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A research platform for miRNA-based treatment of multiple myeloma and chronic lymphoctic leukemia

MicroRNAs  (miRNAs)  are  a  class  of  small  non-coding  RNAs  which  regulate  gene
expression at the post-transcriptional level. miRNAs play a role in tumorigenesis acting as
oncogenes  or  tumor  suppressor  genes.  Aberrant  miRNA  expression  is  associated  to
prognosis  and  therapeutical  response.  Deregulation  of  miRNA  expression  is  involved  in
the  pathogenesis  of  chronic  lymphocytic  leukemia  (CLL)  and  multiple  myeloma  (MM)
where  miRNAs  are  important  therapeutic  targets.  Two  approaches  can  be  theoretically
used to achieve a therapeutic effect by targeting the miRNA regulatory network: i) enforce
the  activity  of  anti-tumor  miRNAs  (miRNAs  as  drug),  ii)  inhibit  the  activity  of  pro-tumor
miRNAs (miRNAs as target) by means of antagomirs.  
The aim of our project is to exploit miRNAs as drugs or targets in innovative therapeutic
strategies for CLL and MM using novel in vitro and in vivo preclinical models and delivery
nanotechnologies.  We  propose  an  experimental  platform  which  includes  all  steps  from
target identification to FIRST in HUMAN studies. In Task 1, miRNAs, whose expression is
consistently deregulated in CLL and MM, as well as in non-tumor cells of the tumor bone
marrow microenvironment (BMM), will be defined  by molecular profiling of clinical samples
from  the  framework  of  nationwide  clinical  trials.  In  Task  2,  we  will  evaluate  the  effects
induced  by  targeting  deregulated  miRNAs  on  cell  survival/proliferation  and  on  selected
pathways  using  molecular  profiling  technologies.    Task  3  will  be  devoted  to  the  design,
preparation,   characterization   and   evaluation   of   liposomes,   supramolecular   lipidic
aggregates  (SLAs)  and  colloidal  polymeric  carriers  for  in  vivo  delivery  of  engineered
miRNAs or antagomirs. Specifically, we will attempt to functionalize nanocarrier surfaces
by humanized mAbs against anti-CLL and -MM-associated antigens. Reagents produced
in this Task will be tested in murine models of CLL and MM (Task 4). The investigation will
take benefit of the E-µu-TCL1 transgenic mouse model of human CLL and of a NOD/SCID
mouse model for in vivo expansion of CLL cells. Moreover, we will use the SCID-hu model
of human MM and an innovative in vivo system (SCID-synth-hu) based on a 3-D bone-like
poly-ε-caprolactone  biopolymeric  scaffold  coated  in  the  3-D  space  with  BMSCs,  which
allow  the  growth  of  primary  MM  cells  in  human  fetal  or  adult  autologous  BMM,
respectively.  Task  5  will  afford  the  clinical  grade  production  of  selected  bioreagents  for
preclinical   pharmacokinetics   and   toxicology   in   animals   in   order   to   achieve   an
investigational  new  drug  status.  These  miRNAs/antagomirs  carrying  nanovectors  will
finally proceed to early clinical trials (Phase 0-I) for FIRST in HUMAN evaluation (Task 6).
The  possibility  of  in  vivo  monitoring  of  effective  nanovector  delivery   with  unique
sophisticated preclinical models as well as the chance of real-time monitoring of patients
undergoing  early  clinical  trials  will  provide  an  array  of  opportunities  for  re-designing  the
molecular  reagents  and  improve  delivery  strategies.  The  design  of  this  project  as  a
platform will provide the best information exchange among investigators and will allow re-
direction of the experimental flow on the basis of available information in order to achieve
the final goal of new treatments for CLL and/or MM by a timely translational network. 

Principal Investigators:
  • ANTONINO NERI loading
Financing institution:
ASS_NAZ - Bandi da Associazioni e altri Finanziatori privati nazionali
Project leader:
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