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

Molecular Therapy: Methods & Clinical Development (Dec 2021)

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

Affiliations

Toloo Taghian: Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, MA 01605, USA; Department of Radiology, University of Massachusetts Medical School, Worcester, MA 01655, USA
Ana Rita Batista: Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, MA 01605, USA; Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01605, USA
Sarah Kamper: Departments of Chemistry, Molecular Biosciences, Neurobiology and Radiology, Northwestern University, Evanston, IL 60208, USA
Michael Caldwell: Departments of Chemistry, Molecular Biosciences, Neurobiology and Radiology, Northwestern University, Evanston, IL 60208, USA
Laura Lilley: Departments of Chemistry, Molecular Biosciences, Neurobiology and Radiology, Northwestern University, Evanston, IL 60208, USA
Hao Li: Departments of Chemistry, Molecular Biosciences, Neurobiology and Radiology, Northwestern University, Evanston, IL 60208, USA
Paola Rodriguez: Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, MA 01605, USA; Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01605, USA
Katerina Mesa: Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, MA 01605, USA; Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01605, USA
Shaokuan Zheng: Department of Radiology, University of Massachusetts Medical School, Worcester, MA 01655, USA
Robert M. King: Department of Radiology, University of Massachusetts Medical School, Worcester, MA 01655, USA; Department of Biomedical Engineering, Worcester Polytechnic Institute, Worcester, MA 01609, USA
Matthew J. Gounis: Department of Radiology, University of Massachusetts Medical School, Worcester, MA 01655, USA
Sophia Todeasa: Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, MA 01605, USA; Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01605, USA
Anne Maguire: Scott-Ritchey Research Center, Auburn University, Auburn, AL 36849, USA
Douglas R. Martin: Scott-Ritchey Research Center, Auburn University, Auburn, AL 36849, USA
Miguel Sena-Esteves: Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, MA 01605, USA; Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01605, USA
Thomas J. Meade: Departments of Chemistry, Molecular Biosciences, Neurobiology and Radiology, Northwestern University, Evanston, IL 60208, USA; Corresponding author: Thomas J. Meade, Departments of Chemistry, Molecular Biosciences, Neurobiology and Radiology, Northwestern University, Evanston, IL 60208, USA.
Heather L. Gray-Edwards: Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, MA 01605, USA; Department of Radiology, University of Massachusetts Medical School, Worcester, MA 01655, USA; Corresponding author: Heather L. Gray-Edwards, Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, MA 01605, USA.

Journal volume & issue: Vol. 23
pp. 128 – 134

Abstract

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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.

Published in Molecular Therapy: Methods & Clinical Development

ISSN: 2329-0501 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Science: Biology (General): Genetics; Science: Biology (General): Cytology
Website: http://www.cell.com/molecular-therapy-family/methods/latest-content

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