Chapter 21 / Future Perspective 365
program in a variety of cells including fibroblasts (82–84). The efficiency of this process
is directly related to the lineage relationship with myoblasts and is highest in fibroblasts
(82–84). Transformation of cardiac fibroblasts in scar tissue of a myocardial infarction
into skeletal myocytes could add to myocardial contractility.
Murry et al. (83) reported successful in situ transduction with MyoD gene transfer
using a rat model of myocardial cryoinjury. One week after cryoinjury, they injected
adenovirus encoding the MyoD gene into myocardial granulation tissue. Rats were
treated with cyclosporine to suppress the adenoviral immune response. One week after
gene transfer, cells that expressed both myogenin and embryonic skeletal myosin
heavy chain were identified. In several hearts, they observed structures resembling
multinucleated myotubes.
Most recently, Lattanzi et al. (82) showed that an adenoviral vector expressing
MyoD can induce massive myogenic conversion of human and murine primary fibrob-
lasts in culture. Primary human fibroblasts were expanded in culture, converted to
myogenesis by adeno-delivered MyoD, and injected into regenerating muscles of
severe combined immunodeficiency/beige (scid/bg) recipient mice, where they formed
apparently normal fibers at an efficiency comparable to that of myogenic satellite cells.
The use of genetically modified autologous myogenic cells should avoid most of the
immunological problems associated with the allogeneic approach and also offer an
abundant resource for cell transplantation. If these promising results in a model of
muscular disease can be replicated in a model of myocardial infarction and heart fail-
ure, it may prove a feasible alternative for cell transplantation and ex vivo gene therapy.
Limitations and Problems. One of the most important difficulties in in vivo gene
therapy is the low transfection efficiency and immune reaction in target tissue (85,86).
Both efficiency and safety need to be improved with the development of better gene-
delivery methods and expression vectors. Genetic engineering has certain risks, such as
the introduction of genetic mutations. Major chromosomal abnormalities and other
somatic mutations could remain silent within the genome until after the time of trans-
plantation, possibly leading to abnormal cell growth and differentiation and to the
development of cancer. Further development in gene therapy vectors is needed to
improve safety, immunological tolerance, and expression of the transgene before this
strategy can be applied in the clinical practice.
Molecular Myoplasty
Heart failure is an attractive candidate for gene therapy, as several targets have been
identified as either functionally impaired or defective (87). Studies using animal
models and failing human hearts have identified several abnormalities that affect exci-
tation–contraction coupling (88,89). In particular, changes at the level of sarcolem-
mal/sarcoplasmic reticulum Ca
2+
transport and contractile proteins are thought to
contribute to depressed contractile function. Cardiomyocytes from failing animal and
human hearts reveal abnormal Ca
2+
homeostasis, such as reduced sarcoplasmic reticu-
lum (SR) Ca
2+
release, elevated diastolic Ca
2+
, and reduced rate of Ca
2+
removal (87).
There is strong evidence that reduced expression or activity of the SR Ca
2+
ATPase
(SERCA) and increased expression of Na
+
–Ca
2+
exchanger are key changes contribut-
ing to alterations in calcium homeostasis in the failing heart (87–89). Abnormalities in
calcium cycling may be responsible for attenuating the frequency potentiation of con-
tractile force in the failing human heart (87–89). SR Ca
2+
ATPase plays a dominant role
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