Gene Therapy for the Enhancement of Fracture Healing - Engineered Bone: Tissue Engineering Intelligence Unit - page 136

Gene Therapy Applications to Bone Fracture Healing
and Tissue Engineering
Gene Therapy for Bone Healing
The success of gene therapy strategies depends on the basic biology and physiology of the
target tissues, the nature of the defect and the limitations of each specific gene therapy tech-
nique. Although gene therapy was initially envisioned to treat heritable genetic disorders, ma-
jor advances in somatic cell gene therapy have indicated an ability to revolutionize modern
medicine. As we further our understanding of the basic biology of cell differentiation to form
tissues and organs of the body, we can design new therapeutic strategies to combat disease and
injury. The microenvironment in which a cell resides is an intricate and dynamic network
composed of soluble and immobilized growth factors and extracellular matrix (ECM) pro-
teins. 130 Characterizing genes that participate in tissue development, maintenance, repair and
degradation leads to an understanding of the unique microenvironment cells require to form
specific tissues in the body. Further, it is known that for bone and other systems, the ECM
participates in signaling for proliferation, differentiation and survival. 131 Bone represents an
ideal system in which to employ gene therapy in tissue engineering to repair defects due to
disease, trauma or aging. Bone has the inherent capacity to regenerate itself. We must use the
known basic biology of the bone microenvironment to reengineer bone. Gene therapy can help
recreate the specific microenvironment necessary for successful bone healing, by providing the
correct cues to cells, enabling them to participate in new bone formation. Traditional treat-
ments for complications associated with fracture healing fall short of mimicking a bone-favorable
microenvironment, have varying success and many disadvantages.
Gene therapy can be used to overcome the complications of conventional treatments for
bony defects. In this section, we will address examples of the successes and failures of gene
therapy for fracture healing. Future directions in bone tissue engineering using gene therapy
will be suggested and its eventual success as a clinical therapy will be evident.
Gene Therapy Strategies for Bone Tissue Engineering
The ideal delivery system must effectively transport a functional protein (or coding DNA)
to the site of the wound and maintain localization of that growth factor with controlled expres-
sion. The DNA transfer must remain functional during transport, be replicable, transcribable
and made into a properly folded, functional protein. Proper delivery of osteoinductive factors
will provide molecular signals to host cells, recruit potential osteoprogenitor cells and enhance
or help recreate the natural microenvironment for bone regeneration. The three main strategies
for growth factor delivery to bone wound sites are shown in Figure 3:
1. Gene therapy: the direct delivery of DNA encoding a growth factor to the patient
2. Cell therapy (ex vivo gene therapy): in vitro transfer of growth factor DNA to cultured
cells, followed by implantation into the would site
3. Protein therapy: direct injection of growth factor to patient via carrier matrix
All three delivery strategies usually make use of a carrier matrix (i.e., polymer) for effective
delivery of DNA, cells or proteins to the wound site. In the case of gene therapy or cell therapy
the vector (plasmid or viral) or cell could serve as the carrier. However, the addition of a poly-
mer scaffold as a carrier matrix could offer several additional levels of protection and release
control. DNA for gene therapy or cultured cells transfected in vitro can be seeded onto scaf-
folds which resemble the natural porous structure of bone. The ideal scaffold mimics the target
tissue, optimizes the activity of the growth factor, stability in vivo, yet biodegradable. Addi-
tional desirable attributes include controlled release of the growth factor or gene and cell growth
conducive. These characteristics often conflict with each other and lead to difficulty finding
the optimal scaffold. Clinicians prefer a material that can be injected percutaneously, however
such a substance would not be cohesive enough to stay localized to the defect. Obviously, it
would be advantageous to use a scaffold of natural origin such as collagen or hydroxyapatite.