Non-viral Gene Delivery Methods for Bone and Joints

Benjamin Gantenbein,Andreas S Croft,Natalia Higuita-Castro,Shirley Tang,Devina Purmessur,Julien Guerrero,Amiq Gazdhar,Ana I Salazar-Puerta

doi:10.3389/fbioe.2020.598466

Abstract

Viral carrier transport efficiency of gene delivery is high, depending on the type of vector. However, viral delivery poses significant safety concerns such as inefficient/unpredictable reprogramming outcomes, genomic integration, as well as unwarranted immune responses and toxicity. Thus, non-viral gene delivery methods are more feasible for translation as these allow safer delivery of genes and can modulate gene expression transiently both in vivo, ex vivo, and in vitro. Based on current studies, the efficiency of these technologies appears to be more limited, but they are appealing for clinical translation. This review presents a summary of recent advancements in orthopedics, where primarily bone and joints from the musculoskeletal apparatus were targeted. In connective tissues, which are known to have a poor healing capacity, and have a relatively low cell-density, i.e., articular cartilage, bone, and the intervertebral disk (IVD) several approaches have recently been undertaken. We provide a brief overview of the existing technologies, using nano-spheres/engineered vesicles, lipofection, and in vivo electroporation. Here, delivery for microRNA (miRNA), and silencing RNA (siRNA) and DNA plasmids will be discussed. Recent studies will be summarized that aimed to improve regeneration of these tissues, involving the delivery of bone morphogenic proteins (BMPs), such as BMP2 for improvement of bone healing. For articular cartilage/osteochondral junction, non-viral methods concentrate on targeted delivery to chondrocytes or MSCs for tissue engineering-based approaches. For the IVD, growth factors such as GDF5 or GDF6 or developmental transcription factors such as Brachyury or FOXF1 seem to be of high clinical interest. However, the most efficient method of gene transfer is still elusive, as several preclinical studies have reported many different non-viral methods and clinical translation of these techniques still needs to be validated. Here we discuss the non-viral methods applied for bone and joint and propose methods that can be promising in clinical use.

Highlights

Non-viral gene therapy holds great premises as it is assumed to be less toxic for the host and much safer in terms of gene delivery compared to viral vectors (NIH Report, 2002; Kaiser, 2007).Generally, gene transfer approaches in clinical trials are much less common than clinical trials in general that may involve drug testing (Figure 1)
Identifying non-viral gene delivery systems for the treatment of intervertebral disk degeneration” (IVD) degeneration is a research priority given the potential of gene therapy-based approaches to regenerate the IVD using discogenic growth factors, RNA interference/silencing and transcription factors and limitations associated with the use of viral vectors
While this is still a growing area for the IVD, the studies described above highlight the clinical applicability and relevance of these methods as safe and efficacious alternatives to viruses that warrant further investigation

Summary

Introduction

Non-viral gene therapy holds great premises as it is assumed to be less toxic for the host and much safer in terms of gene delivery compared to viral vectors (NIH Report, 2002; Kaiser, 2007).Generally, gene transfer approaches in clinical trials are much less common than clinical trials in general that may involve drug testing (Figure 1). Non-viral gene therapy holds great premises as it is assumed to be less toxic for the host and much safer in terms of gene delivery compared to viral vectors (NIH Report, 2002; Kaiser, 2007). With the additional mesh-terms “gene delivery” OR “viral gene therapy” combined with the afore-mentioned orthopedic “specialties” 289 studies were identified for “bone,” only two for the “tendon” and five were found for “IVD” and none for “cartilage” (inlet, Figure 1). “non-viral” AND “gene delivery” resulted in “zero” studies in all fields of orthopedics. This fact reflects the current situation of non-viral gene delivery trials in this field. Non-viral gene therapy seems an attractive alternative to viral gene delivery and is an new and emerging field being applied to regenerative medicine. Preclinical application of such technologies to the musculoskeletal field is still limited

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