7T MRI Predicts Amelioration of Neurodegeneration in the Brain after AAV Gene Therapy
Autor: | Ronald J. Beyers, Ana Rita Batista, Heather L. Gray-Edwards, Miguel Sena-Esteves, Thomas S. Denney, Ashley N. Randle, Lauren E. Ellis, Jey W. Koehler, Nouha Salibi, Anne S Maguire, Taylor L. Voss, Amanda L. Gross, Elise B. Diffie, Amanda R. Taylor, Atoska S. Gentry, Douglas R. Martin, Brandon L. Brunson |
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Jazyk: | angličtina |
Rok vydání: | 2020 |
Předmět: |
0301 basic medicine
Cerebellum Pathology medicine.medical_specialty spectroscopy lcsh:QH426-470 Thalamus GM1 adeno-associated virus Gangliosidosis medicine.disease_cause Deep cerebellar nuclei Article 03 medical and health sciences 0302 clinical medicine Genetics Lysosomal storage disease Medicine lcsh:QH573-671 Molecular Biology Adeno-associated virus business.industry lcsh:Cytology Neurodegeneration biomarkers AAV medicine.disease gangliosidosis gene therapy 3. Good health Astrogliosis lcsh:Genetics 030104 developmental biology medicine.anatomical_structure lysosomal storage disease 030220 oncology & carcinogenesis Molecular Medicine business MRI |
Zdroj: | Molecular Therapy: Methods & Clinical Development, Vol 17, Iss, Pp 258-270 (2020) Molecular Therapy. Methods & Clinical Development |
ISSN: | 2329-0501 |
Popis: | 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. |
Databáze: | OpenAIRE |
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