Real-Time Tracking of Gene Therapy via MR Imaging

Speaker:

Thomas J. Meade, professor of chemistry, Northwestern University

Description:

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.

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 hindrance, 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 are developing of a new class of bioresponsive magnetic resonance imaging probes to track enzymatic activity in any organ, peripheral nervous system (PNS), or central nervous system (CNS) over time. 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

We pioneered the development of bio-responsive MR contrast agents and since then the library of this class of probes has expanded from enzyme activated agents, 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 a substrate (blocking access of water to a Gd(III) ion) is removed by an enzyme that can be changed to accommodate a number of gene therapy targets.