Clinical outcomes following gene therapy in GM1 gangliosidosis correlate with structural and diffusion magnetic resonance imaging derived markers

Authors

• CJ Lewis
• Z Vardar
• AL Kühn
• JM Johnston
• P D’Souza
• WA Gahl
• MS Shazeeb
• CJ Tifft
• MT Acosta

Abstract

GM1 gangliosidosis, a lysosomal storage disorder caused by biallelic mutations in GLB1 resulting in toxic accumulation of GM1 gangliosides primarily in the central nervous system. GM1 is uniformly fatal and has no approved therapies. We compared GM1 Type II patients treated with an AAV9GLB1 intravenous gene therapy vector (n=10, NCT03952637) with untreated GM1 Type II patients from our natural history study (n=16, NCT00029965) and age matched normal controls (n=30). We used anatomical magnetic resonance imaging (MRI), diffusion tensor imaging (DTI), and differential tractography to assess longitudinal changes associated with gene therapy. We compared these results with clinical markers including the cognitive global impression (CGI) scales and Vineland Adaptive Behavioral Scale.

In our preliminary analysis of differential tractography we found gene therapy treated patients showed significant fiber tract count and volume gains compared to untreated patients and normal controls. Untreated patients showed more losses in fiber tract count than treated patients and normal controls and more fiber tract volume loss compared to normal controls. We also found the rate of ventricle volume growth was slowed in treated patients compared to untreated patients. Differential tractography metrics including net fiber tract count and volume alongside changes in ventricle volume correlated with clinical outcomes.

This is the first study demonstrating the utility of differential tractography in evaluating longitudinal changes from therapeutic application. We found group wide effects resulting from gene therapy treatment as assessed by differential tractography and anatomical MRI. We also found changes in differential tractography, and structural MRI correlated with clinical outcomes.

Scientific Focus Area: Clinical Research

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