AAV9/MFSD8 gene therapy is effective in preclinical models of neuronal ceroid lipofuscinosis type 7 disease
Xin Chen, … , Joseph R. Mazzulli, Steven J. Gray
Xin Chen, … , Joseph R. Mazzulli, Steven J. Gray
Published January 13, 2022
Citation Information: J Clin Invest. 2022;132(5):e146286. https://doi.org/10.1172/JCI146286.
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Research Article Neuroscience

AAV9/MFSD8 gene therapy is effective in preclinical models of neuronal ceroid lipofuscinosis type 7 disease

Abstract

Neuronal ceroid lipofuscinosis type 7 (CLN7) disease is a lysosomal storage disease caused by mutations in the facilitator superfamily domain containing 8 (MFSD8) gene, which encodes a membrane-bound lysosomal protein, MFSD8. To test the effectiveness and safety of adeno-associated viral (AAV) gene therapy, an in vitro study demonstrated that AAV2/MFSD8 dose dependently rescued lysosomal function in fibroblasts from a CLN7 patient. An in vivo efficacy study using intrathecal administration of AAV9/MFSD8 to Mfsd8– /– mice at P7–P10 or P120 with high or low dose led to clear age- and dose-dependent effects. A high dose of AAV9/MFSD8 at P7–P10 resulted in widespread MFSD8 mRNA expression, tendency of amelioration of subunit c of mitochondrial ATP synthase accumulation and glial fibrillary acidic protein immunoreactivity, normalization of impaired behaviors, doubled median life span, and extended normal body weight gain. In vivo safety studies in rodents concluded that intrathecal administration of AAV9/MFSD8 was safe and well tolerated. In summary, these results demonstrated that the AAV9/MFSD8 vector is both effective and safe in preclinical models.

Authors

Xin Chen, Thomas Dong, Yuhui Hu, Frances C. Shaffo, Nandkishore R. Belur, Joseph R. Mazzulli, Steven J. Gray

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Figure 2

Experimental design for in vivo efficacy study, GCase activity in mouse brain lysate, and vector biodistribution in central and periphery organs.

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Experimental design for in vivo efficacy study, GCase activity in mouse ...
(A) High (5 × 1011 vg/mouse) or low (1.25 × 1011 vg/mouse) dose of AAV9/MFSD8 vector was administered i.t. to equal numbers of male and female mice at P7–P10 (presymptomatic) or P120 (early symptomatic). Study readouts at each time point at specified age are listed from left to right. (B) GCase activity was measured in brain lysates of mice treated at P7–P10 and harvested at 4.5 months old (n = 3–7). (C) Vector biodistribution was measured in central and periphery organs from mice treated at P7–P10 and harvested at 4.5 months old (n = 3–7). A ROUT test was used first to remove any outlier. Data in B were normalized to Het mice. All data in B and C are presented as mean ± SEM, with the scatter plot representing measurements from individual mice. Data sets in B and C that passed tests for normality or homogeneity of variance were analyzed using 1-way ANOVA with α set at 0.05 and Dunnett’s correction for relevant pairwise comparisons. Data sets that did not pass tests for normality or homogeneity of variance were analyzed using the Kruskal-Wallis test with α set at 0.05 and Dunn’s correction for relevant pairwise comparisons. *P < 0.05; **P < 0.01; ***P < 0.001, compared with KO-Veh.