Real-time MR tracking of AAV gene therapy with βgal-responsive MR probe in a murine model of GM1-gangliosidosis

Toloo Taghian; Ana Rita Batista; Sarah Kamper; Michael Caldwell; Laura Lilley; Hao Li; Paola Rodriguez; Katerina Mesa; Shaokuan Zheng; Robert M King; Matthew J Gounis; Sophia Todeasa; Anne Maguire; Douglas R Martin; Miguel Sena-Esteves; Thomas J Meade; Heather L Gray-Edwards

doi:10.1016/j.omtm.2021.08.003

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. eCollection 2021 Dec 10.

Authors

Toloo Taghian^{1

2}, Ana Rita Batista^{1

3}, Sarah Kamper⁴, Michael Caldwell⁴, Laura Lilley⁴, Hao Li⁴, Paola Rodriguez^{1

3}, Katerina Mesa^{1

3}, Shaokuan Zheng², Robert M King^{2

5}, Matthew J Gounis², Sophia Todeasa^{1

3}, Anne Maguire⁶, Douglas R Martin⁶, Miguel Sena-Esteves^{1

3}, Thomas J Meade⁴, Heather L Gray-Edwards^{1

2}

Affiliations

¹ Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, MA 01605, USA.
² Department of Radiology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
³ Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
⁴ Departments of Chemistry, Molecular Biosciences, Neurobiology and Radiology, Northwestern University, Evanston, IL 60208, USA.
⁵ Department of Biomedical Engineering, Worcester Polytechnic Institute, Worcester, MA 01609, USA.
⁶ Scott-Ritchey Research Center, Auburn University, Auburn, AL 36849, USA.

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 (βgal) using a self-immolative βgal-responsive MRI probe. MRI enhancement in AAV-treated enzyme-deficient mice (GLB-1^-/-) correlates with βgal 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.

Keywords: AAV gene therapy; GM1 gangliosidosis; MR tracking of enzyme expression; enzyme-activated contrast agent probes; magnetic resonance imaging.

Grants and funding

T32 GM105538/GM/NIGMS NIH HHS/United States