Gene Therapy for the Enhancement of Fracture Healing - Engineered Bone: Tissue Engineering Intelligence Unit - page 140

for fracture healing is an attractive technique. Osteogenic genes can be delivered to the correct
anatomical site and the duration of expression can be controlled by the choice of vector. Per-
haps the greatest advantage of gene therapy for fracture healing is the fact that long-term transgene
expression is not necessary. Once the bone is healed, protein over-expression is no longer needed,
and may harm the patient.
Although gene therapy for fracture healing shows much promise for clinical applications,
there have been no published human clinical trials. There are several factors to consider prior to
treatment for humans. First, the physician must consider the condition of the host bed, includ-
ing the quality of the bone present. The degree of vascularity to the soft tissue and the location
of the defect have a significant impact on the success of a gene therapy treatment to the wound
site. Other existing systemic factors such as osteoporosis, diabetes, peripheral vascular disease,
medications and smoking will all have an effect on the effectiveness of a gene therapy applica-
tion. Physicians must find a balance between safety, efficacy and cost to determine in every
individual case if gene transfer is a suitable additional treatment option for fracture healing.
Apart from infection, the major risk factor contributing to fractures and insufficient fracture
healing is osteoporosis.
Osteoporosis is now recognized as a major public health concern. Low bone density, or
osteopenia, caused by either increased osteoclast production or decreased osteoblast produc-
tion or both results in osteoporosis. This causes fatigue degradation, leading to a significant
clinical risk for fractures from minimal trauma. The most common fractures due to osteoporo-
sis occur in the wrist, spine and hip, totalling 1.7 million fractures per year in the United States.
(In comparison, there are 1.2 million new cancer cases each year). 168 Hip fractures account for
the majority of morbidity, mortality and costs associated with osteoporotic fractures. 168 In the
United States, the number of individuals over age 65 is expected to rise from 32 to 69 million
between 1990 and 2050, and the risk for osteoporotic hip fractures increases exponentially
with age. 169 Therefore, if current trends continue, the number of hip fractures in the U.S.
could total 840,000 by 2040. 170 The treatment of choice for hip fractures in the elderly is most
often operative management. The ideal result is fracture fixation that promotes a return to
normal weight-bearing mobility. For most patients, fracture fixation and healing is achieved
with the use of an orthopaedic device made of titanium alloy or stainless steel. In some cases
where joint function cannot be restored or degenerative changes are advanced, instead of an
anatomical reconstruction of the bone, a total joint replacement is performed. Osteopenia at
the fracture site contributes to a less stable hip and complicates the success of this common
treatment. The inability of screws, pins and prosthetic implants to gain adequate access to the
bone stock causes failure in fracture healing and bone regeneration. 168 The most common
complications are fragment displacement, malrotation deformity, nonunion, and periprosthetic
fracture and early aseptic loosening. 168 Other complications not related to osteoporosis may
include breaking or bending of the implant, screw penetration into the joint, and disassocia-
tion of the plate from the shaft. 168 It is feasible to suspect that 5-20% of hip fracture patients
suffer at least one of the above complications; however there is no acceptable method to evalu-
ate fracture healing. 168 Fracture healing for osteoporotic patients is obviously in need of im-
provement. Gene therapy to stimulate bone formation and create denser bone mass is an at-
tractive possibility. Although there have been no clinical trials published thus far. However, the
mostly likely choice for the first human subjects would be Mat-100, a single application, plas-
mid gene therapy for bone fracture repair in osteoporotic elderly patients. 168 In vitro and ani-
mal studies have contributed evidence to support possible success for Mat-100 in humans as a
treatment for osteoporotic fractures. 168 PTH 1-34 peptide is the best studied human bone
growth factor in terms of its anabolic effects on the osteoporotic skeleton. 168,171-174 As stated,
there is an unmet clinical need associated with osteoporotic fractures in the elderly. PTH 1-34
cDNA as the plasmid DNA component of Mat-100 shows promise as a future clinical therapy.
A canine study in which Mat-100 prototypes were used to fill surgical defects in tibiae of
intact, skeletally mature beagles that mimic acute bone fracture in humans suggests potential
for hPTH 1-34 peptide as a therapy. 129 New bone filled these defects and persisted at least 2