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

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^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

12 Scopus citations

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.

Original language	English (US)
Pages (from-to)	128-134
Number of pages	7
Journal	Molecular Therapy Methods and Clinical Development
Volume	23
DOIs	https://doi.org/10.1016/j.omtm.2021.08.003
State	Published - Dec 10 2021

Funding

Graphical abstract was created with BioRender.com . The authors acknowledge the University of Massachusetts Medical School , Northwestern University , and National Institutes of Health grant ( 10R01EB005866-08 ) for providing research funding. S.K. was supported by a pre-doctoral fellowship from the Molecular Biophysics Training Grant at Northwestern ( T32 GM008382 ) and an NSF Graduate Research Fellowship .

Keywords

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

ASJC Scopus subject areas

Molecular Medicine
Molecular Biology
Genetics

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.omtm.2021.08.003

Cite this

Taghian, T., Batista, A. R., Kamper, S., Caldwell, M., Lilley, L., Li, H., Rodriguez, P., Mesa, K., Zheng, S., King, R. M., Gounis, M. J., Todeasa, S., Maguire, A., Martin, D. R., Sena-Esteves, M., Meade, T. J., & Gray-Edwards, H. L. (2021). Real-time MR tracking of AAV gene therapy with βgal-responsive MR probe in a murine model of GM1-gangliosidosis. Molecular Therapy Methods and Clinical Development, 23, 128-134. https://doi.org/10.1016/j.omtm.2021.08.003

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

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",

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

note = "Publisher Copyright: {\textcopyright} 2021 The Authors",

year = "2021",

month = dec,

day = "10",

doi = "10.1016/j.omtm.2021.08.003",

language = "English (US)",

volume = "23",

pages = "128--134",

journal = "Molecular Therapy Methods and Clinical Development",

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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 2021, 'Real-time MR tracking of AAV gene therapy with βgal-responsive MR probe in a murine model of GM1-gangliosidosis', Molecular Therapy Methods and Clinical Development, vol. 23, pp. 128-134. https://doi.org/10.1016/j.omtm.2021.08.003

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T1 - Real-time MR tracking of AAV gene therapy with βgal-responsive MR probe in a murine model of GM1-gangliosidosis

AU - Taghian, Toloo

AU - Batista, Ana Rita

AU - Kamper, Sarah

AU - Caldwell, Michael

AU - Lilley, Laura

AU - Li, Hao

AU - Rodriguez, Paola

AU - Mesa, Katerina

AU - Zheng, Shaokuan

AU - King, Robert M.

AU - Gounis, Matthew J.

AU - Todeasa, Sophia

AU - Maguire, Anne

AU - Martin, Douglas R.

AU - Sena-Esteves, Miguel

AU - Meade, Thomas J.

AU - Gray-Edwards, Heather L.

PY - 2021/12/10

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N2 - 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.

AB - 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.

KW - AAV gene therapy

KW - GM1 gangliosidosis

KW - MR tracking of enzyme expression

KW - enzyme-activated contrast agent probes

KW - magnetic resonance imaging

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ER -

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

Abstract

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ASJC Scopus subject areas

UN SDGs

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