Horae Gene Therapy Center; Department of Radiology; Department of Neurology
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
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.
AAV gene therapy, GM1 gangliosidosis, MR tracking of enzyme expression, enzyme-activated contrast agent probes, magnetic resonance imaging
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Copyright 2021 This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
DOI of Published Version
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
Molecular therapy. Methods and clinical development
Taghian T, Batista AR, Rodriguez P, Mesa K, Zheng S, King RM, Gounis MJ, Todeasa SH, Sena-Esteves M, Meade TJ, Gray-Edwards HL. (2021). Real-time MR tracking of AAV gene therapy with betagal-responsive MR probe in a murine model of GM1-gangliosidosis. Radiology Publications. https://doi.org/10.1016/j.omtm.2021.08.003. Retrieved from https://escholarship.umassmed.edu/radiology_pubs/662
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This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.
Amino Acids, Peptides, and Proteins Commons, Analytical, Diagnostic and Therapeutic Techniques and Equipment Commons, Congenital, Hereditary, and Neonatal Diseases and Abnormalities Commons, Enzymes and Coenzymes Commons, Genetics and Genomics Commons, Radiology Commons