategy where therapeutic agents are delivered preferentially to one side of the physis to intentionally induce asymmetrical growth across the physis, so that angular limb deformities can be corrected.
Current strategies for treating pediatric limb length discrepancies and angular limb deformities are associated with significant morbidity and are often limited in their ability to maximize functional outcomes. This proposal will investigate the therapeutic potential of small non-coding RNAs and their associated transcription factor regulatory networks to act as modulators of limb growth by altering the epigenetic state of the epiphyseal growth plate, with the ultimate clinical goal of treating pediatric limb deformities without the need for complex surgical reconstructions.