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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.
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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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DOI
10.1016/j.omtm.2021.08.003
PubMed ID
34703836
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Full author list omitted for brevity. For the full list of authors, see article.

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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/).