Biomedical Engineering Reference
In-Depth Information
C HAPTER 10
Gene Therapy for the Enhancement
of Fracture Healing
Charles Sfeir, Hannjörg Koch, Julie Jadlowiec, Paul Robbins
and Jeffrey O. Hollinger
The ability to introduce exogenous DNA into cells is a powerful tool for researchers in
the quest to improve treatment options. Recent years have witnessed increased
enthusiasm for gene therapy and the use of this technology to enhance bone repair is
an obvious choice. To gain therapeutic value from gene transfer into a cell, two main technical
requirements have to be met. One is to determine the most efficient delivery vehicle. The other
is transgene choice for local, therapeutic production in a sustained fashion.
To introduce exogenous DNA into the cell and more specifically into the nucleus where the
transcriptional machinery resides, vectors are the delivery vehicles. These vectors could be viral
or nonviral. Each delivery system has advantages and disadvantages. Vector optimization re-
mains an active area of research to achieve the most efficient gene delivery system.
The first part of this chapter will give an overview of the gene delivery technology currently
available to transfer genetic sequences into mammalian cells. Gene therapy applications to
bone will be discussed in the second part.
Gene Delivery Vectors
Vectors are defined as vehicles to enhance DNA entry and subsequent expression in a host
cells. Vectors are grossly divided into two types: viral and nonviral. 1 Although the ideal vector
is yet to be found or designed, certain features of different vectors may be appropriate for
diverse therapeutic approaches. The ideal vector should be safe for the recipient and should not
induce inflammation. It should be stable and easily produced. 2 Another very important feature
of the ideal vector relates to the regulation of gene expression. Following gene transfer to host
cells, control of gene expression is particularly advantageous. 3 This represents an ability to turn
gene expression on and off with discretion and ideally integrate it into a feed-back control
system. However, apart from these general characteristics, ideal vectors for gene transfer must
be tailored to address the unique physiology of each disease state. These variables include speci-
ficity to target cells and duration of protein expression. In most cases, a vector's ability to
transduce both dividing and nondividing cells is desirable. However, for some types of cancers,
it might be beneficial to distinguish between dividing and nondividing cells for targeted gene
transfer. 4,5 Enhancement of fracture healing and fusions, and even treatment of nonunions is
most often accomplished after a significantly shorter period of protein expression than success-
fully completed treatment of large critical bone defects. However, if the pathophysiology of
healing is disturbed by an inappropriately prolonged expression of therapeutic proteins, this
could be detrimental to the bone healing process. Finally, a chronic disease will need a pro-
longed therapy with consistently stable protein expression, regulated by a feed back mecha-
nism. 6
 
Search WWH ::




Custom Search