7T MRI Predicts Amelioration of Neurodegeneration in the Brain after AAV Gene Therapy

Heather L Gray-Edwards; Anne S Maguire; Nouha Salibi; Lauren E Ellis; Taylor L Voss; Elise B Diffie; Jey Koehler; Ashley N Randle; Amanda R Taylor; Brandon L Brunson; Thomas S Denney; Ronald J Beyers; Atoska S Gentry; Amanda L Gross; Ana R Batista; Miguel Sena-Esteves; Douglas R Martin

doi:10.1016/j.omtm.2019.11.023

7T MRI Predicts Amelioration of Neurodegeneration in the Brain after AAV Gene Therapy

Mol Ther Methods Clin Dev. 2019 Dec 24:17:258-270. doi: 10.1016/j.omtm.2019.11.023. eCollection 2020 Jun 12.

Authors

Heather L Gray-Edwards¹, Anne S Maguire^{1

2}, Nouha Salibi³, Lauren E Ellis¹, Taylor L Voss², Elise B Diffie^{1

2}, Jey Koehler⁴, Ashley N Randle¹, Amanda R Taylor⁵, Brandon L Brunson², Thomas S Denney^{6

7}, Ronald J Beyers⁶, Atoska S Gentry¹, Amanda L Gross^{1

2}, Ana R Batista⁸, Miguel Sena-Esteves⁸, Douglas R Martin^{1

2}

Affiliations

¹ Scott-Ritchey Research Center, College of Veterinary Medicine, Auburn University, Auburn, AL, USA.
² Department of Anatomy, Physiology and Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, AL, USA.
³ MR R&D Department, Siemens Healthcare, Malvern, PA, USA.
⁴ Department of Pathobiology, College of Veterinary Medicine, Auburn University, Auburn, AL, USA.
⁵ Department of Clinical Sciences, College of Veterinary Medicine, Auburn University, Auburn, AL, USA.
⁶ MRI Research Center, Auburn University, Auburn, AL, USA.
⁷ Department of Electrical Engineering, Auburn University, Auburn, AL, USA.
⁸ Department of Neurology, University of Massachusetts Medical School, Worcester, MA, USA.

Abstract

GM1 gangliosidosis (GM1) is a fatal neurodegenerative lysosomal storage disease that occurs most commonly in young children, with no effective treatment available. Long-term follow-up of GM1 cats treated by bilateral thalamic and deep cerebellar nuclei (DCN) injection of adeno-associated virus (AAV)-mediated gene therapy has increased lifespan to 8 years of age, compared with an untreated lifespan of ~8 months. Due to risks associated with cerebellar injection in humans, the lateral ventricle was tested as a replacement route to deliver an AAVrh8 vector expressing feline β-galactosidase (β-gal), the defective enzyme in GM1. Treatment via the thalamus and lateral ventricle corrected storage, myelination, astrogliosis, and neuronal morphology in areas where β-gal was effectively delivered. Oligodendrocyte number increased, but only in areas where myelination was corrected. Reduced AAV and β-gal distribution were noted in the cerebellum with subsequent increases in storage, demyelination, astrogliosis, and neuronal degeneration. These postmortem findings were correlated with endpoint MRI and magnetic resonance spectroscopy (MRS). Compared with the moderate dose with which most cats were treated, a higher AAV dose produced superior survival, currently 6.5 years. Thus, MRI and MRS can predict therapeutic efficacy of AAV gene therapy and non-invasively monitor cellular events within the GM1 brain.

Keywords: AAV; GM1; MRI; adeno-associated virus; biomarkers; gangliosidosis; gene therapy; lysosomal storage disease; spectroscopy.

Abstract

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