UMMS Affiliation

Horae Gene Therapy Center; Department of Radiology; Department of Neurology

Publication Date

2021-08-26

Document Type

Article

Disciplines

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

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.

Keywords

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

Rights and Permissions

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

10.1016/j.omtm.2021.08.003

Source

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

Journal/Book/Conference Title

Molecular therapy. Methods and clinical development

Comments

Full author list omitted for brevity. For the full list of authors, see article.

Related Resources

Link to Article in PubMed

PubMed ID

34703836

Creative Commons License

Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.

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