what-when-how
In Depth Tutorials and Information
CHAPTER
57
The Potential of Gene and Cell-
Based Strategies for the Treatment of
Ost
eogenesis Imperfe
cta
David W. Rowe
University of Connecticut Health Center, Farmington, CT, USA
INTRODUCTION
to demonstrate before it progresses to a human study.
Both basic researchers and clinicians involved in the
care of OI subjects should be cautiously optimistic that
eventually a safe and effective therapy will become
available, but until it does, over-promising based on
poor experimental data will only be a disservice to the
patients and families who daily have to cope with the
realities of the disease.
12
While introduction of anti-resorption therapy has
changed the natural history of osteogenesis imperfecta
(OI) in rapidly growing children, there is general con-
sensus that this is not a long-term therapeutic strategy
and ultimately the underlying cause of the genetic dis-
order needs to be corrected.
1-3
The potential for gene
therapy as a viable option for many genetic conditions
has made a remarkable comeback since the collapse of
the approach after the death of a human subject treated
with an adenoviral expression vector.
4,5
Direct injection
of adeno-associated viral (AAV) vectors or lentiviral
vectors expressing growth factors or as gene function
replacement is showing promise for retinal disease,
6
blood
7,8
and immune disorders.
5
Equally promising
but still very premature is the potential of cell-based
therapy utilizing either adult-derived tissue progenitor
cells or somatic cells converted to induced pleuripoten-
tial stem (iPS) cells.
9
Many of the same approaches are
being proposed for both acquired and heritable diseases
of connective tissue including OI,
10
with some of the
unproven concepts even progressing to a clinical trial.
11
As exciting as the possibility of gene or cell therapy for
OI might appear, it has to be done in a rigorous and
transparent manner to avoid a clinical debacle similar
to that which occurred for viral-based gene therapy.
Thus, the purpose of this chapter is to present the
rationale for different forms of gene or cell therapy
for different forms of OI, provide evidence why one
approach appears advantageous over another and
propose criteria that any preclinical animal trial has
SELECTING THE APPROPRIATE
THERAPY FOR THE UNDERLYING
DISE
ASE MECHANISM (
TABLE
57.1
)
As the genetic basis for the different forms of OI have
been uncovered, it has become clear that one form of
therapy does not it all. The most common forms of the
disease (types II, III and IV) have been extensively stud-
ied and the deleterious effect of an amino acid substi-
tution that disrupts the helical structure of the collagen
chain is well understood.
24,25
Specifically, because both
normal and mutant chains become associated either in
the collagen molecule within the cell or within collagen
microfibril in the extracellular matrix, the impact of the
mutation is greater than if there was no collagen chain
being produced from the mutant allele.
13
This dominant
negative effect of the mutation explains why the disease
is transmitted as a Mendelian dominant. Irrespective
of a therapy that alters bone formation or turnover, the
subject will still produce the mutant collagen chain that
will continue to form a defective bone matrix. While
a therapy that suppresses the cytopathic effects of
