Gene Therapy in Bone Regeneration: A Summary of Delivery Approaches for Effective Therapies - Intracellular Delivery: Fundamentals and Applications - page 824

Table 1 (continued)
Gene Site Carrier Comments
VEGF Orthotopic AV VEGF-A expressing AV injected into the muscle surrounding
a bone defect resulted in enhanced periosteal cartilage and
femoral mineral content, and faster endochondral phase
(Tarkka et al. 2003 )
PDGF Orthotopic AV Periodontal lesions filled with collagen containing PDGF
expressing AV led to increased enhanced alveolar bone
regeneration (Jin et al. 2004 ; Chang et al. 2010 )
LMP1 Orthotopic RV LMP-1 led to improved bony union of fracture in rats (Strohbach
et al. 2008 )
Cbfa1 Orthotopic AV Cbfa1 expressing adenovirus led to robust bone regeneration in an
idiopathic osteonecrosis model (Sakai et al. 2008 )
Nell1 Orthotopic AV Adenoviral Nell-1 delivery in demineralised bone matrix led to
better spinal fusion rates than BMP-2 and −7 (Lu et al. 2007 )
Abbreviations : AV adenovirus, AAV adeno-associated virus, RV retrovirus, BMP bone morphoge-
netic protein, TGFb transforming growth factor-b, VEGF vascular endothelial growth factor,
PDGF platelet derived growth factor, LMP1 surface located membrance protein 1, Cbfa1 core
binding factor alpha1 subunit protein (Runx2), Nell1 NEL-like 1
Modified from Varkey et al.

trafficking of DNA molecules, intracellular processing of gene complexes were
emphasized where appropriate and we highlighted the technological approaches to
this end.

3.1 Delivery Considerations for Growth Factors

and Gene Expression Systems

For a therapeutic effect, cells in a tissue must be exposed to protein growth factors
for a prolonged period of time. In animal models utilizing rhBMP-2 implants, the
longer the duration of growth factor retention in implants, the more potent was its
ability to induce bone formation (Uludag et al. 2000, 2001 ). The concentration of
the growth factor is equally important for healing, as too little may be insufficient
for bone induction/regeneration while too much may be detrimental to healing
process due to excess swelling or down-regulation of specific intracellular media-
tors. A local injection of growth factor is marred by the short half-life of proteins
in vivo ; growth factors in particular are cleared from the local site quickly, and can
be easily denatured and degraded, leading to a loss of the protein's function.
Current clinical delivery systems for BMP-2 and OP-1 navigate this barrier by
delivering large amounts of protein in an implantable format. Even with a fast clear-
ance, sufficient protein remains locally to keep a therapeutic concentration for a
period of time sufficient to allow bone regeneration. The milligrams of protein
growth factor required for efficacy make this type of therapy very expensive, and
may show less than ideal pharmacokinetics. Since BMPs act via cell-surface