Biology Reference
In-Depth Information
3.3.7
Potential for Oncogenic Transformation
Any strategy that seeks to modulate cells in order to increase their proliferation and
survival should carefully investigate the risk of oncogenic potential before implanta-
tion into patients. In fact, the microRNAs employed in the cardiac progenitor study
mentioned [
4
] have all previously been found to be overexpressed in tumours and be
involved in tumourigenesis. Furthermore, the earlier study [
73
], in which stem cells
were transduced with telomerase, has demonstrated that such manipulations can
lead to cells with oncogenic potential. However, the same study also demonstrated
that it is possible to generate cells with enhanced proliferative capacity without
apparent oncogenicity. There is probably a fine balance between promoting greater
cell numbers while preventing uncontrolled expansion and transformation. In the
telomerase overexpression study [
73
], it was concluded that conditional or tempo-
rary expression of telomerase would be a safe approach to increase cell prolifera-
tion. Since miRNAs levels are typically modulated in a transient manner, they would
be ideal for this purpose.
3.4
MicroRNA Delivery
Delivery has traditionally been the bottleneck for RNAi-based drugs [
75
] . Apart
from special cases, such as the employment of hydrodynamic pressure [
76
] or using
very small anti-miRNA [
77
], naked RNA cannot be successfully delivered.
MicroRNAs and anti-miRNA are large anionic molecules that do not readily cross
biological membranes such as the cell membrane; therefore, delivery vectors are
needed to enable the miRNA modulators to reach the cellular and subcellular target
sites. Many different vectors have been utilised in regenerative medicine for the
delivery of other nucleic acid species such as plasmids and siRNA [
6
] . Successful
RNA transfection is often a complex compromise between silencing efficiency,
duration and toxicity. There are several delivery routes for miRNA modulation; one
can inject the miRNA with a carrier either systemically or locally, or it can be trans-
planted together with cells and/or implant materials. Delivery in conjunction with
implantable materials such as scaffolds for the durations and timed phases needed
in tissue regeneration complicates the story further, but also opens up new possibili-
ties. Most tissues and organs are composed of different cell types organised in
specific spatial locations, and each of the differentiation pathways leading to these
cells relies on the expression of different miRNAs at different time points [
29
] .
Hence, to mimic natural tissue formation, there is a need for scaffolds that can
release different miRNAs at different locations at controlled time points.
Tissue destruction can be prevented and regeneration promoted by i.v. injection
of the miRNA vector systemically or directly into the damaged site. One study used
tail-vein injections of atelocollagen/miR-146a complexes which circulated systemi-
cally and prevented joint destruction in collagen-induced arthritis [
3
] . However,
many microRNAs play different roles in different tissues, and a systemic delivery
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