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PROFILE
FOCUS ON RNA
Dr Michela Denti of the Centre for Integrative Biology, Laboratory of RNA
Biology and Biotechnology, at the University of Trento, outlines the
centre’s work on genetic diseases and cancers
T
he Laboratory of RNA Biology and Biotechnology at the
Centre for Integrative Biology (CIBIO) of the University of
Trento, Italy, is focusing on RNA to develop better
diagnostic tools and therapeutics for a range of genetic diseases
and cancers. The research projects developed in the laboratory
also aim at unveiling new active roles for RNA molecules in the
mechanisms underlying these diseases.
specifically inactivate genes, either to discover their functions or
for therapeutic intervention.
RNA impacts nearly every aspect of gene expression and it is now
clear that a large portion of human genetic diseases are caused
by mistakes in RNA metabolism. It has become progressively
evident that RNA is not just a carrier of genetic information, but
also a catalyst and a guide for sequence specific recognition and
processing of other RNA molecules.
The Laboratory of RNA Biology and Biotechnology
Differently from DNA, RNA has a hydroxyl group attached on a
specific position of each of the sugars (riboses) that compose this
polymeric molecule. This difference, albeit small, makes RNA
much more flexible than DNA, resulting in a molecule that can
adopt many different structures, thus acquiring several diverse
functions. At the same time, RNA can in some cases ‘use’ these
hydroxyl groups to ‘attack’ and ‘cut’ chemical bonds, thus
functioning as an RNA enzyme (‘ribozyme’).
Finally, similarly to DNA, RNA can bind other RNA molecules
through base pairing rules, which dictate that only complementary
sequences will bind each other, making RNA binding very specific.
These three properties (flexibility, catalytic activity and specificity)
make RNA a fantastic tool in the hands of anybody who wants to
The growing body of knowledge concerning RNAs is opening up
exciting and unprecedented avenues for research: RNA molecules
are today, at the same time, targets of therapeutic intervention,
tools for functional studies and novel therapeutic molecules to
treat human diseases.
Led by Dr Michela Alessandra Denti, the research in the RNA
Biology and Biotechnology laboratory covers various diverse
areas, and researchers focus on two main research interests.
Firstly, the laboratory studies different ways of modulating ‘RNA
splicing’, a process that all messenger RNAs (mRNAs) undergo in
the cell. Several gene mutations, which cause different rare
inherited diseases, affect the splicing of specific mRNAs.
Researchers hope that by interfering with the splicing events, they
could restore the proper splicing of the mRNA, thereby recovering
the production of functional proteins. Based on this approach,
they are developing a possible cure for fronto-temporal dementia
(a neurodegenerative disease) and other genetic diseases.
A second line of research is aimed at studying some very small RNA
molecules called microRNAs (miRNAs) that have only recently been
discovered. Due to their size, these RNA molecules were overlooked
for a long time, but it has become clear in the last decade that
thousands of them are encoded in the genomes of all organisms,
and play a crucial role in cells, fine-tuning the production of
proteins. The deregulation of miRNAs has been implicated in several
diseases, and the laboratory is studying their possible role in
neurodegenerative and cardiac diseases and cancer.
Modulating RNA splicing as a cure for inherited
diseases
Researchers at the Laboratory of RNA Biology and Biotechnology
are amongst those who believe that gene therapy will soon allow
us to cure most genetic diseases. The recent successes in clinical
trials for several inherited diseases support their view. These
successes are the consequence of the work of the whole scientific
community in the course of more than 25 years, during which
scientists optimised safer and more efficient delivery vectors and
tested them in preclinical and clinical trials.
MicroRNAs can be used as diagnostic and prognostic biomarkers in
cancer, cardiac and neurodegenerative diseases
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Gene therapy relies on personal molecular diagnoses, and often
requires knowledge of the specific mutation present in the
patient’s genes. In this respect technological improvements such
as next generation sequencing (NGS) techniques, which have
increased our ability to read genomes and accumulate knowledge
on the molecular bases of diseases, have also contributed to pave
the way for gene therapy.
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PROFILE
Researchers of the Laboratory of RNA Biology and Biotechnology
Neurons of patients affected by FTDP-17 undergo progressive
degeneration (original artwork by Francesco Sega) (left) Tau protein
accumulates in neurons of patients affected by FTDP-17 (original
artistic picture by Michela A Denti) (right)
At variance with mainstream gene therapy approaches, which aim
at replacing the mutated gene with a functional DNA copy of the
gene itself, Denti and her co-workers intend to correct the mRNA
transcribed from the mutated gene, through an approach called
‘exon-skipping’. By introducing small RNA molecules, they mask
the mRNA to the attack of the splicing machinery, inducing it to
jump certain portions of the mRNA, thus restoring the correct
message. The team predicts that exon-skipping holds a great deal
of promise as a potential cure for genetic diseases, and several
clinical trials have supported the notion that the technique could
one day become commonplace.
The group is carrying out studies to develop a cure for a rare
neurodegenerative disease: FrontoTemporal Dementia with
Parkinsonism linked to chromosome 17 (FTDP-17). FTDP-17
patients have single nucleotide mutations in the gene for protein
tau, which induce the aberrant inclusion of an exon in tau mRNA,
and ultimately cause the accumulation of this protein in neurons
and consequently result in neuron’s degeneration. Very recently,
Denti and her colleagues have been successful inducing exonskipping and the correction of tau mRNA through the use small
RNA molecules in cells. They are now working to show the efficacy
of the approach in an animal model of the disease.
carcinomas (SCCs) and adenocarcinomas (ADCs). To do this, the
researchers measured the quantities of miR-205 and miR-21 in
cancer biopsies, and found that the results provided a useful marker
for differentiating between SCCs and ADCs – an identification which
is not always possible via traditional histochemical methods.
Recently, the researchers have discovered that measuring other
miRNAs could enable the differentiation between neuroendocrine
tumours both from the other two lung tumour types, and amongst
themselves. Denti and her research team are now working towards
a method of testing for miRNAs within blood samples, which could
lead to a more rapid and less invasive form of diagnosis.
The group is also focusing on the use of miRNAs as biomarkers of
response to therapy for prostate cancer. In the field of cardiac and
neurodegenerative diseases they attempt to use miRNAs as
biomarkers to allow a precise and early diagnosis. The group is
also working towards the identification of molecular mechanisms
in which miRNAs play a key role, thus representing optimal targets
for a therapeutic approach.
MicroRNAs as biomarkers of cancer, cardiac and
neurodegenerative diseases
The work being carried out in the Laboratory of RNA Biology and
Biotechnology is based on productive partnerships and networks
at local, national and international levels. In these collaborations
the laboratory provides its extensive knowledge of RNA, while
each other group brings its own, specific, complementary
expertise, often bridging across different disciplines.
Amongst the studies which the team in Trento is undertaking is an
investigation into the potential for specific miRNA, to be used as a
tool in the early and accurate diagnosis of cancers, cardiac
diseases and neurodegenerative diseases. It is well established
that the quantities of some miRNAs can become altered in
diseases, and this has opened up the possibility of miRNA
dysregulation being used as a diagnostic and prognostic tool. The
advantage of using miRNAs as biomarkers lies in the ease with
which they can be detected, and in their extreme specificity.
Dr Michela Denti
Head of Laboratory
Laboratory of RNA Biology and Biotechnology
Centre for Integrative Biology
University of Trento
In one project, the group focused on lung cancer, the leading cause
of cancer mortality worldwide. As it is now possible to design
therapies targeted towards specific forms of cancer, Denti and her
colleagues were required to distinguish between squamous cell
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