Gene Therapy for Cardiovascular Disorders - Applications of Biotechnology in Cardiovascular Therapeutics - page 253

miRNA may target hundreds of genes and this “one hit-multiple targets” strategy
might be double-edged and responsible for off-target effects. To overcome this pos-
sible drawback, suggestions have been made to make miRNA actions gene-specific,
for example, miR-1/miR-133 act specifically on HCN2/HCN4 (Xiao et al. 2007 ).
Both positive and negative cardiac actions can be attached to a same miRNA (e.g.,
antihypertrophic and pro-arrhythmogenic effects respectively for miR-1) because
of their many downstream targets.
Finally, the identification of the predicted binding sites (in mRNAs) of disease-
specific miRNAs, using computer algorithms, may point out previously unrecog-
nized protein targets within a disease pathway of interest. On the whole, miRNAs
and miRNA target predictions are likely to represent promising fields for new drug
discovery.
Future Prospects of miRNA in the Cardiovascular Therapeutics
Through the regulation of the expression of genes involved in cell growth, con-
tractility, and electrical conductance, cardiac miRNAs may play a major role in
heart development and function. In vascular cells, miRNAs have been linked to
vasculoproliferative conditions such as angiogenesis and neointimal lesion forma-
tion. Diagnostic use and therapeutic modulation of individual miRNAs or miRNA
clusters in cardiovascular diseases need to be further explored in the future.
Molecules specifically regulating cardiovascular miRNAs, either mimicking or
antagonizing miRNAs actions, will hopefully normalize dysfunctional gene
networks and constitute a new therapy paradigm of cardiovascular diseases
(Scalbert and Bril 2008 ).
Treatments focusing on miRNAs could involve delivery of antisense oligonucle-
otides to block existing miRNA function. The disadvantages of this approach
include the difficulty in delivering enough antisense oligonucleotide or miRNA to
achieve the desired therapeutic effect and potential side effects of nontargeted
delivery of such pharmaceuticals. An alternative approach is to deliver gene therapy
vectors expressing miRNAs to cardiomyocytes (Gray and Samulski 2008 ). This
approach would enable external drug-mediated regulation of expression, and more
than one miRNA or antagonist could be expressed from a single vector. Moreover,
gene therapy vector delivery would require only one administration. The disadvan-
tage of this approach is the use of a gene delivery vector with potential adverse
effects and regulatory restrictions.
Future Prospects of Gene Therapy of Cardiovascular Disorders
Gene therapy for cardiovascular diseases is still in its infancy but it will continue to
grow. Identification of new therapeutic targets and the availability of vectors with
enhanced myocardial tropism offer the opportunity for the design of gene therapies