Real-Time MR Tracking of AAV Gene Therapy with βgal-responsive MR probe in a Murine Model of GM1-Gangliosidosis

2021
Abstract Transformative results of adeno-associated virus (AAV) gene therapy in patients with spinal muscular atrophy and Leber’s congenital amaurosis led to approval of the first two AAV products in the US to treat these diseases1, 2 . These extraordinary results led to a dramatic increase in the number and type of AAV gene therapy programs. However, the field lacks non-invasive means to assess levels and duration of therapeutic protein function in patients. Here, we describe a new MR imaging technology for real-time reporting of gene therapy products in the living animal in the form of an MRI probe that is activated in the presence of therapeutic protein expression. For the first-time, we show reliable tracking of enzyme expression after a now in human clinical trials AAV gene therapy (NTC03952637) encoding lysosomal acid beta-galactosidase (βgal) using a self-immolative βgal-responsive MR imaging probe. MRI enhancement in AAV treated enzyme deficient mice (GLB1-/-) correlates with βgal activity in central nervous system and peripheral organs after intracranial or intravenous AAV gene therapy, respectively. With >1800 gene therapies in phase I/II clinical trials (clinicaltrials.gov), development of a non-invasive method to track gene expression over time in patients is crucial to the future of gene therapy field.
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