Multi-functional magnetic nanorods for constructing theranostic extracellular vesicles for treating myocardial infarction - PROJECT SUMMARY
Cardiovascular disease (CVD) remains the leading cause of death and a global public health burden.
Myocardial injury with infarction (MI) is a common CVD that is associated with heart failure and even death. Cell-,
especially stem cell (SC)-based therapies has been of great interest for treating heart diseases, because 1) the
adult heart has a limited number of SCs and thus limited capacity of self-repair and regeneration, and 2) current
treatment strategies are only able to limit the ensuing adverse dilatation and impaired contractile function.
However, clinical translation of SC-based therapies remains cumbersome with very few successes, in a large
part due to the safety and ethical concerns over uncontrollable differentiation of injected cells in patients. As
mounting evidence reveals the SC-induced repairing functions predominately derived from the paracrine effect
mediated by extracellular vesicles (EVs), therapies based on SC-derived EVs (SC-EVs) have emerged as a
highly promising approach for cell-free regenerative medicine that delivers high potency but less side-effect
associated with conventional cell-based therapy. A major limiting factor to the efficacy of EV-based treatment is
the effectiveness of EV delivery to target tissues. Indeed, most animal studies employed direct cardiac injection
in order to achieve significant treatment effects, although systemic administration is much preferred in the clinic.
Moreover, clinical translation of new EV therapies requires non-invasive imaging for monitoring and quantification
of EV delivery and treatment responses inpatients, which have not been fully developed yet. The overall goal of
this STTR Phase I project takes an important first step to translate an MRI-guided, theranostic (therapeutics +
diagnostics) EV platform developed in the research lab for effectively treating injured myocardium in acute MI.
This collaborative project, between 5M Biomed and Kennedy Krieger Institute (KKI)/Johns Hopkins University
(JHU), is built on our innovations in magnetic labeling and purification of therapeutic human SC-EVs, MRI-based
EV tracking, and ultra-magnetic iron oxide nanorods (IONRs). We will focus on developing and validating a
translatable theranostic EV system, using multifunctional ultra-magnetic IONRs that are suitable for efficient
magnetic purification/enrichment, magnetic targeting, and non-invasive MRI of EVs. We will collaborate closely
to 1) develop and optimize ultra-magnetic IONRs for efficient preparation of MagEV with high MRI contrast effect,
and 2) test and validate the delivery and efficacy of MagEV labeled with IONRs in imaging and treating MI. The
benchmark of success is to achieve an optimal formulation of MagEV, i.e., minimal interference of IONRs on
MagEV functionalities and therapeutic potential together with high MRI capability and magnetism. The success
of Phase I study will lead to the Phase II project, which will focus on scale-up manufacturing of MagEVs towards
investigational new drug (IND) application and large-animal testing which will guide subsequent first-in-human
studies.
