Real-time MR tracking of AAV gene therapy with betagal-responsive MR probe in a murine model of GM1-gangliosidosis
Taghian, Toloo ; Batista, Ana Rita ; Rodriguez, Paola ; Mesa, Katerina ; Zheng, Shaokuan ; King, Robert M. ; Gounis, Matthew J ; Todeasa, Sophia H. ; Sena-Esteves, Miguel ; Meade, Thomas J. ... show 1 more
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GM1 gangliosidosis
MR tracking of enzyme expression
enzyme-activated contrast agent probes
magnetic resonance imaging
Amino Acids, Peptides, and Proteins
Analytical, Diagnostic and Therapeutic Techniques and Equipment
Congenital, Hereditary, and Neonatal Diseases and Abnormalities
Enzymes and Coenzymes
Genetics and Genomics
Radiology
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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 United States to treat these diseases. 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 magnetic resonance imaging (MRI) 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 trial AAV gene therapy (ClinicalTrials.gov: NTC03952637) encoding lysosomal acid beta-galactosidase (betagal) using a self-immolative betagal-responsive MRI probe. MRI enhancement in AAV-treated enzyme-deficient mice (GLB-1(-/-)) correlates with betagal activity in central nervous system and peripheral organs after intracranial or intravenous AAV gene therapy, respectively. With > 1,800 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 the gene-therapy field.
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Taghian T, Batista AR, Kamper S, Caldwell M, Lilley L, Li H, Rodriguez P, Mesa K, Zheng S, King RM, Gounis MJ, Todeasa S, Maguire A, Martin DR, Sena-Esteves M, Meade TJ, Gray-Edwards HL. Real-time MR tracking of AAV gene therapy with βgal-responsive MR probe in a murine model of GM1-gangliosidosis. Mol Ther Methods Clin Dev. 2021 Aug 26;23:128-134. doi: 10.1016/j.omtm.2021.08.003. PMID: 34703836; PMCID: PMC8517204. Link to article on publisher's site
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Full author list omitted for brevity. For the full list of authors, see article.