Real-Time Tracking of Gene Therapy by Bioactivated MR contrast Probes - Abstract: Real-Time Tracking of Gene Therapy by Bioactivated MR contrast Probes
With mean survival rate of 5 years (and most cases are fatal) lysomal storage diseases (LSD) are among
the most dismal of prognosis in all of medicine. LSD's represent a large number of monogenetic diseases and
while rare the prevalence is to hemophilia. As monogenetic diseases with clearly defined genotype-phenotype
relations, lysosomal storage diseases are excellent candidates for gene therapy. The transformative results
documented in an adeno-associated virus (AAV) gene therapy clinical trial in infants affected by spinal
muscular atrophy demonstrated unequivocally the potential of in vivo gene transfer to treat monogenic
neurological disorder.
However, to date, there is a lack of non-invasive ways to determine biodistribution or activity levels of these
AAV therapies in patients. This is a significant hinderance, leaving investigators guessing which organs or
structures are effectively treated and, due to the lag time associated with clinical disease progression, this
limitation ultimately impacts the evolution of treatment modalities.
In order to overcome these limitations, we propose the development of a new magnetic resonance imaging
(MRI)-based technology to track enzymatic activity in any organ, peripheral nervous system (PNS), or central
nervous system (CNS) over time and thus have the potential to be applicable to any LSD caused by an
enzymatic deficiency. Magnetic resonance imaging is an ideal technique for the study of neurological
disorders. This technique is has become a gold standard in diagnostic radiology as a result of the absence of
ionizing radiation and is capable of true 3D imaging and has been in use for several decades . Detailed
structural information can be obtained in minutes, and single slices in seconds. However, the need to
differentiate regions of tissues or organs that are magnetically similar but histologically distinct has been a
major impetus for the development of contrast enhancement agents. Greater than 40% of all MR procedures
employ contrast agents with more than 450,000 million doses to date have been administered to patients and
Gd(III) based contrast agents are among the safest clinical probes in use.
We pioneered the development of bio-responsive (i.e., conditionally activated) MR contrast agents and
since that time a library of this class of probes has expanded from enzyme activated agents to pH sensitive,
the detection of ions such as Zn(II) and Ca(II), and redox activated. Here, we describe the development of a
platform where the substrate (that prevents access of water to a Gd(III) ion) is removed by an enzyme which
can be substituted to accommodate a number of gene therapy targets.
