Abstract
Bone defects and improper healing of fractures are an increasing public health burden, and there is an unmet clinical need in their successful repair. Gene therapy has been proposed as a possible approach to improve or augment bone healing with the potential to provide true functional regeneration. While large numbers of studies have been performed in vitro or in vivo in small animal models that support the use of gene therapy for bone repair, these systems do not recapitulate several key features of a critical or complex fracture environment. Larger animal models are therefore a key step on the path to clinical translation of the technology. Herein, the current state of orthopedic gene therapy research in preclinical large animal models was investigated based on performed large animal studies. A summary and an outlook regarding current clinical studies in this sector are provided. It was found that the results found in the current research literature were generally positive but highly methodologically inconsistent, rendering a comparison difficult. Additionally, factors vital for translation have not been thoroughly addressed in these model systems, and the risk of bias was high in all reviewed publications. These limitations directly impact clinical translation of gene therapeutic approaches due to lack of comparability, inability to demonstrate non-inferiority or equivalence compared with current clinical standards, and lack of safety data. This review therefore aims to provide a current overview of ongoing preclinical and clinical work, potential bottlenecks in preclinical studies and for translation, and recommendations to overcome these to enable future deployment of this promising technology to the clinical setting.
Highlights
While bone is highly competent at regeneration (Hadjidakis and Androulakis, 2006), a variety of situations can lead to damage that cannot be fully repaired by endogenous mechanisms
Automated machine reading data analysis of all 33 publication abstracts of the manuscripts selected for systematic review illustrates that the most common converging topic areas are centered around the use of bone marrow stromal cells (BMSCs) and bone morphogenetic protein (BMP) genes (Figure 4A)
The author word cloud (Figure 4B) illustrates the most prolific authors found in the dataset but is not a representation of overall publication activity or leadership in the gene therapy field, as it might represent a skewed dataset in this regard due to the performed preselection
Summary
While bone is highly competent at regeneration (Hadjidakis and Androulakis, 2006), a variety of situations can lead to damage that cannot be fully repaired by endogenous mechanisms. Large bone defects that cannot be repaired by endogenous mechanisms leaving a permanent gap in the bone are termed “critical defects” (see Figure 1). In humans, a defect of >1–2 cm in length where 50% of the bone circumference is lost will be critical (Lindsey et al, 2006; Spicer et al, 2012; Schemitsch, 2017). It is important to note that defect site and other factors have a major influence and may lead to defects that do not fit these parameters becoming critical or those that do fit them healing fully (Sanders et al, 2014; Schemitsch, 2017)
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