Research ArticleGene Therapy

Gene therapy reduces Parkinson’s disease symptoms by reorganizing functional brain connectivity

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Science Translational Medicine  28 Nov 2018:
Vol. 10, Issue 469, eaau0713
DOI: 10.1126/scitranslmed.aau0713
  • Fig. 1 AAV2-GAD–treated subjects exhibit a treatment-related metabolic brain network.

    (A) GAD-related pattern (GADRP) is characterized by increases (red) and decreases (blue) in metabolic activity (see text for specific regions). Voxel weights on network regions were reliable on bootstrap estimation [ICV = (−3.19, 3.05), P < 0.003; 1000 iterations]. (B) Baseline-corrected GADRP expression values for trial participants receiving gene therapy (red line) or sham surgery (blue line) over time (****P < 0.0001, post hoc Bonferroni tests relative to baseline). Baseline-corrected GADRP values for an independent PD natural history cohort (gray line) are presented for reference (see text). Left inset: Baseline-corrected GADRP expression at 12 months in the gene therapy (red) and sham surgery (blue) groups (****P < 0.0001, Student’s t test between groups). Right inset: The rate of change in GADRP expression in the gene therapy (red), sham surgery (blue), and natural history/PD progression (gray) groups (****P < 0.0001, post hoc Bonferroni tests).

  • Fig. 2 STN AAV2-GAD gives rise to new functional connections between GADRP network nodes.

    (A and B) Node-to-node connectivity for subjects randomized to either sham surgery or gene therapy. GADRP regions (seven per hemisphere; see Table 1) are represented by spheres with radius proportional to the corresponding nodal connectivity (degree centrality). Connections linking pairs of nodes are represented by cyan lines with thickness proportional to the magnitude of the corresponding correlation coefficient (|r|): Values less than or equal to 0.5 are represented by fine lines, between 0.5 and 0.6 by medium lines, and greater than or equal to 0.6 by thicker lines. Significant positive and negative correlations are represented by bold red and blue lines, respectively.

  • Fig. 3 GAD therapy induces bilateral changes in degree centrality at key GADRP nodes.

    Degree centrality averaged across hemispheres for the caudate (blue), premotor (green), and supramarginal (red) nodes, plotted over time for the (A) AAV2-GAD and (B) sham groups (see table S2). *P < 0.001, relative to baseline; permutation test, corrected for multiple comparisons.

  • Fig. 4 Graph theory reveals network-level changes in information processing within the GADRP space.

    (A) Degree centrality. (B) Normalized clustering coefficient (C/Crandom). (C) Normalized characteristic path length (L/Lrandom). (D) Small-worldness (see text). Threshold levels 1 to 7 correspond to cutoff thresholds r = 0.3 to 0.6 with increments of 0.05. Permutation tests (5000 iterations) were used to determine the significance of the treatment (6/12 months) versus baseline differences observed for each of the four network measures at the various threshold levels. Differences were considered significant at P < 0.05, corrected for multiple network parameters (n = 4) and cost levels (n = 7); permutation tests. Red asterisk: P < 0.05, relative to baseline; permutation test, corrected for multiple comparisons; black asterisk: P < 0.05, relative to baseline and healthy controls (HC); permutation test, corrected for multiple comparisons.

  • Fig. 5 GADRP expression is unaffected by unblinding.

    (A) Mean GADRP and SSRP expression values plotted over time in the AAV2-GAD (left) and sham surgery (right) groups. (B) GADRP expression, blinded and unblinded, in the AAV2-GAD (left) and sham (right) groups. (C) SSRP expression in the AAV2-GAD group (left) and the sham group (right).

  • Fig. 6 GAD therapy improves clinical symptoms without suppressing PDRP expression.

    Changes in GADRP expression (∆GADRP, left) and PDRP expression (∆PDRP, right) after STN AAV2-GAD (red) and sham surgery (blue) were compared with changes after STN DBS surgery (gray). *P < 0.05, ****P < 0.0001; post hoc Bonferroni tests.

  • Table 1 Regions contributing to the GADRP metabolic topography.

    GP, globus pallidus; BA, Brodmann area.

    Brain regionCoordinates*
    Zmax
    ZmaxAAL
    xyz
    Decreasing activity
    Thalamus (VA/MD), left−14−4145.6277
    Caudate
      Left−101425.4871
      Right161664.3272
    Putamen/GP, right180145.0874/76
    Inferior frontal gyrus (BA
    47/44)/insula, left
    −5416−24.1915/29
    Increasing activity
    Premotor cortex (BA 6)−282703.963
      Motor cortex (BA 4), left−19−19773.951
    Supramarginal gyrus (BA
    40/39)
    −44−30323.7063

    *Montreal Neurological Institute standard space (44).

    †AAL indicates Anatomic-Automatic Labeling atlas (38). The number given for each significant region denotes the standardized ROI from the atlas that was used in the graph theory analysis (see text).

    ‡Values at peak voxel for each region thresholded at Z = ±3.29, P < 0.001, two tailed. Voxel weights of these network regions reliable at P < 0.003 based on bootstrap estimation [ICV = (−3.19, 3.05); 1000 iterations], with the exception of the subregion of motor cortex (italics).

    • Table 2 New nodal connections developing after gene therapy.

      m, month.

      Connections*AAV2-GADSham
      Node 1Node 20 m6 m12 m0 m6 m12 m
      LeftSuperior frontal (3)Supramarginal (63)0.160.100.610.090.180.18
      LeftSuperior frontal (3)Caudate (71)−0.30−0.11−0.63−0.34−0.31−0.34
      RightSuperior frontal (4)Supramarginal (64)0.190.370.790.140.020.09
      LeftPutamen (73)Thalamus (77)0.150.060.680.350.370.44
      LeftGlobus pallidus (75)Thalamus (77)0.240.270.600.410.500.49

      *GADRP nodes are denoted by standardized ROIs defined by the AAL atlas (AAL numbers provided in parentheses; see Materials and methods). Each anatomical ROI included the corresponding network cluster identified in the voxel-wise covariance analysis (Table 1; see fig. S3). Nodal connections at each time point were determined by computing respective correlation coefficients and considered significant for |r| > 0.60 (P < 0.05; Pearson’s correlation). Significant connections gained after gene therapy (see Materials and methods for criteria) are italicized.

      Supplementary Materials

      • www.sciencetranslationalmedicine.org/cgi/content/full/10/469/eaau0713/DC1

        Fig. S1. Patients treated with GAD therapy showed greater improvement in UPDRS ratings but also increases in PDRP.

        Fig. S2. Metabolic changes over time in GADRP regions.

        Fig. S3. GAD therapy induces a specific sequence of functional connectivity changes within the GADRP space.

        Fig. S4. Neither sham surgery nor STN DBS increases degree centrality.

        Fig. S5. Longitudinal changes in UPDRS motor ratings and expression values for the GADRP, SSRP, and PDRP networks.

        Table S1. Demographics and clinical measurements.

        Table S2. Nodal connections within the GADRP space (91 edges) at baseline, 6 months, and 12 months.

        Table S3. Changes in degree centrality at GADRP nodes after gene therapy or sham surgery.

        Table S4. Individual patient data: off-state UPDRS motor ratings and expression values (z-scored) for GADRP, SSRP, and PDRP at each time point.

      • The PDF file includes:

        • Fig. S1. Patients treated with GAD therapy showed greater improvement in UPDRS ratings but also increases in PDRP.
        • Fig. S2. Metabolic changes over time in GADRP regions.
        • Fig. S3. GAD therapy induces a specific sequence of functional connectivity changes within the GADRP space.
        • Fig. S4. Neither sham surgery nor STN DBS increases degree centrality.
        • Fig. S5. Longitudinal changes in UPDRS motor ratings and expression values for the GADRP, SSRP, and PDRP networks.
        • Table S1. Demographics and clinical measurements.
        • Legend for Table S2
        • Table S3. Changes in degree centrality at GADRP nodes after gene therapy or sham surgery.
        • Legend for Table S4

        [Download PDF]

        Other Supplementary Material for this manuscript includes the following:

        • Table S2 (Microsoft Excel format). Nodal connections within the GADRP space (91 edges) at baseline, 6 months, and 12 months.
        • Table S4 (Microsoft Excel format). Individual patient data: off-state UPDRS motor ratings and expression values (z-scored) for GADRP, SSRP, and PDRP at each time point.

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