Gains In Neuronal Tracks In Gm1 Patients Following Intravenous Gene Therapy: Dt As A Robust Outcome Metric

Introduction GM1 gangliosidosis, a lysosomal storage disorder caused by biallelic mutations in GLB1, results in progressive neurodegeneration, is uniformly fatal, and has no approved therapies. We compared GM1 patients treated with AAV9-GLB1 intravenous gene therapy (GT) (N=6) with age-matched normal controls (NC)(N=18) and untreated GM1 Type II patients (UT)(N=5). Differential tractography (DT) compared neuronal fiber tracts in participants over time.

Methods DT was performed using DSI Studio (Figure 1). Whole brain fiber tractography gains and losses were calculated using a 20% fractional anisotropy threshold and compared using Welch’s two sample t-tests. Follow-up interval was 2.5±0.7 years for GT, 1.2±0.4 years for the UT, and 2.5 ± 0.7 for NC.

Results There were no statistically significant differences in age between the three populations. GT patients showed more gained fibers than both the UT (t=5.6457, p=0.002259, Figure 2) and NC (t=3.8941, p=0.007614). Gained fiber volume was also greater in GT patients than the UT (t=6.6923, p=0.00109, Figure 3) and NC (t=5.3654, p=0.002088). However, UT patients showed more fiber loss than the GT (t=3.2387, p=0.0211) and NC (t=4.1534, p=0.01415) and a greater decrease in fiber volume than NC (t=4.398, p=0.0115).

Conclusion GT patients showed significant increases in volume and number of neural fibers by DT compared to NC and UT patients. We conclude that DT may be a sensitive biomarker for patient outcomes in therapeutic trials for GM1 and possibly other neurodegenerative